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Dissemination in pediatric low-grade gliomamay occur in about 4%-10% of patients according to retrospective cohort studies. Due to its low incidence, there is no consensus on treatment for these patients. According to the constitutional activation of the MAPK/ERK pathway in these tumors, MEK inhibitors such as trametinib have been used successfully in the relapsed setting. Skin toxicity is frequent in patients receiving trametinib, normally mild to moderate, but sometimes severe, needing to discontinue the drug, limiting the efficacy in the tumor. There is notmuch information in the literature regarding whether reducing the dose of trametinib is able to maintain efficacy while, at the same time, decreasing toxicity. Here, we present an adolescent, with severe skin toxicity, whose trametinib dose was reduced by 50% and efficacy on the tumor continued while skin toxicity significantly decreased. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore a radiomics-clinical model for predicting the response to initial superselective arterial embolization (SAE) in renal angiomyolipoma (RAML). Materials and methods: A total of 78 patients with RAML were retrospectively enrolled. Clinical data were recorded and evaluated. Radiomic features were extracted from preoperative contrast-enhanced CT (CECT). Least absolute shrinkage and selection operator (LASSO) and intra- and inter-class correlation coefficients (ICCs) were used in feature selection. Logistic regression analysis was performed to develop the radiomics, clinical, and combined models where the fivefold cross-validation method was used. The predictive performance and calibration were evaluated by the receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was used to measure clinical usefulness. Results: The tumor shrinkage rate was 29.7% in total, and both fat and angiomyogenic components were significantly reduced. In the radiomics model, 12 significant features were selected. In the clinical model, maximum diameter (p = 0.001), angiomyogenic tissue ratio (p = 0.032), aneurysms (p = 0.048), and post-SAE time (p = 0.002) were significantly associated with greater volume reduction after SAE. Because of the severe linear dependence between radiomics signature and some clinical parameters, the combined model eventually included Rad-score, aneurysm, and post-SAE time. The radiomics-clinical model showed better discrimination (mean AUC = 0.83) than the radiomics model (mean AUC = 0.60) and the clinical model (mean AUC = 0.82). Calibration curve and DCA showed the goodness of fit and clinical usefulness of the radiomicsclinical model. Conclusions: The radiomics-clinical model incorporating radiomics features and clinical parameters can potentially predict the positive response to initial SAE in RAML and provide support for clinical treatment decisions. [ABSTRACT FROM AUTHOR]

Dissemination in pediatric low-grade glioma may occur in about 4%–10% of patients according to retrospective cohort studies. Due to its low incidence, there is no consensus on treatment for these patients. According to the constitutional activation of the MAPK/ERK pathway in these tumors, MEK inhibitors such as trametinib have been used successfully in the relapsed setting. Skin toxicity is frequent in patients receiving trametinib, normally mild to moderate, but sometimes severe, needing to discontinue the drug, limiting the efficacy in the tumor. There is not much information in the literature regarding whether reducing the dose of trametinib is able to maintain efficacy while, at the same time, decreasing toxicity. Here, we present an adolescent, with severe skin toxicity, whose trametinib dose was reduced by 50% and efficacy on the tumor continued while skin toxicity significantly decreased.

Background: The role of platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) as independent prognostic markers in different tumors is well established. However, there is a limited review of the potential of NLR and PLR as predictors of treatment outcomes from immune checkpoint inhibitors (ICIs). Objective: To establish a correlation between NLR and PLR and the potential of clinical benefit from ICIs. Methods: The literature search was performed for studies that reported the association between NLR, PLR, and treatment outcomes among cancer patients treated with ICIs. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). ORR was the summation of patients who achieved complete response and partial response. DCR included patients who achieved stable disease. PD was the proportion of patients who progressed, relapsed, or discontinued the treatment. Statistical analysis was performed using the STATA 12.0 package. Heterogeneity was determined by the I² value. Quality assessment was performed using the Newcastle-Ottawa Scale. Egger's test was used to establish publication bias and sensitivity analysis. Results: A total of 40 papers that met the inclusion criteria were included in the systematic review. However, only 17 studies were used in the meta-analysis to determine the correlation between NLR, PLR, and treatment response. We found that treatment with ICIs and monitoring of outcomes and adverse events using PLR and NLR parameters have been studied in different tumors. Our analysis showed that low NLR correlated with higher ORR (OR = 0.62 (95% CI 0.47-0.81, p = 0.001) and higher DCR (OR = 0.23, 95% CI 0.14-0.36, p < 0.001). Higher NLR predicted a higher probability of PD (OR = 3.12, 95% CI 1.44, 6.77, p = 0.004). Similarly, low PLR correlated with higher ORR (OR = 0.69, 95% CI 0.5, 0.95, p = 0.025). Generally, patients with low NLR and PLR were more likely to achieve clinical benefit and better response (p-value < 0.001). Meanwhile, patients with high ratios were more likely to progress (p-value < 0.005), although there was significant heterogeneity among studies. There was no significant publication bias observed. Conclusion: The study showed that high NLR and PLR either at baseline or during treatment is associated with poorer treatment outcome. Therefore, these ratios can be utilized in clinical practice with other markers to determine treatment efficacy from immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies targeting immune checkpoint pathways, such as programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), have achieved unprecedented therapeutic success in treating various types of cancer. The prominent and persistent clinical responses to immune checkpoint blockade (ICB) therapy are currently constrained to a subset of patients. Owing to discrete individual tumor and immune heterogeneity, most patients fail to benefit from ICB treatment, demonstrating either primary or acquired resistance. A thorough comprehension of the mechanisms restricting the efficacy of immune checkpoint inhibitors (ICIs) is required to extend their clinical applicability to a broader spectrum of patients and cancer types. Numerous studies are presently investigating potential prognostic markers of responsiveness, the complex dynamics underlying the therapeutic and adverse effects of ICB, and tumor immune evasion throughout the course of immunotherapy. In this article, we have reviewed the extant literature elucidating the mechanisms underlying the response and resistance to ICB, with a particular emphasis on PD-1 and CTLA-4 pathway blockade in the context of anti-tumor immunity. Furthermore, we aimed to explore potential approaches to overcome cancer therapeutic resistance and develop a rational design for more personalized ICB-based combinational regimens. [ABSTRACT FROM AUTHOR]

BackgroundThe role of platelet–lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR) as independent prognostic markers in different tumors is well established. However, there is a limited review of the potential of NLR and PLR as predictors of treatment outcomes from immune checkpoint inhibitors (ICIs).ObjectiveTo establish a correlation between NLR and PLR and the potential of clinical benefit from ICIs.MethodsThe literature search was performed for studies that reported the association between NLR, PLR, and treatment outcomes among cancer patients treated with ICIs. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). ORR was the summation of patients who achieved complete response and partial response. DCR included patients who achieved stable disease. PD was the proportion of patients who progressed, relapsed, or discontinued the treatment. Statistical analysis was performed using the STATA 12.0 package. Heterogeneity was determined by the I2 value. Quality assessment was performed using the Newcastle–Ottawa Scale. Egger’s test was used to establish publication bias and sensitivity analysis.ResultsA total of 40 papers that met the inclusion criteria were included in the systematic review. However, only 17 studies were used in the meta-analysis to determine the correlation between NLR, PLR, and treatment response. We found that treatment with ICIs and monitoring of outcomes and adverse events using PLR and NLR parameters have been studied in different tumors. Our analysis showed that low NLR correlated with higher ORR (OR = 0.62 (95% CI 0.47–0.81, p = 0.001) and higher DCR (OR = 0.23, 95% CI 0.14–0.36, p < 0.001). Higher NLR predicted a higher probability of PD (OR = 3.12, 95% CI 1.44, 6.77, p = 0.004). Similarly, low PLR correlated with higher ORR (OR = 0.69, 95% CI 0.5, 0.95, p = 0.025). Generally, patients with low NLR and PLR were more likely to achieve clinical benefit and better response (p-value < 0.001). Meanwhile, patients with high ratios were more likely to progress (p-value < 0.005), although there was significant heterogeneity among studies. There was no significant publication bias observed.ConclusionThe study showed that high NLR and PLR either at baseline or during treatment is associated with poorer treatment outcome. Therefore, these ratios can be utilized in clinical practice with other markers to determine treatment efficacy from immunotherapy.

