Progression-free Survival In Patients Research Articles

HAPLN1 matrikine: a bone marrow homing factor linked to poor outcomes in patients with MM

AbstractThe bone marrow (BM) microenvironment is critical for dissemination, growth, and survival of multiple myeloma (MM) cells. Homing of myeloma cells to the BM niche is a crucial step in MM dissemination, but the mechanisms involved are incompletely understood. In particular, any role of matrikines, neofunctional peptides derived from extracellular matrix proteins, remains unknown. Here, we report that a matrikine derived from hyaluronan and proteoglycan link protein 1 (HAPLN1) induces MM cell adhesion to the BM stromal components, such as fibronectin, endothelial cells, and stromal cells and, furthermore, induces their chemotactic and chemokinetic migration. In a mouse xenograft model, we show that MM cells preferentially home to HAPLN1 matrikine–conditioned BM. The transcription factor STAT1 is activated by HAPLN1 matrikine and is necessary to induce MM cell adhesion, migration, migration-related genes, and BM homing. STAT1 activation is mediated by interferon beta (IFN-β), which is induced by NF-κB after stimulation by HAPLN1 matrikine. Finally, we also provide evidence that higher levels of HAPLN1 in BM samples correlate with poorer progression-free survival of patients with newly diagnosed MM. These data reveal that a matrikine present in the BM microenvironment acts as a chemoattractant, plays an important role in BM homing of MM cells via NF-κB–IFN-β–STAT1 signaling, and may help identify patients with poor outcomes. This study also provides a mechanistic rationale for targeting HAPLN1 matrikine in MM therapy.

Prognostic significance of TM4SF1 and DDR1 expression in epithelial ovarian cancer.

Transmembrane 4 L6 family member 1 (TM4SF1) and discoidin domain receptor 1 (DDR1) are expressed in numerous types of cancer, but their expression in epithelial ovarian cancer and the association between their expression and patient prognosis are unclear. The present study aimed to explore the expression of TM4SF1 and DDR1 and their relationship with prognosis in epithelial ovarian cancer. Firstly, the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) platforms were used to compare the expression levels of TM4SF1 and DDR1 in ovarian cancer and normal ovarian tissue, and Kaplan-Meier plotter was used to analyze the association between gene expression and patient prognosis. The proteins interacting with TM4SF1 and DDR1 were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways was conducted for the interacting proteins. Furthermore, immunohistochemical staining was performed to detect the expression of TM4SF1 and DDR1 protein in epithelial ovarian cancer tissue and to analyze the association between expression and prognosis. The Oncomine and GEPIA analyses showed that the expression levels of TM4SF1 and DDR1 were significantly higher in epithelial ovarian cancer than in normal ovarian tissue, and the analysis of clinical samples revealed that TM4SF1 and DDR1 were coexpressed in some cases. STRING analysis indicated that the TM4SF1 and DDR1 proteins interact with each other. The overall survival and progression-free survival of patients whose epithelial ovarian cancer coexpressed TM4SF1 and DDR1 were significantly shorter than those of patients lacking TM4SF1 and DDR1 coexpression. Multivariate analysis indicated that TM4SF1 and DDR1 protein coexpression was an independent prognostic factor. In summary, TM4SF1 and DDR1 proteins were coexpressed in some epithelial ovarian cancer tissues and appear to be adverse prognostic factors for epithelial ovarian cancer. In addition, TM4SF1 and DDR1 may have an interactive or mutual regulatory mechanism.

Retrospective evaluation of our patients diagnosed with advanced pancreatic cancer

