Progression-free Survival In Patients Research Articles

Elacestrant for ER-Positive HER2-Negative Advanced Breast Cancer.

This article aims to discuss elacestrant, an oral selective estrogen receptor downregulator approved by the Food and Drug Administration (FDA) in January 2023 for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. PubMed, Embase, Medline, Clinicaltrials.gov, and the National Comprehensive Cancer Network (NCCN) were searched from inception to August 31, 2023. Clinical trials published in English were included and relevant information regarding methodology and results were extracted. Phase 1 and 3 trials showed elacestrant was safe and improved progression-free survival in patients with endocrine receptor 1 (ESR1) mutations who failed cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus 1 prior endocrine therapy compared with standard of care (SOC) (fulvestrant, anastrozole, letrozole, or exemestane monotherapy). Elacestrant maintains a comparable adverse event profile with other endocrine therapies and offers an alternative to typical sequential therapy which can delay the use of or be used after traditional chemotherapy. Elacestrant is currently being studied in CDK 4/6 inhibitor naïve patients and as a component of combination therapy for first-line use which could lead to future indications. Elacestrant gained FDA approval in January 2023 and can be considered in patients with HR+ HER2- advanced breast cancer and ESR1 mutations who have progressed despite therapy with either CDK 4/6i plus aromatase inhibitors (AI) or fulvestrant or chemotherapy.

Updated Review Article: Cyclin-Dependent Kinase 4/6 Inhibitor Impact, FDA Approval, and Resistance Pathways.

Objective: To describe the mechanism of cyclin-dependent kinase (CDK) 4/6 inhibitors, mechanisms of resistance, and summarize various clinical trials used to determine the efficacy and safety of CDK4/6 inhibitor used for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. Data Sources: An extensive literature search using PubMed and notable sources was performed (2016 to February 2022) using the following search terms: CDK4/6 inhibitors, palbociclib, abemaciclib, ribociclib, CDK4/6 inhibitor resistance, FAT1 gene, luminal A breast cancer, luminal B breast cancer, HR+/HER2- breast cancer. Abstracts from conferences, national clinical trials, and drug monographs were reviewed. Study Selection and Data Extraction: Relevant clinical studies or those conducted in humans and updated clinical trials were considered. Data synthesis: The various clinical trials reviewed and results have led to numerous studies and expansions of U.S. Food and Drug Administration (FDA) approval. Although the use of CDK4/6 inhibitors has improved progression-free survival in patients with HR+, HER2- breast cancer, studies have shown that resistance pathways can cause cells to be insensitive to CDK4/6 inhibitors, leading to continued cell proliferation. Conclusions: CDK4/6 inhibitors are recommended as first-line therapy in combination with endocrine therapy for patients with HR+/HER2- advanced breast cancer. However, mutations and acquired resistance can occur that affect a patient's response to treatment. Additional research needs to be conducted on strategies to overcome resistance and determine how ethnicity plays a role in resistance pathways.

Tissue Circular RNA_0004018 and 0003570 as Novel Prognostic Biomarkers for Hepatitis B-Related Hepatocellular Carcinoma.

The clinical significance of hsa_circ_0004018 and hsa_circ_0003570 in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) is unclear. We aimed to explore the clinical significance and prognostic utility of these two circular RNAs (circRNAs) in patients with HBV-HCC. Based on 86 paired tissue samples of HCC and adjacent non-HCC, the relative expression profiles of hsa_circ_0004018 and hsa_circ_0003570 were determined using quantitative real-time polymerase chain reactions. The cut-off values were the median expression of each of the two circRNAs in 86 patients with HBV-HCC. The combination group comprised patients with high levels of the two circRNAs. Clinicopathological features, body composition profiles at the L3 level, and survival rates were investigated. The expression of hsa_circ_0004018 and hsa_circ_0003570 was downregulated in HCC tissues compared with non-HCC tissues. High expression levels of hsa_circ_0003570 (hazard ratio (HR), 0.437; p = 0.009) and hsa_circ_0004018 (HR, 0.435; p = 0.005) were inversely independent risk factors for overall and progression-free survival in patients with HBV-HCC, whereas the combination group was also an inversely independent risk factor for overall (HR, 0.399; p = 0.005) and progression-free survival (HR, 0.422; p = 0.003) in patients with HBV-HCC. The combination of hsa_circ_0003570 and hsa_circ_0004018 may be a potential prognostic biomarker for HBV-HCC.