Introduction: As the top 3 cancer in terms of incidence and mortality, the firstline treatment for CRC includes FOLFOX, FOLFIRI, Cetuximab or immunotherapy. However, the drug sensitivity of patients to regimens is different. There has been increasing evidence that immune components of TME can affect the sensitivity of patients to drugs. Therefore, it is necessary to define novo molecular subtypes of CRC based on TME immune components, and screen patients who are sensitive to the treatments, to make personalized therapy possible. Methods: We analyzed the expression profiles and 197 TME-related signatures of 1775 patients using ssGSEA, univariate Cox proportional risk model and LASSOCox regression model, and defined a novo molecular subtype (TMERSS) of CRC. Simultaneously, we compared the clinicopathological factors, antitumor immune activity, immune cell abundance and differences of cell states in different TMERSS subtypes. In addition, patients sensitive to the therapy were screened out by correlation analysis between TMERSS subtypes and drug responses. Results: Compared with low TMERSS subtype, high TMERSS subtype has a better outcome, which may be associated to higher abundance of antitumor immune cell in high TMERSS subtype. Our findings suggested that the high TMERSS subtype may have a higher proportion of respondents to Cetuximab agent and immunotherapy, while the low TMERSS subtype may be more suitable for treatment with FOLFOX and FOLFIRI regimens. Discussion: In conclusion, the TMERSS model may provide a partial reference for the prognosis evaluation of patients, the prediction of drug sensitivity, and the implementation of clinical decision-making. [ABSTRACT FROM AUTHOR]

Aim: In this study, we aimed to compare the diagnostic values of MRI and FDGPET for the prediction of the response to neoadjuvant chemoradiotherapy (NACT) of patients with locally advanced Rectal cancer (RC). Methods: Electronic databases, including PubMed, Embase, and the Cochrane library, were systematically searched through December 2021 for studies that investigated the diagnostic value of MRI and FDG-PET in the prediction of the response of patients with locally advanced RC to NACT. The quality of the included studies was assessed using QUADAS. The pooled sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), and the area under the ROC (AUC) of MRI and FDG-PET were calculated using a bivariate generalized linear mixed model, random-effects model, and hierarchical regression. Results: A total number of 74 studies with recruited 4,105 locally advanced RC patients were included in this analysis. The pooled sensitivity, specificity, PLR, NLR, and AUC for MRI were 0.83 (95% CI: 0.77-0.88), 0.85 (95% CI: 0.79-0.89), 5.50 (95% CI: 4.11-7.35), 0.20 (95% CI: 0.14-0.27), and 0.91 (95% CI: 0.88-0.93), respectively. The summary sensitivity, specificity, PLR, NLR and AUC for FDGPET were 0.81 (95% CI: 0.77-0.85), 0.75 (95% CI: 0.70-0.80), 3.29 (95% CI: 2.64-4.10), 0.25 (95% CI: 0.20-0.31), and 0.85 (95% CI: 0.82-0.88), respectively. Moreover, there were no significant differences between MRI and FDG-PET in sensitivity (P = 0.565), and NLR (P = 0.268), while the specificity (P = 0.006), PLR (P = 0.006), and AUC (P = 0.003) of MRI was higher than FDG-PET. Conclusions: MRI might superior than FGD-PET for the prediction of the response of patients with locally advanced RC to NACT. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NAC) is widely accepted as a primary treatment for inoperable or locally advanced breast cancer before definitive surgery. However, not all advanced breast cancers are sensitive to NAC. Contrastenhanced ultrasonography (CEUS) has been considered to assess tumor response to NAC as it can effectively reflect the condition of blood perfusion and lesion size. Therefore, this study aimed to evaluate the diagnostic performance of CEUS to predict early response in different regions of interest in breast tumors under NAC treatment. This prospective study included 82 patients with advanced breast cancer. Parameters of TIC (timeintensive curve) between baseline and after the first cycle of NAC were calculated for the rate of relative change (Δ), including Dpeak, ΔTTP (time to peak), ΔRBV (regional blood volume), DRBF (regional blood flow) and ΔMTT (mean transit time). The responders and non-responders were distinguished by the Miller-Payne Grading (MPG) system and parameters from different regions of tumors were compared in these two groups. For ROI 1(the greatest enhancement area in the central region of the tumor), there were significant differences in Dpeak1, ΔRBV1 and ΔRBF1 between responders and nonresponders. For ROI 2 (the greatest enhancement area on edge of the tumor), there were significant differences in Dpeak2 and DRBF2 between the groups. The Dpeak1 and ΔRBF2 showed good prediction (AUC 0.798-0.820, p = 0.02) after the first cycle of NAC. When the cut-off value was 0.115, the ΔRBF2 had the highest diagnostic accuracy and the maximum NPV. Quantitative TIC parameters could be effectively used to evaluate early response to NAC in advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been widely used in treating different malignancies. Several studies have reported that the gut microbiota modulates the response and adverse events (AEs) to ICIs in melanoma, non-small cell lung cancer (NSCLC), renal cell cancer and hepatocellular carcinoma, but data on other cancer types and ICI combination therapy are limited. Methods: Stool samples were collected from patients with cancer who received anti-PD-1 and chemotherapy combination treatment and were analyzed by fecal metagenomic sequencing. The microbiota diversity and composition were compared between the responder (R) and non-responder (NR) groups and the AE vs. the non-AE (NAE) groups. In addition, associated functional genes and metabolic pathways were identified. Results: At baseline, the microbiota diversity of the groups was similar, but the genera Parabacteroides, Clostridia bacterium UC5.1_2F7, and Bifidobacterium dentium were enriched in the R group, whereas Bacteroides dorei and 11 species of Nocardia were enriched in the NR group. At 6 weeks, the beta diversity was significantly different between the R and NR groups. Further analysis found that 35 genera, such as Alipes, Parabacteroides, Phascolarctobacterium, Collinsella, Ruminiclostridium, Porphyromonas, and Butyricimonas and several genera of the Fibrobacteraceae family, were frequently distributed in the R group, whereas 17 genera, including Enterococcus, Lachnoclostridium, Hungatella, and Bilophila and several genera of the Pseudonocardiaceae and Beijerinckiaceae families, were more abundant in the NR group. A total of 66 and 52 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs (KOs) were significantly enriched in the R and NR groups, respectively. In addition, pathway analysis revealed functional differences in the gut microbacteria in the R group, including the enrichment of anabolic pathways and DNA damage repair (DDR) pathways. Dynamic comparisons of the bacterial composition at baseline, 6 weeks, and 12 weeks showed that the abundance of Weissella significantly increased in the R group at 6 weeks and the abundance of Fusobacterium and Anaerotruncus significantly increased in the NR group at 12 weeks. Linear discriminant analysis effect size analysis indicated that bacteria of Bacteroidetes, especially Bacteroides, were enriched in the NAE group, whereas flora of Firmcutes, such as Faecalibacterium prausnitzii, Bacteroides fragilis, and Ruminococcus lactaris, were enriched in the AE group. Conclusion: Beta diversity and differences in the gut microbiota modulated AEs and the response to anti-PD-1 blockade combined with chemotherapy, by regulating related anabolic and DDR pathways. Dynamic changes in the intestinal microbiome may predict the efficacy of PD-1 inhibitor-based therapy. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 immediately became a major consideration in the management of chronic myeloid leukemia (CML). The influence of such considerations on viral transmission rates and leukemic control remain to be explored. We conducted this study to identify these alterations and to investigate their clinical consequences. Methods: This was a cross-sectional study, performed at a single institution on CML patients who were interviewed with a survey. We compared variables concerning new attitudes in the pandemic era between the 12-month periods before and after the pandemic onset. Outcome data were attained from the hospital archives. Findings: The number of patients receiving regular outpatient care for CML in chronic phase was 210, 91% had achieved at least major molecular responses. We assessed survival, progression, number of clinical visits of all, performed the survey on 89% and evaluated molecular responses on 86.6% of these patients. The frequency of clinical and molecular monitoring was significantly reduced during the pandemic deviating significantly from the guidelines. Frequency of death, progression, loss of molecular response was not significantly increased during the pandemic era despite a few cases where the delay in assessment possibly played a role in the unfavorable outcomes. There were no COVID related deaths or disabilities. Conclusion: The case-based untoward events would have probably been better managed with a more efficient communication web between patients, hematologists, and the laboratory. Therefore, it seems reasonable to consider whether such communicative paths are functional before giving up on the set schedule of CML management at times of uncertainty. [ABSTRACT FROM AUTHOR]