Aims: Pancreatic cancer attracts attention with its increasing frequency among gastrointestinal cancers. It has the worst prognosis of all cancer types. In this study, we aimed to retrospectively evaluate the clinical features and treatment results of our patients with advanced pancreatic cancer. Methods: In this study, 131 patients diagnosed with advanced pancreatic cancer and admitted to the Ankara Numune Training and Research Hospital Medical Oncology Polyclinic between November 2002 and January 2014 were retrospectively analyzed. Demographic characteristics of the patients, smoking, family history, basal CEA and basal CA 19-9 levels, treatment modalities, metastasis sites, progression-free survival, and overall survival times were evaluated. Results: The study population consisted of 131 patients, including 94 males and 37 females. Twenty of the patients were in the locally advanced stage, and 111 were in the metastatic stage. The median age of the patients was 60 years. 53.4% of the patients were smokers, and the median amount of smoking was 30 packs/year. Adenocancer was the most common histopathological subtype. The median basal CEA and Ca 19-9 levels were high at the time of diagnosis. Neoadjuvant chemotherapy was given to all locally advanced patients. The most commonly used chemotherapy regimens were single-agent gemcitabine and gemcitabine-cisplatin combination therapies. While 10 of the locally advanced patients received local treatment (chemotherapy or surgery) after neoadjuvant chemotherapy, the remaining 10 patients could not receive local treatment. The median overall and progression-free survival times were found to be significantly longer in patients with locally advanced disease who received local treatment after neoadjuvant chemotherapy [(18 months vs. 6.5 months; p=0.008), (11.3 months vs. 6.4 months; p=0.05)]. The most common site of metastasis in our patients with metastatic pancreatic cancer was the liver (80%). Cisplatin-gemcitabine was preferred as a KT regimen in 63.4% of metastatic cases. The median overall survival time of the patients in the metastatic stage was 8.1 months, and the median progression-free survival time was 5.7 months. The median progression-free survival of all patients included in the study was 6.2 months, while the median overall survival was 8.8 months. Conclusion: The median overall survival of patients with locally advanced pancreatic cancer was significantly longer compared to metastatic patients (18 months vs. 8.1 months; p=0.028). Progression-free survival and overall survival of patients with locally advanced disease who received or did not receive local treatment after neoadjuvant chemotherapy were found to be significantly longer in patients who received local treatment. (11.3 months vs. 6.4 months; p=0.05) (18 months vs. 6.5 months; p=0.008). Response rates of patients with metastatic pancreatic cancer; It was 49% in the gemcitabine-cisplatin combination arm and 30% in the single-agent gemcitabine arm.

Adverse kidney outcomes of CDK 4/6 inhibitors for metastatic breast cancer

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved overall and progression free survival of patients with metastatic breast cancer, but their effect on short and long-term kidney function is unknown. We found that early, mild estimated glomerular filtration rate (eGFR) decline was common in patients treated with CDK 4/6 inhibitors; however, severe kidney injury is rare and long-term eGFR decline is uncommon.

Progression free survival in patients of HCC on atezolizumab/bevacizumab in Pakistan.

46 Background: Liver cancers had been the second leading cause of cancer related deaths, globally and hepatocellular carcinoma (HCC) accounts for 75-85% of the primary liver malignancies. Recently, the combination of Atezolizumab-Bevacizumab (atezo-beva) had been considered to be the standard of care for unresectable HCC. This study aims to assess the impact of the atezo-beva combination therapy on patients with HCC in Pakistan that will help to improve the standard of care and could lead to better health outcomes for our patients. Methods: A retrospective, uni-center study was conducted among the patients of HCC presented in the oncology department of Hameed Latif Hospital, Lahore, Pakistan, with the sample size of 46. The diagnosed patients of unresectable HCC were included. The combination of Atezolizumab 1200mg and Bevacizumab 15mg per kg were administered intravenous every 3 weekly. The therapeutic response to treatment was assessed by CT or MRI after 3 months of initiation of treatment as per Response Evaluation Criteria in Solid Tumors for immunotherapy (iRECIST). Results: A total of 46 participants were included with the median age of 61.5 years. 91.3% and 8.7% participants were male and female, respectively. Majority, 78.3% had viral etiology for HCC and the median level of alpha fetoprotein (AFP) was 99.43 ng/ml. The response to atezo-beva combination after 4 cycles of treatment was partial response (45.17%), progressive disease (15.2%), and stable disease (10.9%). Moreover, the current status of the participants was as ongoing treatment (67.4%), progressive disease (13.0%), drug side effects (6.5%), lost to follow up (6.5%) and mortality (6.5%). Conclusions: The effect of atezo-beva combination on unresectable HCC showed the majority to have partial response. However further studies are needed to validate these findings as well as to assess the PFS and OS of atezo-beva combination in Pakistani population.

Safety and efficacy of anlotinib hydrochloride capsules in advanced non-small-cell lung cancer: a multicenter, real-world study.