Current and Emerging Role of Monoclonal Antibody-Based First-Line Treatment in Advanced Gastro-Esophageal and Gastric Cancer.

Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.

Effect of hyperthermia on intestinal microecology, immune function, and progression-free survival in patients with advanced unresectable lung adenocarcinoma

This study aims to investigate the effects of hyperthermia on intestinal microecology, immune function, and progression-free survival of patients with advanced unresectable lung adenocarcinoma. A total of twenty patients with lung adenocarcinoma in the study group received the advanced standard first-line treatment protocol, which included pemetrexed + cisplatin combined with sintilimab immunotherapy and hyperthermia. Additionally, twenty patients with lung adenocarcinoma in the control group received the advanced standard first-line treatment protocol, which included pemetrexed + cisplatin combined with sintilimab immunotherapy. The T-lymphocyte subpopulation and CD4/CD8 cell ratio of each sample were detected using flow cytometry. The intestinal flora was evaluated using 16S rRNA gene sequencing. The study observed the changes in the abundance, distribution, composition, and structure of fecal gut microorganisms before and after the treatment in both groups of patients. Significant differences were observed in the intestinal flora between the two groups. The patients in the study group showed improved immunity after treatment, whereas there was no significant change in the immunity of the control group before and after treatment. However, the difference in progression-free survival between the two groups was not statistically significant. Hyperthermia has a significant impact on improving the microecology of intestinal flora and the immunity of patients, but it does not have a significant effect on prolonging the progression-free survival of patients.

Observational analysis of clinical and pathological characteristics and their prognostic impact in Mexican patients with breast cancer: A multi-center study.

Breast cancer is the most incidental and deadly neoplasm worldwide; in Mexico, very few epidemiologic reports have analyzed the pathological features and its impact on their clinical outcome. Here, we studied the relation between pathological features and the clinical presentation at diagnosis and their impact on the overall and progression-free survival of patients with breast cancer. For this purpose, we collected 199 clinical records of female patients, aged at least 18 years old (y/o), with breast cancer diagnosis confirmed by biopsy. We excluded patients with incomplete or conflicting clinical records. Afterward, we performed an analysis of overall and progression-free survival and associated risks. Our results showed an average age at diagnosis of 52 y/o (24-85), the most common features were: upper outer quadrant tumor (32%), invasive ductal carcinoma (76.8%), moderately differentiated (44.3%), early clinical stages (40.8%), asymptomatic patients (47.8%), luminal A subtype (47.8%). Median overall survival was not reached, but median progression-free survival was 32.2 months (29.75-34.64, CI 95%) associated risk were: clinical stage (p <0.0001) symptomatic presentation (p =0.009) and histologic grade (p =0.02). Therefore, we concluded that symptom presence at diagnosis impacts progression-free survival, and palpable symptoms are related to an increased risk for mortality.

The effect of PLK1 inhibitor in Osimertinib resistant NCI-H1975 cell lines.