IntroductionCOVID-19 immediately became a major consideration in the management of chronic myeloid leukemia (CML). The influence of such considerations on viral transmission rates and leukemic control remain to be explored. We conducted this study to identify these alterations and to investigate their clinical consequences.MethodsThis was a cross-sectional study, performed at a single institution on CML patients who were interviewed with a survey. We compared variables concerning new attitudes in the pandemic era between the 12-month periods before and after the pandemic onset. Outcome data were attained from the hospital archives.FindingsThe number of patients receiving regular outpatient care for CML in chronic phase was 210, 91% had achieved at least major molecular responses. We assessed survival, progression, number of clinical visits of all, performed the survey on 89% and evaluated molecular responses on 86.6% of these patients. The frequency of clinical and molecular monitoring was significantly reduced during the pandemic deviating significantly from the guidelines. Frequency of death, progression, loss of molecular response was not significantly increased during the pandemic era despite a few cases where the delay in assessment possibly played a role in the unfavorable outcomes. There were no COVID related deaths or disabilities.ConclusionThe case-based untoward events would have probably been better managed with a more efficient communication web between patients, hematologists, and the laboratory. Therefore, it seems reasonable to consider whether such communicative paths are functional before giving up on the set schedule of CML management at times of uncertainty.

Purpose: Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab (N/I) are important treatment options for advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in these ICI-treated patients is largely unknown. Methods: Twenty-four patients treated with N/I between July 2015 and June 2020 were analyzed. Multiplexed immunohistochemistry (mIHC) was conducted to define the TME, including various T cell subsets, B cells, macrophages, and dendritic cells. Results: The median age of the study patients was 61 years (range, 39–80) and 75.0% of these cases were men. The objective response rate with N/I was 50.0%. The densities of the CD8+ cytotoxic T cells (P=0.005), specifically CD137+ CD8+ T cells (P=0.017), Foxp3- CD4+ helper T cells (P=0.003), Foxp3+ CD4+ regulatory T cells (P=0.045), CD68+ CD206- M1 macrophages (P=0.008), and CD68+ CD206+ M2 macrophages (P=0.021) were significantly higher in the treatment responders. At a median follow-up duration of 24.7 months, the median progression-free survival (PFS) was 11.6 months. The high densities (≥median) of Foxp3- CD4+ helper T cells (P=0.016) and CD68+ CD206- M1 macrophages (P=0.008) were significantly associated with better PFS, and the density of CD137+ CD8+ cytotoxic T cells (P=0.079) was marginally associated with better PFS. After multivariate analysis, the higher density of Foxp3- CD4+ helper T cells was independently associated with better PFS (hazard ratio 0.19; P=0.016). Conclusion: The properties and clinical implications of the TME properties in RCC indicate that Foxp3- CD4+ helper T cells, M1 macrophages, and CD137+ CD8+ T cells are potential predictive biomarkers and treatment targets. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) induce durable responses, but only a minority of patients achieve clinical benefits. The development of gene expression profiling of tumor transcriptomes has enabled identifying prognostic gene expression signatures and patient selection with targeted therapies. Methods: Immune exclusion score (IES) was built by elastic net-penalized Cox proportional hazards (PHs) model in the discovery cohort and validated via four independent cohorts. The survival differences between the two groups were compared using Kaplan-Meier analysis. Both GO and KEGG analyses were performed for functional annotation. CIBERSORTx was also performed to estimate the relative proportion of immune-cell types. Results: A fifteen-genes immune exclusion score (IES) was developed in the discovery cohort of 65 patients treated with anti-PD-(L)1 therapy. The ROC efficiencies of 1- and 3- year prognosis were 0.842 and 0.82, respectively. Patients with low IES showed a longer PFS (p=0.003) and better response rate (ORR: 43.8% vs 18.2%, p=0.03). We found that patients with low IES enriched with high expression of immune eliminated cell genes, such as CD8+ T cells, CD4+ T cells, NK cells and B cells. IES was positively correlated with other immune exclusion signatures. Furthermore, IES was successfully validated in four independent cohorts (Riaz's SKCM, Liu's SKCM, Nathanson's SKCM and Braun's ccRCC, n = 367). IES was also negatively correlated with T cell–inflamed signature and independent of TMB. Conclusions: This novel IES model encompassing immune-related biomarkers might serve as a promising tool for the prognostic prediction of immunotherapy. [ABSTRACT FROM AUTHOR]

BackgroundImmune checkpoint inhibitors (ICIs) induce durable responses, but only a minority of patients achieve clinical benefits. The development of gene expression profiling of tumor transcriptomes has enabled identifying prognostic gene expression signatures and patient selection with targeted therapies.MethodsImmune exclusion score (IES) was built by elastic net-penalized Cox proportional hazards (PHs) model in the discovery cohort and validated via four independent cohorts. The survival differences between the two groups were compared using Kaplan-Meier analysis. Both GO and KEGG analyses were performed for functional annotation. CIBERSORTx was also performed to estimate the relative proportion of immune-cell types.ResultsA fifteen-genes immune exclusion score (IES) was developed in the discovery cohort of 65 patients treated with anti-PD-(L)1 therapy. The ROC efficiencies of 1- and 3- year prognosis were 0.842 and 0.82, respectively. Patients with low IES showed a longer PFS (p=0.003) and better response rate (ORR: 43.8% vs 18.2%, p=0.03). We found that patients with low IES enriched with high expression of immune eliminated cell genes, such as CD8+ T cells, CD4+ T cells, NK cells and B cells. IES was positively correlated with other immune exclusion signatures. Furthermore, IES was successfully validated in four independent cohorts (Riaz’s SKCM, Liu’s SKCM, Nathanson’s SKCM and Braun’s ccRCC, n = 367). IES was also negatively correlated with T cell–inflamed signature and independent of TMB.ConclusionsThis novel IES model encompassing immune-related biomarkers might serve as a promising tool for the prognostic prediction of immunotherapy.

Response evaluation criteria in solid tumours (RECIST) v1.1 are currently the reference standard for evaluating efficacy of therapies in patients with solid tumours who are included in clinical trials, and they are widely used and accepted by regulatory agencies. This expert statement discusses the principles underlying RECIST, as well as their reproducibility and limitations. While the RECIST framework may not be perfect, the scientific bases for the anticancer drugs that have been approved using a RECIST-based surrogate endpoint remain valid. Importantly, changes in measurement have to meet thresholds defined by RECIST for response classification within thus partly circumventing the problems of measurement variability. The RECIST framework also applies to clinical patients in individual settings even though the relationship between tumour size changes and outcome from cohort studies is not necessarily translatable to individual cases. As reproducibility of RECIST measurements is impacted by reader experience, choice of target lesions and detection/interpretation of new lesions, it can result in patients changing response categories when measurements are near threshold values or if new lesions are missed or incorrectly interpreted. There are several situations where RECIST will fail to evaluate treatment-induced changes correctly; knowledge and understanding of these is crucial for correct interpretation. Also, some patterns of response/progression cannot be correctly documented by RECIST, particularly in relation to organ-site (e.g. bone without associated soft-tissue lesion) and treatment type (e.g. focal therapies). These require specialist reader experience and communication with oncologists to determine the actual impact of the therapy and best evaluation strategy. In such situations, alternative imaging markers for tumour response may be used but the sources of variability of individual imaging techniques need to be known and accounted for. Communication between imaging experts and oncologists regarding the level of confidence in a biomarker is essential for the correct interpretation of a biomarker and its application to clinical decision-making. Though measurement automation is desirable and potentially reduces the variability of results, associated technical difficulties must be overcome, and human adjudications may be required. [ABSTRACT FROM AUTHOR]