Objective: To investigate the safety and efficacy of anlotinib hydrochloride capsules in stage III-IV non-small-cell lung cancer (NSCLC). Methods: NSCLC patients received anlotinib monotherapy or combination therapy. The primary end point was adverse reactions during anlotinib treatment and the secondary end point was progression-free survival. Results: During anlotinib treatement, 41.85% (167/399) of patients experienced adverse reactions, and the monotherapy group had a lower incidencethan thecombination group (36.89vs 49.68%; p=0.012). The median progression-free survival of patients in the monotherapy group was significantly lower than that in the combination group (5 vs 6months; p=0.0119). Conclusion: Compared with anlotinib monotherapy, combination therapy resulted in longer PFS and a higher incidence of adverse reactions in patients with NSCLC.

Advances in the molecular mechanism and targeted therapy of radioactive-iodine refractory differentiated thyroid cancer.

Most patients with differentiated thyroid cancer have a good prognosis afterradioactive iodine-131 treatment, but there are still a small number of patients who are not sensitive to radioiodine treatment and may subsequently show disease progression. Therefore, radioactive-iodine refractory differentiated thyroid cancer treated with radioiodine usually shows reduced radioiodine uptake. Thus, when sodium iodine symporter expression, basolateral membrane localization and recycling degradation are abnormal, radioactive-iodine refractory differentiated thyroid cancer may occur. In recent years, with the deepening of research into the pathogenesis of this disease, an increasing number of molecules have become or are expected to become therapeutic targets. The application of corresponding inhibitors or combined treatment regimens for different molecular targets may be effective for patients with advanced radioactive-iodine refractory differentiated thyroid cancer. Currently, some targeted drugs that can improve the progression-free survival of patients with radioactive-iodine refractory differentiated thyroid cancer, such as sorafenib and lenvatinib, have been approved by the FDA for the treatment of radioactive-iodine refractory differentiated thyroid cancer. However, due to the adverse reactions and drug resistance caused by some targeted drugs, their application is limited. In response to targeted drug resistance and high rates of adverse reactions, research into new treatment combinations is being carried out; in addition to kinase inhibitor therapy, gene therapy and rutin-assisted iodine-131 therapy for radioactive-iodine refractory thyroid cancer have also made some progress. Thus, this article mainly focuses on sodium iodide symporter changes leading to the main molecular mechanisms in radioactive-iodine refractory differentiated thyroid cancer, some targeted drug resistance mechanisms and promising new treatments.

The use of deep learning models to predict progression-free survival in patients with neuroendocrine tumors.

Aim: The RAISE project assessed whether deep learning could improve early progression-free survival (PFS) prediction in patients with neuroendocrine tumors. Patients & methods: Deep learning models extracted features from CT scans from patients in CLARINET (NCT00353496) (n=138/204). A Cox model assessed PFS prediction when combining deep learning with the sum of longest diameter ratio (SLDr) and logarithmically transformed CgA concentration (logCgA), versus SLDr and logCgA alone. Results: Deep learning models extracted features other than lesion shape to predict PFS at week 72. No increase in performance was achieved with deep learning versus SLDr and logCgA models alone. Conclusion: Deep learning models extracted relevant features to predict PFS, but did not improve early prediction based on SLDr and logCgA.

Comparison of Alectinib/Crizotinib Data in First-Line Therapy in Patients with Anaplastic LymphomakinasePositive Nonsmall Cell Lung Carcinoma with Poor Prognostic Features for Alectinib.

Alectinib has a much better central nervous system transmission than crizotinib in patients diagnosed with anaplastic lymphoma kinase mutation-positive nonsmall cell lung carcinoma. We aimed to investigate alectinib's efficacy in the treatment and its place in the first-line treatment and report our real-life data. The data of 38 patients who were diagnosed with anaplastic lymphoma kinase-positive nonsmall cell lung carcinoma in our clinic between 2016 and 2021, who did not receive any treatment before were retrospectively analyzed. Of the 19 patients who received alectinib, 14 had multiple, and 6 had pretreatment brain metastases. No newly emerging brain metastases were detected during the treatment period. The progression-free survival of patients was 23.5 ± 4.2 months, and overall survival was 24.6 ± 4.1 months. Progression was observed in 10 (52.6%) patients. Of the 19 patients who received crizotinib, 7 had multiple metastases, and brain metastases were detected in 1 patient before treatment and 6 patients during the treatment period. Progression-free survival of crizotinib patients was 17.1 ± 4.8 months and their overall survival was 26.5 ± 6.1 months. Progression was observed in 17 (89.5%) patients. The second line of alectinib could be given to 8 of these patients. Overall survival after second-line treatment of alectinib was 18.2 ± 7.0 months. Overall survival of the patients who could not receive second-line treatment of alectinib was 4.0 ± 2.0 months. The progression rate was lower in alectinib than the crizotinib patients, although there were more patients with multiple metastases and brain metastases in the alectinib arm.