To investigate the effects of PLK1 inhibitors on Osimertinib-resistant NCI-H1975 cell lines and the anti-tumor effect combined with Osimertinib. Osimertinib resistant NCI-H1975 cell lines were constructed by the methods of concentration-increasing.; The classical tumor pathway inhibitor library compounds were combined with Osimertinib on Osimertinib-resistant cells to screen compounds with synergistic effects with Osimertinib; The gene set enrichment analysis (GSEA) was used to investigate the activations of signaling pathways in Osimertinib-resistant cells; Sulforhodamine B (SRB) staining was used to investigate the inhibitory effect of PLK1 inhibitors on Osimertinib-resistant cells and the anti-tumor effect of PLK1 inhibitors combined with Osimertinib. Osimertinib-resistant cells lines H1975-resistance (resistance index=43.45) were successfully established. The PLK1 inhibitors BI 2536 and GSK461324 have synergistic effect with Osimertinib. Compared with Osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in Osimertinib-resistant cells. In a cohort of NSCLC patients with epidermal growth factor receptor mutations treated with Osimertinib, PLK1 mRNA levels were negatively correlated with progression free survival of patients (R=0.62, P<0.05), confirming that excessive activation of PLK1 in NSCLC cells may cause cell resistance to Osimertinib. Further vitro experiments showed that, The IC50 of PLK1 inhibitors BI 6727 and GSK461324 in Osimertinib-resistant cells were lower than those in sensitive ones. Compared to the mono treatment of Osimertinib, PLK1 inhibitors combined with Osimertinib behave significantly stronger effect on the proliferation of Osimertinib-resistant cells. PLK1 inhibitors combined with Osimertinib behave stronger anti-tumor effect to Osimertinib-resistant NSCLC cells and may be used for intervention and treatment of Osimertinib resistance.

Poly (ADP-Ribose) Polymerase Inhibitors in Patients With Urothelial Cancer.

Poly ADP-ribose polymerase inhibitors (PARPis) have clinical activity in several cancers. The rationale of their therapeutic use in urothelial cancer (UC) resides in the high homologous-recombination repair (HRR) deficiency (HRD) prevalence and potential cross-sensitivity with platinum-based chemotherapy (PBCT). This review aims to summarize and analyze trials exploring the activity of PARPis in UC, focusing on patients who may benefit from those agents, the best clinical setting for the treatment and the benefit of the association with immune-checkpoint inhibitors (ICIs). We included all the available trials analyzing the activity of PARPis in UC in neoadjuvant, adjuvant, first or subsequent lines, and maintenance setting. We included PARPis in monotherapy and in association with other agents. The results in the maintenance setting are intriguing: ATLANTIS trial showed signals of improved progression-free survival in patients with known HRR aberrations, although the Meet-URO12 trial, with its negative results, suggested the failure of clinical selection based on platinum sensitivity only. Single-agent PARPis in pretreated patients showed discouraging results in an unselected population of chemo-refractory patients. Concerning the association of PARPis with ICIs, several trials are exploring their role in platinum-naïve setting; the results in the advanced setting were globally negative. Prior selection of HRD status is essential to identify patients who might benefit from PARPis. The ideal clinical settings seem to be the maintenance treatment and the combination with ICIs in platinum-naïve patients. Definitive results of ongoing and further trials will delineate the position for PARPis, if any, in UC therapy.

CCDC103 as a Prognostic Biomarker Correlated with Tumor Progression and Immune Infiltration in Glioma.