Background: It is estimated that 35% of gastric cancer patients appear with synchronous distant metastases—the vast majority of patients presenting with metastatic hepatic disease. How to choose the most appropriate drugs or regimens is crucial to improve the prognosis of patients. We conducted this retrospective cohort analysis to evaluate the efficacy of OncoVee™-MiniPDX-guided treatment for these patients. Methods: Gastric cancer patients with liver metastases (GCLM) were enrolled. Patients were divided into MiniPDX and control group according to their wishes. In the observation group, the OncoVee™-MiniPDX model was conducted to screen the most sensitive drug or regimens to determine the clinical administration. Meanwhile, patients were treated with regular medications in the control group according to the guidelines without the MiniPDX model. The primary endpoint was overall survival (OS), and the secondary outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 68 patients with GCLM were included, with the observation and control groups of 21 and 47 patients, respectively. The baseline characteristics of patients were balanced between these two groups. MiniPDX drug sensitivity tests were associated with the increased use of targeted drugs when compared with the control group (33.3 vs. 0%, p=0.032). Median OS was estimated to be 9.4 (95% CI, 7.9–11.2) months and 7.9 (95% CI, 7.2–8.7) months in the observation and control group, respectively. Both univariate (control group vs. MiniPDX group: HR=2.586, 95% CI= 1.362–4.908, p=0.004) and multivariate regression analyses (Control group vs. MiniPDX group: adjusted HR (aHR)=4.288, 95% CI= 1.452–12.671, p=0.008) showed the superiority of the observation group on OS. Similarly, MiniPDX-based regiments significantly improve the PFS of these cases (median PFS 6.7 months vs. 4.2 months, aHR=2.773, 95% CI=1.532–3.983, p=0.029). ORR and DCR were also improved in MiniPDX group comparing with control group (ORR, 57.14 vs. 25.53%, p=0.029; DCR: 85.71 vs. 68.08%, p=0.035). Conclusion: OncoVee™-MiniPDX model, which was used to select drugs to guide antitumor treatment, was promising to prolong survival and improve the response rate of patients with GCLM. Further well-designed studies are needed to confirm the clinical benefits of MiniPDX. [ABSTRACT FROM AUTHOR]

BackgroundIt is estimated that 35% of gastric cancer patients appear with synchronous distant metastases—the vast majority of patients presenting with metastatic hepatic disease. How to choose the most appropriate drugs or regimens is crucial to improve the prognosis of patients. We conducted this retrospective cohort analysis to evaluate the efficacy of OncoVee™-MiniPDX-guided treatment for these patients.MethodsGastric cancer patients with liver metastases (GCLM) were enrolled. Patients were divided into MiniPDX and control group according to their wishes. In the observation group, the OncoVee™-MiniPDX model was conducted to screen the most sensitive drug or regimens to determine the clinical administration. Meanwhile, patients were treated with regular medications in the control group according to the guidelines without the MiniPDX model. The primary endpoint was overall survival (OS), and the secondary outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).ResultsA total of 68 patients with GCLM were included, with the observation and control groups of 21 and 47 patients, respectively. The baseline characteristics of patients were balanced between these two groups. MiniPDX drug sensitivity tests were associated with the increased use of targeted drugs when compared with the control group (33.3 vs. 0%, p=0.032). Median OS was estimated to be 9.4 (95% CI, 7.9–11.2) months and 7.9 (95% CI, 7.2–8.7) months in the observation and control group, respectively. Both univariate (control group vs. MiniPDX group: HR=2.586, 95% CI= 1.362–4.908, p=0.004) and multivariate regression analyses (Control group vs. MiniPDX group: adjusted HR (aHR)=4.288, 95% CI= 1.452–12.671, p=0.008) showed the superiority of the observation group on OS. Similarly, MiniPDX-based regiments significantly improve the PFS of these cases (median PFS 6.7 months vs. 4.2 months, aHR=2.773, 95% CI=1.532–3.983, p=0.029). ORR and DCR were also improved in MiniPDX group comparing with control group (ORR, 57.14 vs. 25.53%, p=0.029; DCR: 85.71 vs. 68.08%, p=0.035).ConclusionOncoVee™-MiniPDX model, which was used to select drugs to guide antitumor treatment, was promising to prolong survival and improve the response rate of patients with GCLM. Further well-designed studies are needed to confirm the clinical benefits of MiniPDX.

Response evaluation criteria in solid tumours (RECIST) v1.1 are currently the reference standard for evaluating efficacy of therapies in patients with solid tumours who are included in clinical trials, and they are widely used and accepted by regulatory agencies. This expert statement discusses the principles underlying RECIST, as well as their reproducibility and limitations. While the RECIST framework may not be perfect, the scientific bases for the anticancer drugs that have been approved using a RECIST-based surrogate endpoint remain valid. Importantly, changes in measurement have to meet thresholds defined by RECIST for response classification within thus partly circumventing the problems of measurement variability. The RECIST framework also applies to clinical patients in individual settings even though the relationship between tumour size changes and outcome from cohort studies is not necessarily translatable to individual cases. As reproducibility of RECIST measurements is impacted by reader experience, choice of target lesions and detection/interpretation of new lesions, it can result in patients changing response categories when measurements are near threshold values or if new lesions are missed or incorrectly interpreted. There are several situations where RECIST will fail to evaluate treatment-induced changes correctly; knowledge and understanding of these is crucial for correct interpretation. Also, some patterns of response/progression cannot be correctly documented by RECIST, particularly in relation to organ-site (e.g. bone without associated soft-tissue lesion) and treatment type (e.g. focal therapies). These require specialist reader experience and communication with oncologists to determine the actual impact of the therapy and best evaluation strategy. In such situations, alternative imaging markers for tumour response may be used but the sources of variability of individual imaging techniques need to be known and accounted for. Communication between imaging experts and oncologists regarding the level of confidence in a biomarker is essential for the correct interpretation of a biomarker and its application to clinical decision-making. Though measurement automation is desirable and potentially reduces the variability of results, associated technical difficulties must be overcome, and human adjudications may be required.

Metastatic tumor deposits in bone marrow elicit differential bone responses that vary with the type of malignancy. This results in either sclerotic, lytic, or mixed bone lesions, which can change in morphology due to treatment effects and/or secondary bone remodeling. Hence, morphological imaging is regarded unsuitable for response assessment of bone metastases and in the current Response Evaluation Criteria In Solid Tumors 1.1 (RECIST1.1) guideline bone metastases are deemed unmeasurable. Nevertheless, the advent of functional and molecular imaging modalities such as whole-body magnetic resonance imaging (WB-MRI) and positron emission tomography (PET) has improved the ability for follow-up of bone metastases, regardless of their morphology. Both these modalities not only have improved sensitivity for visual detection of bone lesions, but also allow for objective measurements of bone lesion characteristics. WB-MRI provides a global assessment of skeletal metastases and for a one-step "all-organ" approach of metastatic disease. Novel MRI techniques include diffusion-weighted imaging (DWI) targeting highly cellular lesions, dynamic contrast-enhanced MRI (DCE-MRI) for quantitative assessment of bone lesion vascularization, and multiparametric MRI (mpMRI) combining anatomical and functional sequences. Recommendations for a homogenization of MRI image acquisitions and generalizable response criteria have been developed. For PET, many metabolic and molecular radiotracers are available, some targeting tumor characteristics not confined to cancer type (e.g. 18F-FDG) while other targeted radiotracers target specific molecular characteristics, such as prostate specific membrane antigen (PSMA) ligands for prostate cancer. Supporting data on quantitative PET analysis regarding repeatability, reproducibility, and harmonization of PET/CT system performance is available. Bone metastases detected on PET and MRI can be quantitatively assessed using validated methodologies, both on a whole-body and individual lesion basis. Both have the advantage of covering not only bone lesions but visceral and nodal lesions as well. Hybrid imaging, combining PET with MRI, may provide complementary parameters on the morphologic, functional, metabolic and molecular level of bone metastases in one examination. For clinical implementation of measuring bone metastases in response assessment using WB-MRI and PET, current RECIST1.1 guidelines need to be adapted. This review summarizes available data and insights into imaging of bone metastases using MRI and PET. [ABSTRACT FROM AUTHOR]