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study

PurposeIn the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). Patients and methodsPatients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. ResultsQuestionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). ConclusionPatients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Monocyte subsets associated with the efficacy of anti‑PD‑1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.

Comprehensive analysis of the expression, prognosis and biological significance of FSCN family in clear cell renal cell carcinoma.

Fascin (FSCN) is an actin-binding protein that serves a critical role in cell migration and invasion, contributing to tumor metastasis. However, there is little known about the function of FSCN family in kidney renal clear cell carcinoma (KIRC). The present study used the UALCAN, gene expression profiling interactive analysis, The Cancer Genome Atlas, cBioPortal, STRING and The Tumor Immune Estimation Resource databases to investigate the transcription level, genetic alteration and biological function of FSCNs in KIRC and their association with the prognosis value and immune cell infiltration in patients with KIRC. Results showed that the expression of FSCN1 and FSCN3 was markedly upregulated in patients with KIRC, while the expression of FSCN2 showed an opposite trend, which was the same as the experiments. Furthermore, the expression levels of FSCNs were associated with pathological stage, molecular subtypes and tumor grade. The expression levels of FSCNs were statistically correlated with the immune cell infiltration in KIRC. Higher expression levels of FSCN1 and FSCN3 were associated with worse overall survival (OS) and progression-free interval of patients bearing KIRC. Univariate and multivariate analysis demonstrated that FSCN2 was an independent risk factor for OS time in KIRC. Furthermore, mutations in FSCNs were significantly associated with poor OS and progression-free survival in patients with KIRC. The FSCNs were involved in pathways including focal adhesion, endocytosis, hypertrophic cardiomyopathy, regulation of actin cytoskeleton. The results indicated that FSCN2 might serve as an independent prognostic factor for OS of KIRC and that FSCN1 and FSCN3 can be used as favorable biomarkers for predicting clinical outcomes in KIRC.

Cabozantinib for Advanced Hepatocellular Carcinoma in the Latest Real-World Practice: A Multicenter Retrospective Analysis.

Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC. We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021. During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child-Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7months. Regarding patients with Child-Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20mg was lower than those who initialized at 60mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%). Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib. The preprint version of this work is available on https://www.researchsquare.com/article/rs-2655181/v1 .

Extracellular Matrix- and Integrin Adhesion Complexes-Related Genes in the Prognosis of Prostate Cancer Patients' Progression-Free Survival.

Prostate cancer is a heterogeneous disease, and one of the main obstacles in its management is the inability to foresee its course. Therefore, novel biomarkers are needed that will guide the treatment options. The extracellular matrix (ECM) is an important part of the tumor microenvironment that largely influences cell behavior. ECM components are ligands for integrin receptors which are involved in every step of tumor progression. An underlying characteristic of integrin activation and ligation is the formation of integrin adhesion complexes (IACs), intracellular structures that carry information conveyed by integrins. By using The Cancer Genome Atlas data, we show that the expression of ECM- and IACs-related genes is changed in prostate cancer. Moreover, machine learning methods revealed that they are a source of biomarkers for progression-free survival of patients that are stratified according to the Gleason score. Namely, low expression of FMOD and high expression of PTPN2 genes are associated with worse survival of patients with a Gleason score lower than 9. The FMOD gene encodes protein that may play a role in the assembly of the ECM and the PTPN2 gene product is a protein tyrosine phosphatase activated by integrins. Our results suggest potential biomarkers of prostate cancer progression.