The Coiled-coil domain-containing proteins (CCDCs) are expressed in many cancers, but the role of Coiled-coil domain-containing protein 103 (CCDC103) in cancers remains unclear. Further investigations are necessary to ascertain its diagnostic significance and understand its biological function in cancers. This study aims to elucidate the biological functionalities of CCDC103 in glioma and evaluate the correlation between CCDC103 expression with glioma progression. Clinical data on glioma patients were acquired from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO). The evaluation encompassed the examination of correlations between CCDC103 expression, pathological characteristics, and clinical outcomes. Furthermore, the analysis included the assessment of the correlations between CCDC103 expression and immune cell infiltration as well as glioma progression. Gliomas have higher levels of CCDC103 expression than the para-carcinoma tissues. Poorer prognosis, unfavorable histological characteristics, the absence of IDH gene mutations, and the absence of chromosome 1p and 19q deletions were all associated with higher expression of CCDC103 in gliomas. In addition to patient age, tumor grade, the absence of IDH mutations, and the absence of chromosome 1p and 19q deletions, univariate and multivariate Cox analyses showed that CCDC103 expression was independently prognostic of overall survival, disease-free survival, and progression-free survival in patients with glioma. Furthermore, tumor infiltration of B cells, neutrophils, macrophages, and dendritic cells were all linked with elevated expression of CCDC103. High CCDC103 expression was linked to immune response-related signaling pathways and cell proliferation, according to gene set enrichment analysis (GSEA). Notably, the knockdown of CCDC103 in glioma cell lines resulted in a significant reduction in cell proliferation and migration. The correlation between CCDC103 expression and both glioma progression and immune cell infiltration implies that CCDC103 expression holds promise as a valuable prognostic biomarker for glioma.

604P Overall and progression-free survival of patients with metastatic colorectal cancer: A real-world prospective, longitudinal cohort study on the continuum of care (PROMETCO)

604P Overall and progression-free survival of patients with metastatic colorectal cancer: A real-world prospective, longitudinal cohort study on the continuum of care (PROMETCO)

Expression and Prognostic Significance of Ferroptosis-related Proteins SLC7A11 and GPX4 in Renal Cell Carcinoma.

The ferroptosis inhibitory gene solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) inhibit ferroptosis in carcinoma cells. However, whether SLC7A11 and GPX4 serve as an oncogene in renal cell carcinoma (RCC) remains unclear. Immunohistochemistry (IHC) assays were performed to assess the expression of SLC7A11 and GPX4 in human RCC tissues. Clinical-pathological analysis was performed to explore the correlation between SLC7A11 and GPX4 expression. Kaplan-Meier survival analysis was performed to characterise the associations between protein expression and patient progressionfree survival (PFS). The upregulation of SLC7A11 and GPX4 was detected by IHC in RCC tissues compared with that in normal renal tissues. Meanwhile, the expression level of SLC7A11 and GPX4 was correlated with tumour diameter and distant metastasis (P<0.05). Kaplan-Meier survival analysis indicated that patients with high SLC7A11 and GPX4 expression levels exhibited worse PFS than those with low SLC7A11 and GPX4 expression levels (P<0.05). The upregulation of SLC7A11 and GPX4 expression was associated with poor prognosis in patients with RCC. SLC7A11 and GPX4 may serve as diagnostic and prognostic biomarkers for patients with RCC.

Utility of PSMA PET Guided Metastasis-Directed Radiotherapy

Metastasis-directed radiotherapy (MDT) is becoming a mainstay in the management of oligometastatic prostate cancer (PCa), and PSMA-PET is currently the most sensitive imaging modality for PCa metastasis screening. The efficacy of MDT guided by PSMA-PET imaging has not yet been well characterized. Moreover, the optimal role of androgen deprivation therapy (ADT) in the context of MDT is not known. We sought to assess the efficacy of PSMA PET-guided MDT in patients with metastatic PCa treated with and without ADT. This is a single institutional retrospective study of patients diagnosed with metastatic prostate cancer by PSMA-PET imaging who were treated with MDT. Biochemical progression was defined as a PSA increase of ≥ 25% and ≥ 2 ng/mL if PSA was ≥ 2 ng/mL at time of initiating salvage treatment, or a PSA increase of ≥ 25% if PSA was < 2 ng/mL at time of salvage treatment. Survival analyses were performed using the Kaplan-Meier method with log-rank testing for significance. Cumulative incidence analyses were performed with Gray's testing for significance. Adverse event data were assessed per CTCAE v5 guidelines. A total of 196 PSMA PET-avid lesions from 101 patients were irradiated with stereotactic body radiotherapy (SBRT). Median time from prior definitive locoregional therapy to MDT was 6.2 years. 79 patients had hormone-sensitive PCa (HSPC) and 22 patients had castration-resistant PCa (CRPC) at time of MDT. 47 of 79 (59%) patients with HSPC received ADT along with MDT, and 20 of the 47 patients received augmented ADT. 25 of the 32 (78%) HSPC patients receiving MDT without ADT had undergone at least one prior course of ADT, and none had castrate levels of testosterone at time of MDT with a median testosterone level of 341 ng/dl. With a median follow-up of 22.4 months, 5 of 196 lesions (2.6%) demonstrated radiographic progression. 2-year cumulative incidence of progression from HSPC to CRPC was 11% in patients who received ADT at time of MDT and 35% in those who did not (P = 0.027). Median biochemical progression free survival of patients with CRPC, HSPC treated without ADT, and HSPC treated with ADT following MDT was 5.4, 7.6, and 43.9 months respectively (P<0.0001). 2-year overall survival of the abovementioned groups was 72.2%, 100%, and 97.5% respectively (P<0.001). No Grade 3-5 adverse effects were observed. MDT guided by PSMA-PET imaging is well-tolerated and delays biochemical progression in patients with CRPC and HSPC, with a greater effect observed in patients also receiving ADT.