Metastatic tumor deposits in bone marrow elicit differential bone responses that vary with the type of malignancy. This results in either sclerotic, lytic, or mixed bone lesions, which can change in morphology due to treatment effects and/or secondary bone remodeling. Hence, morphological imaging is regarded unsuitable for response assessment of bone metastases and in the current Response Evaluation Criteria In Solid Tumors 1.1 (RECIST1.1) guideline bone metastases are deemed unmeasurable. Nevertheless, the advent of functional and molecular imaging modalities such as whole-body magnetic resonance imaging (WB-MRI) and positron emission tomography (PET) has improved the ability for follow-up of bone metastases, regardless of their morphology. Both these modalities not only have improved sensitivity for visual detection of bone lesions, but also allow for objective measurements of bone lesion characteristics. WB-MRI provides a global assessment of skeletal metastases and for a one-step “all-organ” approach of metastatic disease. Novel MRI techniques include diffusion-weighted imaging (DWI) targeting highly cellular lesions, dynamic contrast-enhanced MRI (DCE-MRI) for quantitative assessment of bone lesion vascularization, and multiparametric MRI (mpMRI) combining anatomical and functional sequences. Recommendations for a homogenization of MRI image acquisitions and generalizable response criteria have been developed. For PET, many metabolic and molecular radiotracers are available, some targeting tumor characteristics not confined to cancer type (e.g. 18F-FDG) while other targeted radiotracers target specific molecular characteristics, such as prostate specific membrane antigen (PSMA) ligands for prostate cancer. Supporting data on quantitative PET analysis regarding repeatability, reproducibility, and harmonization of PET/CT system performance is available. Bone metastases detected on PET and MRI can be quantitatively assessed using validated methodologies, both on a whole-body and individual lesion basis. Both have the advantage of covering not only bone lesions but visceral and nodal lesions as well. Hybrid imaging, combining PET with MRI, may provide complementary parameters on the morphologic, functional, metabolic and molecular level of bone metastases in one examination. For clinical implementation of measuring bone metastases in response assessment using WB-MRI and PET, current RECIST1.1 guidelines need to be adapted. This review summarizes available data and insights into imaging of bone metastases using MRI and PET.

Background: PD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction. Patients and Methods: Tumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS). Results: Tissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008). Conclusion: Pre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate tumor blood flow (TBF) as a predictor of radiotherapy response for nasopharyngeal carcinoma (NPC). Materials and Method: A total of 134 patients were divided into two groups, the complete response (CR) group and the partial response (PR) group based on RECIST 1.1 recommendations. The statistical difference was evaluated for pre- and mid- or post-treatment TBF and changes of TBF for tumors and metastatic lymph nodes between CR and PR, respectively. The receiver operation characteristic (ROC) curve was utilized to evaluate the accuracy of TBF in predicting the response of radiation therapy. The association between TBF and SUVmax was also investigated. Results: The reduction of TBF in CR was significantly lower than that in PR for primary tumors (P < 0.001) and metastatic lymph nodes (P < 0.001). The multivariate logistic regression analysis indicated that the reduction of TBF is an independent predictor of the response of radiation therapy for primary tumors (P < 0.001) and metastatic lymph nodes (P < 0.001). The accuracy of TBF reduction in predicting the response of radiation therapy was 0.817 in primary tumors and 0.924 in metastatic lymph nodes, respectively. No significant correlation was observed between the TBF values and SUVmax of primary tumors (r = -0.008, P = 0.954) and metastasis lymph nodes (r = -0.061, P = 0.652). Conclusion: This study suggests that the reduction of TBF is a promising parameter for evaluating the response of radiation therapy. [ABSTRACT FROM AUTHOR]

BackgroundPD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction.Patients and MethodsTumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS).ResultsTissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008).ConclusionPre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use.

PurposeThe aim of this study was to evaluate tumor blood flow (TBF) as a predictor of radiotherapy response for nasopharyngeal carcinoma (NPC).Materials and MethodA total of 134 patients were divided into two groups, the complete response (CR) group and the partial response (PR) group based on RECIST 1.1 recommendations. The statistical difference was evaluated for pre- and mid- or post-treatment TBF and changes of TBF for tumors and metastatic lymph nodes between CR and PR, respectively. The receiver operation characteristic (ROC) curve was utilized to evaluate the accuracy of TBF in predicting the response of radiation therapy. The association between TBF and SUVmax was also investigated.ResultsThe reduction of TBF in CR was significantly lower than that in PR for primary tumors (P

BackgroundGiven the controversial roles of FMS-like tyrosine kinase 3 inhibitors (FLT3i) in various treatment stages of acute myeloid leukemia (AML), this study was designed to assess this problem and further explored which FLT3i worked more effectively.MethodsA systematic review, meta-analysis and network meta-analysis (NMA) were conducted by filtering PubMed, Embase, Cochrane library, and Chinese databases. We included studies comparing therapeutic effects between FLT3i and non-FLT3i group in AML, particularly FLT3(+) patients, or demonstrating the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in FLT3(+) AML. Relative risk (RR) with 95% confidence intervals (CI) was used for estimating complete remission (CR), early death and toxicity. Hazard ratio (HR) was used to assess overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR).ResultsAfter addressing all criteria, 39 studies were eventually analyzed. Better CR was accomplished by FLT3i in untreated AML (RR 0.88, p = 0.04) and refractory and relapsed FLT3(+) AML (rrAML) (RR 0.61, p < 0.01) compared to non-FLT3i arm, followed by improved survival (untreated AML: OS, HR 0.76; EFS, HR 0.67; RFS, HR 0.72; all p < 0.01; FLT3(+) rrAML: OS, HR 0.60, p < 0.01; RFS, HR 0.40, p = 0.01). In addition, allo-HSCT improved survival in FLT3(+) AML (OS, HR 0.53; EFS, HR 0.50; RFS, HR 0.57; CIR, HR 0.26; all p < 0.01), which was further prolonged by FLT3i administrated after allo-HSCT (OS, HR 0.45; RFS, HR 0.34; CIR, HR 0.32; all p < 0.01). Additionally, FLT3i consistently improved OS (p < 0.05) regardless of FLT3-ITD ratio, when compared to non-FLT3i group. Besides, FLT3i showed significantly increased risk of thrombocytopenia, neutropenia, anemia, skin- and cardiac-related adverse effects, increased alanine aminotransferase, and increased risk of cough and dyspnea (p < 0.05). In NMA, gilteritinib showed the highest probability for improved prognosis.ConclusionsFLT3i safely improved prognosis in induction/reinduction stage of FLT3(+) AML and further boosted survival benefits from allo-HSCT as maintenance therapy, suggesting better prognosis if FLT3i is combined before and after allo-HSCT. In NMA, gilteritinib potentially achieved the best prognosis, which should be identified in direct trials.

Background: Given the controversial roles of FMS-like tyrosine kinase 3 inhibitors (FLT3i) in various treatment stages of acute myeloid leukemia (AML), this study was designed to assess this problem and further explored which FLT3i worked more effectively. Methods: A systematic review, meta-analysis and network meta-analysis (NMA) were conducted by filtering PubMed, Embase, Cochrane library, and Chinese databases. We included studies comparing therapeutic effects between FLT3i and non-FLT3i group in AML, particularly FLT3 (+) patients, or demonstrating the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in FLT3 (+) AML. Relative risk (RR) with 95% confidence intervals (CI) was used for estimating complete remission (CR), early death and toxicity. Hazard ratio (HR) was used to assess overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR). Results: After addressing all criteria, 39 studies were eventually analyzed. Better CR was accomplished by FLT3i in untreated AML (RR 0.88, p = 0.04) and refractory and relapsed FLT3 (+) AML (rrAML) (RR 0.61, p < 0.01) compared to non-FLT3i arm, followed by improved survival (untreated AML: OS, HR 0.76; EFS, HR 0.67; RFS, HR 0.72; all p < 0.01; FLT3 (+) rrAML: OS, HR 0.60, p < 0.01; RFS, HR 0.40, p = 0.01). In addition, allo-HSCT improved survival in FLT3 (+) AML (OS, HR 0.53; EFS, HR 0.50; RFS, HR 0.57; CIR, HR 0.26; all p < 0.01), which was further prolonged by FLT3i administrated after allo-HSCT (OS, HR 0.45; RFS, HR 0.34; CIR, HR 0.32; all p < 0.01). Additionally, FLT3i consistently improved OS (p < 0.05) regardless of FLT3-ITD ratio, when compared to non-FLT3i group. Besides, FLT3i showed significantly increased risk of thrombocytopenia, neutropenia, anemia, skin- and cardiac-related adverse effects, increased alanine aminotransferase, and increased risk of cough and dyspnea (p < 0.05). In NMA, gilteritinib showed the highest probability for improved prognosis. Conclusions: FLT3i safely improved prognosis in induction/reinduction stage of FLT3 (+) AML and further boosted survival benefits from allo-HSCT as maintenance therapy, suggesting better prognosis if FLT3i is combined before and after allo-HSCT. In NMA, gilteritinib potentially achieved the best prognosis, which should be identified in direct trials. [ABSTRACT FROM AUTHOR]

IntroductionTumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. However, the prevalence of hypoxia has not been fully evaluated in colorectal liver metastases, and hypoxic response to anti-angiogenic therapy has not been clearly established. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis.MethodsPatients with metastatic colorectal carcinoma planned for treatment with bevacizumab and chemotherapy received routine staging investigations prior to any treatment, including a FDG PET scan. A FMISO PET scan was performed within 4 weeks of staging tests, with blood specimens collected at that time for serum VEGF and osteopontin measurement. Follow-up FDG and FMISO scans were performed after 1 cycle of treatment. Results were compared to response (RECIST), progression free survival (PFS), and overall survival (OS).ResultsA total of 15 patients were recruited into this prospective trial, of which 13 patients were evaluable for assessment of treatment follow-up. Baseline FDG uptake was higher than FMISO uptake, and there was a significant decrease in FDG uptake (SUVmax and TGV) but not FMISO uptake (SUVmax and TNR) after treatment. There was a positive correlation between FDG and FMISO SUVmax on both baseline and post-treatment PET scans. Blood biomarkers of serum VEGF and osteopontin were significantly correlated with the FDG and FMISO PET parameters.ConclusionsThis study shows that hypoxia in metastatic colorectal cancer, assessed by FMISO PET, shows minor changes following initial treatment with anti-angiogenic therapy, but is associated with therapeutic response. FDG PET uptake changes (SUVmax, TLG) are also associated with response to anti-angiogenic therapy. These findings demonstrate the interplay between tumor metabolism and hypoxic regulation following anti-angiogenic treatment of metastatic colorectal cancer.

Introduction: Tumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. However, the prevalence of hypoxia has not been fully evaluated in colorectal liver metastases, and hypoxic response to anti-angiogenic therapy has not been clearly established. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis. Methods: Patients with metastatic colorectal carcinoma planned for treatment with bevacizumab and chemotherapy received routine staging investigations prior to any treatment, including a FDG PET scan. A FMISO PET scan was performed within 4 weeks of staging tests, with blood specimens collected at that time for serum VEGF and osteopontin measurement. Follow-up FDG and FMISO scans were performed after 1 cycle of treatment. Results were compared to response (RECIST), progression free survival (PFS), and overall survival (OS). Results: A total of 15 patients were recruited into this prospective trial, of which 13 patients were evaluable for assessment of treatment follow-up. Baseline FDG uptake was higher than FMISO uptake, and there was a significant decrease in FDG uptake (SUVmax and TGV) but not FMISO uptake (SUVmax and TNR) after treatment. There was a positive correlation between FDG and FMISO SUVmax on both baseline and post-treatment PET scans. Blood biomarkers of serum VEGF and osteopontin were significantly correlated with the FDG and FMISO PET parameters. Conclusions: This study shows that hypoxia in metastatic colorectal cancer, assessed by FMISO PET, shows minor changes following initial treatment with anti-angiogenic therapy, but is associated with therapeutic response. FDG PET uptake changes (SUVmax, TLG) are also associated with response to anti-angiogenic therapy. These findings demonstrate the interplay between tumor metabolism and hypoxic regulation following anti-angiogenic treatment of metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

BackgroundInduction chemotherapy (IC) significantly improves the rate of larynx preservation; however, some patients could not benefit from it. Hence, it is of clinical importance to predict the response to IC to determine the necessity of IC. We aimed to develop a clinical nomogram for predicting the treatment response to IC in locally advanced hypopharyngeal carcinoma.MethodsWe retrospectively include a total of 127 patients with locally advanced hypopharyngeal carcinoma who underwent MRI scans prior to IC between January 2014 and December 2017. The clinical characteristics were collected, which included age, sex, tumor location, invading sites, histological grades, T-stage, N-stage, overall stage, size of the largest lymph node, neutrophil-to-lymphocyte ratio, hemoglobin concentration, and platelet count. Univariate and multivariate logistic regression was used to select the significant predictors of IC response. A nomogram was built based on the results of stepwise logistic regression analysis. The predictive performance and clinical usefulness of the nomogram were determined based on the area under the curve (AUC), calibration curve, and decision curve.ResultsAge, T-stage, hemoglobin, and platelet were four independent predictors of IC treatment response, which were incorporated into the nomogram. The AUC of the nomogram was 0.860 (95% confidence interval [CI]: 0.780-0.940), which was validated using 3-fold cross-validation (AUC, 0.864; 95% CI: 0.755-0.973). The calibration curve demonstrated good consistency between the prediction by the nomogram and actual observation. Decision curve analysis shows that the nomogram was clinically useful.ConclusionThe proposed nomogram resulted in an accurate prediction of the efficacy of IC for patients with locally advanced hypopharyngeal carcinoma.

This retrospective analysis was conducted to evaluate the feasibility and safety of high-intensity focused ultrasound ablation for primary liver cancer and metastatic liver cancer. Patients with liver cancer who received high-intensity focused ultrasound were included in this analysis, including a primary liver cancer cohort (n=80) and a metastatic liver cancer cohort (n=195). The primary endpoint of our research was tumor response. The secondary endpoints included survival outcomes, visual analog scale pain scores, alpha-fetoprotein relief, and complications. Objective response rate and disease control rate were observed to be 71.8% and 81.2%, respectively, in patients with primary liver cancer and were 63.7% and 83.2% in cases with metastatic liver cancer. Alpha-fetoprotein levels and visual analogue scale levels significantly decreased after treatment compared with the baseline levels in patients with primary liver cancer (p

Purpose: The aim of this study was to explore a radiomics-clinical model for predicting the response to initial superselective arterial embolization (SAE) in renal angiomyolipoma (RAML)., Materials and Methods: A total of 78 patients with RAML were retrospectively enrolled. Clinical data were recorded and evaluated. Radiomic features were extracted from preoperative contrast-enhanced CT (CECT). Least absolute shrinkage and selection operator (LASSO) and intra- and inter-class correlation coefficients (ICCs) were used in feature selection. Logistic regression analysis was performed to develop the radiomics, clinical, and combined models where the fivefold cross-validation method was used. The predictive performance and calibration were evaluated by the receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was used to measure clinical usefulness., Results: The tumor shrinkage rate was 29.7% in total, and both fat and angiomyogenic components were significantly reduced. In the radiomics model, 12 significant features were selected. In the clinical model, maximum diameter ( p = 0.001), angiomyogenic tissue ratio ( p = 0.032), aneurysms ( p = 0.048), and post-SAE time ( p = 0.002) were significantly associated with greater volume reduction after SAE. Because of the severe linear dependence between radiomics signature and some clinical parameters, the combined model eventually included Rad-score, aneurysm, and post-SAE time. The radiomics-clinical model showed better discrimination (mean AUC = 0.83) than the radiomics model (mean AUC = 0.60) and the clinical model (mean AUC = 0.82). Calibration curve and DCA showed the goodness of fit and clinical usefulness of the radiomics-clinical model., Conclusions: The radiomics-clinical model incorporating radiomics features and clinical parameters can potentially predict the positive response to initial SAE in RAML and provide support for clinical treatment decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GC declared a shared parent affiliation with the author(s) to the handling editor at the time of review., (Copyright © 2024 Zechuan, Tianshi, Tiantian, Shoujin, Hang, Ziping, Haitao, Zeyang, Yinghua and Jian.)