THE ROLE OF ICAM1 IN TUMOR ASSOCIATED MACROPHAGES IN GLIOBLASTOMA TUMORIGENESIS

Abstract Glioblastoma (GBM) is a fatal brain cancer in adults with ineffective treatment methods. Cell adhesion molecules (CAMs) are proteins that are expressed on the surface of cells and enable them to interact with one another and the surrounding microenvironment. Intracellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule expressed by various cell types. Preliminary data showed that ICAM-1 is associated with poorer overall and progression free survival in patients and ICAM-1 expression levels increase in recurrent tumors. TAMs enhance GBM tumor growth. The aim of this study was to determine if ICAM-1 expression on TAMs contributes to GBM tumorigenesis, specifically within the hypoxic tumor microenvironment. We hypothesized that ICAM1 facilitates TAM migration, proliferation, cell adhesion and phagocytosis, thus enhancing tumor growth. We found that upon incubation of human and mouse primary macrophages in hypoxia, ICAM-1 expression levels increased and were further exasperated upon culturing with tumor cell-conditioned medium. The migration, cell adhesion and phagocytosis of ICAM-1 deficient macrophages was lower than wild type macrophages, and effects were further exasperated upon culturing with tumor conditioned media and incubation in hypoxia. Intracranial injection of tumor cells into ICAM-1 deficient and wild type mice revealed that ICAM1 deficient mice survived longer with lower overall tumor volume than wild type mice, with survival and volume differences being rescued upon ICAM1 bone marrow reconstitution. In conclusion, the expression of ICAM1 in TAMs likely promotes GBM tumorigenesis and hypoxia further enhances the expression of ICAM-1 in macrophages which is associated with more aggressive GBM.

Association of lncRNA and transcriptome intersections with response to targeted therapy in metastatic renal cell carcinoma.

Long non-coding RNAs (lncRNAs) serve an important role in cancer progression and may be used as efficient molecular biomarkers. The present study aimed to identify lncRNAs associated with the response to the receptor tyrosine kinase inhibitor sunitinib and transcriptome profile and clinical features of metastatic renal cell carcinoma (mRCC). The gene expression of 84 cancer-associated lncRNAs in tumor and non-malignant tissue samples of 38 patients with mRCC was evaluated using quantitative PCR. In addition, the coding transcriptome was estimated using RNA sequencing in a subgroup of 20 patients and mRNA-lncRNA intersections were identified. In total, 37 and 13 lncRNAs were down- and upregulated, respectively, in tumor compared with non-malignant adjacent tissue samples. A total of 10 and 4 lncRNAs were up- and downregulated, respectively, in good responders to sunitinib compared with poor responders. High expression of HNF1A-AS1 and IPW lncRNAs was associated with prolonged progression-free survival of patients and a high expression of the TUSC7 lncRNA was associated with poor response and worse survival. Significant associations of dysregulated MEG3 and SNHG16 lncRNAs with expression of protein-coding genes representing various pathways, were identified. Furthermore, a significantly higher expression of CLIP4 gene was observed in good responders. The present study revealed promising candidates for predictive and prognostic biomarkers with further therapeutic potential.

Clinicopathological features and prognosis of SMARCA4-deficient non-small cell lung carcinoma: an analysis of 127 cases

Objective: To investigate and elucidate the clinicopathological and prognostic characteristics of SMARCA4-deficient non-small cell lung cancer. Methods: The clinicopathological and prognostic data were collected in 127 patients with SMARCA4-deficient non-small cell lung cancer diagnosed in Shanghai Pulmonary Hospital, Shanghai, China from January 2020 to March 2022. The variation and expression of biomarkers related to treatment were retrospectively reviewed. Results: One hundred and twenty-seven patients were eligible for enrollment. Among them 120 patients (94.5%) were male and 7 cases (5.5%) were female, while the average age was 63 years (range 42-80 years). There were 41 cases (32.3%) of stage Ⅰ cancer, 23 cases (18.1%) of stage Ⅱ, 31 cases (24.4%) of stage Ⅲ and 32 cases (25.2%) of stage Ⅳ. SMARCA4 expression detected by immunohistochemistry was completely absent in 117 cases (92.1%) and partially absent in 10 cases (7.9%). PD-L1 immunohistochemical analyses were performed on 107 cases. PD-L1 was negative, weakly positive and strongly positive in 49.5% (53/107), 26.2% (28/107) and 24.3% (26/107) of the cases, respectively. Twenty-one cases showed gene alterations (21/104, 20.2%). The KRAS gene alternation (n=10) was most common. Mutant-type SMARCA4-deficient non-small cell lung cancer was more commonly detected in females, and was associated with positive lymph nodes and advanced clinical stage (P<0.01). Univariate survival analysis showed that advanced clinical stage was a poor prognosis factor, and vascular invasion was a poor predictor of progression-free survival in patients with surgical resection. Conclusions: SMARCA4-deficient non-small cell lung cancer is a rare tumor with poor prognosis, and often occurs in elderly male patients. However, SMARCA4-deficient non-small cell lung cancers with gene mutations are often seen in female patients. Vascular invasion is a prognostic factor for disease progression or recurrence in patients with resectable tumor. Early detection and access to treatment are important for improving patient survivals.