Progression-Free Survival in Patients with WHO-2 Meningioma Undergoing Active Surveillance Based on DOTATATE PET Evidence of Gross Total Resection: Prospective Observational Study

MRI is the standard of care for meningioma radiotherapy planning, but lacks sensitivity for postoperative small volume disease and osseous or parenchymal invasion. NRG-BN003 (NCT03180268) randomizes patients with WHO-2 meningiomas and MRI-determined gross total resection (GTR) to observation or 60 Gy IMRT to the resection bed. More sensitive and specific imaging biomarkers than MRI may improve clinical outcomes in meningioma by limiting unnecessary irradiation of normal tissues and improving radiotherapy targeting. [68Ga]-DOTATATE, a PET radiotracer targeting somatostatin receptor 2 (SSTR2) is a highly sensitive and specific meningioma biomarker. Our dedicated DOTATATE brain PET/MRI and PET/CT protocol allows meningioma differentiation from post-treatment change, using SUV analysis and Patlak modeling. Our prospective IRB-approved observational trial (NCT04081701) has imaged >100 patients with meningioma. In the sub-analysis presented here, we prospectively evaluated PFS in patients with WHO-2 tumors and postoperative GTR as determined by [68Ga]-DOTATATE brain PET/MRI or PET/CT who were managed solely with active surveillance. We hypothesized that the PFS of patients with GTR by PET managed with active surveillance would be higher than reported PFS data for patients with MRI-determined GTR, using NRG-BN003's observation arm (randomized trial comparing observation to fractionated RT) as a reference standard. From the cohort of >100 patients with SSTR2-positive brain neoplasms enrolled between 9/2019 and 10/2022 and imaged according to our previously published protocol, a sub-cohort of patients were selected with WHO-2 meningioma, postoperative findings of GTR, and postoperative active surveillance with periodic MRI every 3-6 months. Kaplan-Meier survival analysis was performed. A total of 12 patients met inclusion criteria. Mean patient age was 64 years and 5 (42%) were female. Mean follow up period was 23.4 months (range: 7-38). 83% (10/12) patients underwent postoperative PET/MRI and 17% (2/12) underwent PET/CT. 2 patients (17%) progressed, at 22 and 34 months, respectively; the remainder remain progression-free. Both patients who had progression were successfully salvaged with focal fractionated radiosurgery. Kaplan-Meier analysis demonstrated PFS at almost 3 years to be 75%, which is substantially higher than the reported 3-year PFS of 60% in the literature. Overall survival was 100%. [68Ga]-DOTATATE PET can improve the specificity of imaging-based assessment of the extent of resection of WHO-2 meningiomas, thereby improving clinical outcomes. In this cohort of patients with completely resected WHO-2 meningiomas (as assessed by postoperative gadolinium-enhanced MRI and DOTATATE PET) who are conservatively managed, recurrences have been rare and amenable to radiosurgical salvage.