OCT3/4 is a potential immunohistochemical biomarker for diagnosis and prognosis of primary intracranial germ cell tumors: a systematic review and meta-analysis.

Intracranial germ cell tumors (iGCTs), comprising of germinoma (GE) and non-germinomatous GCT (NGGCT), are a group of heterogenous brain tumors. Immunohistochemical markers, such as placental-like alkaline phosphatase (PLAP), are commonly used in diagnosis but show moderate sensitivity. Organic cation transporter 3/4 (OCT3/4) has been proposed as a novel biomarker for diagnosis and prognosis of iGCTs. This paper aimed to compare OCT3/4 with PLAP as potential immunohistochemical biomarkers in iGCTs diagnosis and clarify the relationship between OCT3/4 and prognosis of patients with iGCTs. Meta-analyses were performed to estimate pooled percentage point differences in positive rates between OCT3/4 and PLAP, their sensitivities, and correlation between OCT3/4 and prognosis in iGCTs. Nine articles were included representing of 241 patients. A fixed-effects model meta-analysis revealed that OCT3/4s positive rate was 8.6% higher (95% CI, 0.7% lower to 17.9% higher) than that of PLAP. Using fixed-effects models, sensitivities of OCT3/4 as a potential immunohistochemical biomarker in CNS GE and NGGCT were 85% (95% CI, 79% to 89%) and 56% (95% CI, 39% to 71%), respectively. In comparison, PLAP had lower sensitivities in both GE (73%; 95% CI, 64% to 91%) and NGGCT (43%; 95% CI, 27% to 61%). Moreover, OCT3/4 was significantly negatively correlated with 5-year progression free survival in patients with CNS GE (HR = 2.56, 95 % CI 1.47 to 4.44; p = 0.0008). Sensitivity analyses showed similar results. This study provides the first comprehensive assessment of the efficacies of OCT3/4 and PLAP in iGCTs detection and prognosis prediction, indicating OCT3/4 seems to be a more sensitive and reliable immunohistochemical marker in iGCT diagnosis.

Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.

Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.

Circulating tumour HPV16 DNA quantification – A prognostic tool for progression-free survival in patients with HPV-related oropharyngeal carcinoma receiving curative chemoradiotherapy

Background and PurposeCirculating tumour (ct) human papillomavirus (HPV) DNA is detectable in HPV-related oropharyngeal carcinoma (OPSCC) patients and has the potential to become an important clinical tool. This study aimed to evaluate the prognostic significance of ctHPV16-DNA kinetics during treatment with chemoradiotherapy in HPV-related OPSCC. Patients with p16-positive OPSCC recruited to the ARTSCAN III trial, comparing radiotherapy plus cisplatin with radiotherapy plus cetuximab, constituted the study cohort. Materials and methodsBlood samples before start and at the end of treatment of 136 patients were analysed. ctHPV16-DNA was quantified by real-time (q)PCR. The correlation between ctHPV16-DNA levels and tumour burden was investigated with Pearson regression analysis. The prognostic value of ctHPV16-DNA levels at baseline and decline during treatment was evaluated by area-under-the-curve (AUC) calculations and analysed with univariable and multivariable Cox proportional hazards models. ResultsctHPV16-DNA was detectable with qPCR in 108/136 patients before start of treatment and cleared in 74% of these patients at the end of treatment. Disease burden was significantly correlated with baseline ctHPV16-DNA levels (R = 0.39, p=<0.001). Both lower baseline levels and AUC-ctHPV16DNA were associated with improved progression-free survival (p = 0.01 and p < 0.001), overall survival (p = 0.013 and p = 0.002), but not local tumour control (p = 0.12 and p = 0.2, respectively), with a stronger association for AUC-ctHPV16DNA (likelihood ratio test 10.5 vs 6.5 in Cox regression analyses of progression-free survival). In multivariable analysis including tumour volume (GTV-T) and treatment allocation (cisplatin vs cetuximab), AUC-ctHPV16DNA remained a significant prognostic marker of progression-free survival. ConclusionctHPV16-DNA is an independent prognostic factor in HPV-related OPSCC.