Maintenance Therapy for Recurrent or Metastatic Cervical Cancer: A Multicenter, Cohort Study

Maintenance therapy with alternative agents after chemotherapy was shown to improve the overall survival in some advanced cancers such as breast cancer, lung cancer, ovarian cancer and so on. However, maintenance therapy is not accepted as the standard treatment for recurrent/metastatic cervical cancer. Aim of this study is to elucidate the efficacy of maintenance therapy in cervical cancer and to explore the factors associated with the prognosis of recurrent or metastatic cervical cancer. In this multicenter cohort study, we retrospectively collected patients with a diagnosis of either recurrent or stage IVB cervical cancer to receive first-line chemotherapy with or without maintenance therapy. Patients did not have disease progression with first-line chemotherapy and were divided into maintenance therapy group (Arm A) and conventional chemotherapy group (Arm B). Information on clinical characteristics, metastasis information, treatment outcome and survival of patients was collected using an electronic medical record system. The endpoints of the study were OS and PFS. Data were analyzed for general characteristics and survival using statistical software, and the results were considered statistically significant at P < 0.05. Between January 2019 and July 2021, a total of 270 patients were enrolled from 6 institutions in China. 26 patients were excluded because of short treatment cycles (less than 3 cycles). Finally, a total of 66 patients in Arm A and 178 patients in Arm B were analyzed for survival. The addition of maintenance significantly prolonged overall survival. Overall survival at 3 year was 50.1% in Arm A and 27.8% in Arm B (median overall survival, ≥36 months vs. 22 months; P<0. 001). The median progression-free survival was 21 months in Arm A and 14 months in Arm B (P = 0.025). Univariate survival analysis showed that age, maintenance therapy, combined radiotherapy, and number of extra-pelvic metastases were associated with PFS. Further multifactorial analysis showed that maintenance therapy, combined radiotherapy, and number of extra-pelvic metastases were independent prognostic factors for patients with recurrent or metastatic cervical cancer. The addition of maintenance therapy significantly prolonged overall survival as well as progression-free survival in patients with recurrent or metastatic cervical cancer and did not increase the incidence of serious adverse events. It is time to consider maintenance therapy as the standard treatment after conventional chemotherapy for recurrent or metastatic cervical cancer, rather than waiting for disease progression.

A novel signature for predicting prognosis and immune landscape in cutaneous melanoma based on anoikis-related long non-coding RNAs

Anoikis is a unique form of apoptosis associated with vascularization and distant metastasis in cancer. Eliminating anoikis resistance in tumor cells could be a promising target for improving the prognosis of terminal cancer patients. However, current studies have not elaborated on the prognosis effect of anoikis-related long non-coding RNAs (lncRNAs) in cutaneous melanoma. Pre-processed data, including RNA sequences and clinical information, were retrieved from TCGA and GTEx databases. After a series of statistical analyses, anoikis-related lncRNAs with prognostic significance were identified, and a unique risk signature was constructed. Risk scores were further analyzed in relation to the tumor microenvironment, tumor immune dysfunction and exclusion, immune checkpoint genes, and RNA methylation genes. The indicators were also used to predict the potentially sensitive anti-cancer drugs. An anoikis-related lncRNAs risk signature consisting of LINC01711, POLH-AS1, MIR205HG, and LINC02416 was successfully established in cutaneous melanoma. Overall survival and progression-free survival of patients were strongly linked with the risk score, independently of other clinical factors. The low-risk group exhibited a more beneficial immunological profile, was less affected by RNA methylation, and was more sensitive to the majority of anti-cancer drugs, all of which indicated a better prognostic outcome. The 4 hub lncRNAs may be fundamental to studying the mechanism of anoikis in cutaneous melanoma and provide personalized therapy for salvaging drug resistance.

Cancer/testis antigen CAGE mediates osimertinib resistance in non-small cell lung cancer cells and predicts poor prognosis in patients with pulmonary adenocarcinoma

CAGE, a cancer/testis antigen, was originally isolated from the sera of patients with gastric cancers. Previously, we have shown the role of CAGE in resistance to chemotherapy and target therapy. The aim of this study was to investigate the role of CAGE in osimertinib resistance and determine the prognostic value of CAGE in patients with pulmonary adenocarcinomas. The clinicopathological correlation with CAGE and autophagy flux in patients was examined using immunohistochemistry and in situ hybridization. The possible role of autophagy in osimertinib resistance was analyzed using immune blot, immune fluorescence staining and immunohistochemistry. This study found that immunohistochemical staining (IHC) showed CAGE expression in more than 50% of patients with pulmonary adenocarcinomas (pADCs). CAGE expression was increased in pADCs after the acquisition of EGFR-TKIs resistance. High expression of CAGE was correlated with shorter overall survival and progression free survival in patients with pADCs. Thus, CAGE mediates osimertinib resistance and predicts poor prognosis in patients with pADCs. Osimertinib-resistant non-small cell lung cancer cells (PC-9/OSI) were established and mechanistic studies of CAGE-mediated osimertinib resistance were performed. PC-9/OSI cells showed increased autophagic flux and CAGE expression compared with parental sensitive PC-9 cells. PC-9/OSI cells showed higher tumorigenic, metastatic, and angiogenic potential compared with parental PC-9 cells. CAGE CRISPR-Cas9 cell lines showed decreased autophagic flux, invasion, migration potential, and tumorigenic potential compared with PC-9/OSI cells in vitro and in vivo. CAGE plays a crucial role in the cancer progression by modulating autophagy and can predict the poor prognosis of patients with pulmonary adenocarcinomas. Our findings propose CAGE as a potential therapeutic target for developing anticancer drugs that can overcome osimertinib resistance.

Thyroid dysfunction induced by anti-PD-1 therapy is associated with a better progression-free survival in patients with advanced carcinoma

PurposeThyroid dysfunction is the most common immune-related adverse event during anti-programmed cell death 1 (anti-PD-1) therapy. In this study, we monitored patients with advanced malignant tumors who received anti-PD-1 therapy to observe the characteristic of anti-PD-1 therapy-induced thyroid dysfunction and its correlation with prognosis.MethodsPatients with advanced carcinoma treated with anti-PD-1 therapy were evaluated for thyroid function at baseline and after treatment initiation from August 2020 to March 2022. Seventy-three patients were finally included in the study.ResultsAmong these patients, 19 (26.03%) developed thyroid dysfunction after receiving anti-PD-1 therapy. Primary hypothyroidism and thyrotoxicosis were the most common clinical manifestation. Anti-PD-1-induced thyroid dysfunction occurred 63 (26–131) days after administration; thyrotoxicosis appeared earlier than primary hypothyroidism. In Kaplan–Meier survival analysis, the progression-free survival (PFS) of the thyroid dysfunction group was better than that of the no thyroid dysfunction group (227 (95% confidence interval (CI) 50.85–403.15) days vs 164 (95% CI 77.76–250.24) days, p = 0.026). Male patients had better PFS than female patients (213 (95% CI 157.74–268.26) days vs 74 (95% CI 41.23–106.77) days, p = 0.031). In cox proportional hazards regression model, anti-PD-1-induced thyroid dysfunction remained an independent predictor of better PFS (hazard ratio (HR) = 0.339(0.136–0.848), p = 0.021).ConclusionThyroid dysfunction is a common immune-related adverse events in advanced cancer patients treated with anti-PD-1 therapy and predicts a better prognosis.Trial registrationThis study was retrospectively registered with Trial ClinicalTrials.gov (NCT05593744) on October 25, 2022.

Efficacy and safety of olaparib, olaparib plus bevacizumab and niraparib maintenance treatment in Japanese patients with platinum-sensitive advanced ovarian cancer.

To investigate whether maintenance treatment could be safely and effectively performed with olaparib, olaparib plus bevacizumab and niraparib in platinum-sensitive advanced ovarian cancer at multiple institutions in Japan. We investigated progression-free survival and adverse events in 117 patients with platinum-sensitive advanced ovarian cancer treated with maintenance therapy. The median progression-free survival of 117 patients was 20.1months. Patients with germline BRCA pathogenic variants had a significantly better prognosis than the other groups (P<0.001). Furthermore, in the multivariate analysis, stage IV (P=0.016) and germline BRCA wild-type (P≤0.001) were significantly associated with worse progression-free survival in patients with advanced ovarian cancer. Regarding adverse events, all three types of maintenance treatment were significantly worse than chemotherapy given before maintenance treatment with respect to renal function (olaparib, P=0.037; olaparib plus bevacizumab, P<0.001; and niraparib, P=0.016). Maintenance treatment was performed effectively and safely. Renal function deterioration is likely to occur during maintenance treatment, and careful administration is important in platinum-sensitive advanced ovarian cancer.

Impact of Choroidal Melanoma Characteristics on Progression-Free Survival in Patients Undergoing Hypofractionated Stereotactic Photon Radiotherapy.

In an effort to replace ultrasonography-based thickness measurements, we investigated whether choroidal melanoma characteristics are related to progression-free survival (PFS) in patients monitored after linear accelerator (LINAC)-based hypofractionated stereotactic photon radiotherapy. In a retrospective dataset, we used a linear mixed model to assess the associations between PFS and tumor characteristics; in particular, thickness, largest basal diameter (LBD), base area and volume. Thickness and LBD are statistically significantly associated with PFS. In a subgroup of 16 patients undergoing enucleation due to melanoma recurrence or progression, there were statistically significant changes in mean thickness and LBD before surgery. Mean PFS was 42 ± 30months. Ultrasonography-based thickness measurements may not be necessary for treated choroidal melanoma monitoring; instead, we propose sequential LBD assessments, which should preferably be performed using fundus photography in future.

Circulating Plasma Cell-free DNA (cfDNA) as a Predictive Biomarker for Radiotherapy: Results from a Prospective Trial in Head and Neck Cancer.

The plasma levels of cell-free DNA (cfDNA) in cancer patients increase due to rapid cancer cell proliferation and death. Therefore, cfDNA can be used to study specific tumor-DNA features. In addition, the non-specific cfDNA concentration may be an important biomarker of cancer prognosis. We prospectively examined the predictive role of cfDNA levels and the kinetics in the outcome of chemo-radiotherapy (CRT) in a cohort of 47 patients with locally advanced squamous cell head-neck cancer (SCHNC) treated with definitive chemo-radiotherapy. Increased cfDNA levels after therapy completion (after/before treatment ratio; A/B-ratio >1) were found in 26/47 patients (55.3%). Locally advanced T4-stage was significantly associated with higher cfDNA levels after CRT (3.3 ng/μl in T4-stage vs. 1.3 ng/μl in T1-3 stages, p=0.007). Patients who responded to CRT (partial/complete response) had significantly lower cfDNA levels before therapy (mean values 1.2 ng/μl vs. 2.7 ng/μl, p=0.03). A significantly worse locoregional progression-free survival in patients with an A/B-ratio >1 was documented (p=0.01; hazard ratio 3.5, 95%CI=1.2-9.7). This was also confirmed in multivariate analysis, where the A/B-ratio was an independent predictive variable of locoregional relapse (p=0.03, hazard ratio 3.9, 95%CI=1.2-13). High post-CRT cfDNA levels could be an early biomarker for the immediate recruitment of patients with SCHNC in consolidation chemo-immunotherapy protocols.