Background: Induction chemotherapy (IC) significantly improves the rate of larynx preservation; however, some patients could not benefit from it. Hence, it is of clinical importance to predict the response to IC to determine the necessity of IC. We aimed to develop a clinical nomogram for predicting the treatment response to IC in locally advanced hypopharyngeal carcinoma. Methods: We retrospectively include a total of 127 patients with locally advanced hypopharyngeal carcinoma who underwent MRI scans prior to IC between January 2014 and December 2017. The clinical characteristics were collected, which included age, sex, tumor location, invading sites, histological grades, T-stage, N-stage, overall stage, size of the largest lymph node, neutrophil-to-lymphocyte ratio, hemoglobin concentration, and platelet count. Univariate and multivariate logistic regression was used to select the significant predictors of IC response. A nomogram was built based on the results of stepwise logistic regression analysis. The predictive performance and clinical usefulness of the nomogram were determined based on the area under the curve (AUC), calibration curve, and decision curve. Results: Age, T-stage, hemoglobin, and platelet were four independent predictors of IC treatment response, which were incorporated into the nomogram. The AUC of the nomogram was 0.860 (95% confidence interval [CI]: 0.780-0.940), which was validated using 3-fold cross-validation (AUC, 0.864; 95% CI: 0.755-0.973). The calibration curve demonstrated good consistency between the prediction by the nomogram and actual observation. Decision curve analysis shows that the nomogram was clinically useful. Conclusion: The proposed nomogram resulted in an accurate prediction of the efficacy of IC for patients with locally advanced hypopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

This retrospective analysis was conducted to evaluate the feasibility and safety of high-intensity focused ultrasound ablation for primary liver cancer and metastatic liver cancer. Patients with liver cancer who received high-intensity focused ultrasound were included in this analysis, including a primary liver cancer cohort (n =80) and a metastatic liver cancer cohort (n =195). The primary endpoint of our research was tumor response. The secondary endpoints included survival outcomes, visual analog scale pain scores, alpha-fetoprotein relief, and complications. Objective response rate and disease control rate were observed to be 71.8% and 81.2%, respectively, in patients with primary liver cancer and were 63.7% and 83.2% in cases with metastatic liver cancer. Alpha-fetoprotein levels and visual analogue scale levels significantly decreased after treatment compared with the baseline levels in patients with primary liver cancer (p <0.05). Median overall survival was estimated to be 13.0 and 12.0 months in the primary liver cancer and metastatic liver cancer cohorts. The 1-year survival rate was 70.69% and 48.00%, respectively. Multivariate regression analysis showed that visual analogue scale ≥ 5, longest diameter ≥ 5 cm, and portal vein invasion were the independent risk factors for poor survival in primary liver cancer. For patients with metastatic liver cancer, independent risk factors were identified as visual analogue scale ≥ 5, longest diameter ≥ 5 cm, existence of extrahepatic metastases, existence of portal vein invasion, and time to high-intensity focused ultrasound treatment from diagnosis < 3 months. Severe adverse events were rarely reported. In conclusion, high-intensity focused ultrasound might be an effective and safe option for patients with liver cancer regardless of primary and metastatic lesions. [ABSTRACT FROM AUTHOR]

When evaluating metastatic tumor response to systemic therapies, dissociated response is defined as the coexistence of responding and non-responding lesions within the same patient. Although commonly observed on interim whole-body imaging, the current response criteria in solid cancer do not consider this evolutive pattern, which is, by default, assimilated to progression. With targeted therapies and chemotherapies, dissociated response is observed with different frequencies, depending on the primary cancer type, treatment, and imaging modality. Because FDG PET/CT can easily assess response on a lesion-by-lesion basis, thus quickly revealing response heterogeneity, a PET/CT dissociated response has been described in up to 48% of women treated for a metastatic breast cancer. Although some studies have underlined a specific prognostic of dissociated response, it has always ended up being described as an unfavorable prognostic pattern and therefore assimilated to the “Progressive Disease” category of RECIST/PERCIST. This dichotomous imaging report (response vs. progression) provides a simple information for clinical decision-support, which probably explains the relatively low consideration for the dissociated response pattern to chemotherapies and targeted therapies until now. With immune checkpoint inhibitors, this paradigm is quickly changing. Dissociated response is observed in around 10% of advanced lung cancer patients and appears to be associated to treatment efficiency. Indeed, for this subset of patients, a clinical benefit of immunotherapy and favorable prognosis are usually observed. This specific pattern should therefore be considered in the future immunotherapy-adapted criteria for response evaluation using CT and PET/CT, and specific clinical managements should be evaluated for this response pattern.

Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, ke, among patients who achieved favorable responses (N = 64) than those for patients who suffered unfavorable response (N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28–3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher (P = 0.01) and its P/T ratio was significantly lower (P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response (P = 0.01), lower Cl, Ke and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher Css. The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response (P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients.

Introduction: Patients with locally advanced rectal cancer (LARC) are undergoing neoadjuvant chemoradiotherapy (NCRT) prior to surgery. Although in some patients the NCRT is known to prevent local recurrence, it is also accompanied by side effects. Accordingly, there is an unmet need to identify predictive markers allowing to identify non-responders to avoid its adverse effects. We monitored circulating tumor DNA (ctDNA) as a potential liquid biopsy-based biomarker. We have investigated ctDNA changes plasma during the early days of NCRT and its relationship to the overall therapy outcome.Methods and Patients: The studied cohort included 36 LARC patients (stage II or III) undergoing NCRT with subsequent surgical treatment. We have detected somatic mutations in tissue biopsies taken during endoscopic examination prior to the therapy. CtDNA was extracted from patient plasma samples prior to therapy and at the end of the first week. In order to optimize the analytical costs of liquid-biopsy testing, we have utilized a two-level approach in which first a low-cost detection method of denaturing capillary electrophoresis was used followed by examination of initially negative samples by a high-sensitivity BEAMING assay. The ctDNA was related to clinical parameters including tumor regression grade (TRG) and TNM tumor staging.Results: We have detected a somatic mutation in 33 out of 36 patients (91.7%). Seven patients (7/33, 21.2%) had ctDNA present prior to therapy. The ctDNA positivity before treatment reduced post-operative disease-free survival and overall survival by an average of 1.47 and 1.41 years, respectively (p = 0.015, and p = 0.010). In all patients, ctDNA was strongly reduced or completely eliminated from plasma by the end of the first week of NCRT, with no correlation to any of the parameters analyzed.Conclusions: The baseline ctDNA presence represented a statistically significant negative prognostic biomarker for the overall patient survival. As ctDNA was reduced indiscriminately from circulation of all patients, dynamics during the first week of NCRT is not suited for predicting the outcome of LARC. However, the general effect of rapid ctDNA disappearance apparently occurring during the initial days of NCRT is noteworthy and should further be studied.

When evaluating metastatic tumor response to systemic therapies, dissociated response is defined as the coexistence of responding and non-responding lesions within the same patient. Although commonly observed on interim whole-body imaging, the current response criteria in solid cancer do not consider this evolutive pattern, which is, by default, assimilated to progression. With targeted therapies and chemotherapies, dissociated response is observed with different frequencies, depending on the primary cancer type, treatment, and imaging modality. Because FDG PET/CT can easily assess response on a lesion-by-lesion basis, thus quickly revealing response heterogeneity, a PET/CT dissociated response has been described in up to 48% of women treated for a metastatic breast cancer. Although some studies have underlined a specific prognostic of dissociated response, it has always ended up being described as an unfavorable prognostic pattern and therefore assimilated to the "Progressive Disease" category of RECIST/PERCIST. This dichotomous imaging report (response vs. progression) provides a simple information for clinical decision-support, which probably explains the relatively low consideration for the dissociated response pattern to chemotherapies and targeted therapies until now. With immune checkpoint inhibitors, this paradigm is quickly changing. Dissociated response is observed in around 10% of advanced lung cancer patients and appears to be associated to treatment efficiency. Indeed, for this subset of patients, a clinical benefit of immunotherapy and favorable prognosis are usually observed. This specific pattern should therefore be considered in the future immunotherapy-adapted criteria for response evaluation using CT and PET/CT, and specific clinical managements should be evaluated for this response pattern. [ABSTRACT FROM AUTHOR]

Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, ke, among patients who achieved favorable responses (N = 64) than those for patients who suffered unfavorable response (N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28–3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher (P = 0.01) and its P/T ratio was significantly lower (P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response (P = 0.01), lower Cl, Ke and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher Css. The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response (P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients. [ABSTRACT FROM AUTHOR]

Introduction: Patients with locally advanced rectal cancer (LARC) are undergoing neoadjuvant chemoradiotherapy (NCRT) prior to surgery. Although in some patients the NCRT is known to prevent local recurrence, it is also accompanied by side effects. Accordingly, there is an unmet need to identify predictive markers allowing to identify non-responders to avoid its adverse effects. We monitored circulating tumor DNA (ctDNA) as a potential liquid biopsy-based biomarker. We have investigated ctDNA changes plasma during the early days of NCRT and its relationship to the overall therapy outcome. Methods and Patients: The studied cohort included 36 LARC patients (stage II or III) undergoing NCRT with subsequent surgical treatment. We have detected somatic mutations in tissue biopsies taken during endoscopic examination prior to the therapy. CtDNA was extracted from patient plasma samples prior to therapy and at the end of the first week. In order to optimize the analytical costs of liquid-biopsy testing, we have utilized a two-level approach in which first a low-cost detection method of denaturing capillary electrophoresis was used followed by examination of initially negative samples by a high-sensitivity BEAMING assay. The ctDNA was related to clinical parameters including tumor regression grade (TRG) and TNM tumor staging. Results: We have detected a somatic mutation in 33 out of 36 patients (91.7%). Seven patients (7/33, 21.2%) had ctDNA present prior to therapy. The ctDNA positivity before treatment reduced post-operative disease-free survival and overall survival by an average of 1.47 and 1.41 years, respectively (p = 0.015, and p = 0.010). In all patients, ctDNA was strongly reduced or completely eliminated from plasma by the end of the first week of NCRT, with no correlation to any of the parameters analyzed. Conclusions: The baseline ctDNA presence represented a statistically significant negative prognostic biomarker for the overall patient survival. As ctDNA was reduced indiscriminately from circulation of all patients, dynamics during the first week of NCRT is not suited for predicting the outcome of LARC. However, the general effect of rapid ctDNA disappearance apparently occurring during the initial days of NCRT is noteworthy and should further be studied. [ABSTRACT FROM AUTHOR]

Circulating proteins hold a potential benefit as biomarkers for precision medicine. Previously, we showed that systemic levels of neuropilin-1 (NRP-1) and its associated molecules correlated with poor-prognosis breast cancer. To further identify the role of NRP-1 and its interacting molecules in correspondence with patients' response to neoadjuvant chemotherapy (NAC), we conducted a comparative study on blood and tissue samples collected from a cohort of locally advanced breast cancer patients, before and after neoadjuvant chemotherapy (NAC). From a panel of tested proteins and genes, we found that the levels of plasma NRP-1, placenta growth factor (PlGF) and immune cell expression of the transcription factor SNAI1 before and after NAC were significantly different. Paired t-test analysis of 22 locally advanced breast cancer patients showed that plasma NRP-1 levels were increased significantly (p = 0.018) post-NAC in patients with pathological partial response (pPR). Kaplan–Meier analysis indicated that patients who received NAC cycles and their excised tumors remained with high levels of NRP-1 had a lower overall survival compared with patients whose tissue NRP-1 decreased post-NAC (log-rank p = 0.049). In vitro validation of the former result showed an increase in the secreted and cellular NRP-1 levels in resistant MDA-MB-231 cells to the most common NAC regimen Adriyamicin/cyclophosphamide+Paclitaxel (AC+PAC). In addition, NRP-1 knockdown in MDA-MB-231 cells sensitized the cells to AC and more profoundly to PAC treatment and the cells sensitivity was proportional to the expressed levels of NRP-1. Unlike NRP-1, circulating PlGF was significantly increased (p = 0.014) in patients with a pathological complete response (pCR). SNAI1 expression in immune cells showed a significant increase (p = 0.018) in patients with pCR, consistent with its posited protective role. We conclude that increased plasma and tissue NRP-1 post-NAC correlate with pPR and shorter overall survival, respectively. These observations support the need to consider anti-NRP-1 as a potential targeted therapy for breast cancer patients who are identified with high NRP-1 levels. Meanwhile, the increase in both PlGF and SNAI1 in pCR patients potentially suggests their antitumorigenic role in breast cancer that paves the way for further mechanistic investigation to validate their role as potential predictive markers for pCR in breast cancer.

Circulating proteins hold a potential benefit as biomarkers for precision medicine. Previously, we showed that systemic levels of neuropilin-1 (NRP-1) and its associated molecules correlated with poor-prognosis breast cancer. To further identify the role of NRP-1 and its interacting molecules in correspondence with patients' response to neoadjuvant chemotherapy (NAC), we conducted a comparative study on blood and tissue samples collected from a cohort of locally advanced breast cancer patients, before and after neoadjuvant chemotherapy (NAC). From a panel of tested proteins and genes, we found that the levels of plasma NRP-1, placenta growth factor (PlGF) and immune cell expression of the transcription factor SNAI1 before and after NAC were significantly different. Paired t -test analysis of 22 locally advanced breast cancer patients showed that plasma NRP-1 levels were increased significantly (p = 0.018) post-NAC in patients with pathological partial response (pPR). Kaplan–Meier analysis indicated that patients who received NAC cycles and their excised tumors remained with high levels of NRP-1 had a lower overall survival compared with patients whose tissue NRP-1 decreased post-NAC (log-rank p = 0.049). In vitro validation of the former result showed an increase in the secreted and cellular NRP-1 levels in resistant MDA-MB-231 cells to the most common NAC regimen Adriyamicin/cyclophosphamide+Paclitaxel (AC+PAC). In addition, NRP-1 knockdown in MDA-MB-231 cells sensitized the cells to AC and more profoundly to PAC treatment and the cells sensitivity was proportional to the expressed levels of NRP-1. Unlike NRP-1, circulating PlGF was significantly increased (p = 0.014) in patients with a pathological complete response (pCR). SNAI1 expression in immune cells showed a significant increase (p = 0.018) in patients with pCR, consistent with its posited protective role. We conclude that increased plasma and tissue NRP-1 post-NAC correlate with pPR and shorter overall survival, respectively. These observations support the need to consider anti-NRP-1 as a potential targeted therapy for breast cancer patients who are identified with high NRP-1 levels. Meanwhile, the increase in both PlGF and SNAI1 in pCR patients potentially suggests their antitumorigenic role in breast cancer that paves the way for further mechanistic investigation to validate their role as potential predictive markers for pCR in breast cancer. [ABSTRACT FROM AUTHOR]

Recent years have seen cancer emerge as one of the leading cause of mortality worldwide with breast cancer being the second most common cause of death among women. Individuals harboring BRCA mutations are at a higher risk of developing breast and/or ovarian cancers. This risk is much greater in the presence of germline mutations. BRCA1 and BRCA2 play crucial role in the DNA damage response and repair pathway, a function that is critical in preserving the integrity of the genome. Mutations that interfere with normal cellular function of BRCA not only lead to onset and progression of cancer but also modulate therapy outcome of treatment with platinum drugs. In this review, we discuss the structural and functional impact of some of the prevalent BRCA mutations in breast and ovarian cancers and their role in platinum therapy response. Understanding the response of platinum drugs in the context of BRCA mutations may contribute toward developing better therapeutics that can improve survival and quality of life of patients.

Cancer immunotherapies targeting immune checkpoint pathways, such as programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), have achieved unprecedented therapeutic success in treating various types of cancer. The prominent and persistent clinical responses to immune checkpoint blockade (ICB) therapy are currently constrained to a subset of patients. Owing to discrete individual tumor and immune heterogeneity, most patients fail to benefit from ICB treatment, demonstrating either primary or acquired resistance. A thorough comprehension of the mechanisms restricting the efficacy of immune checkpoint inhibitors (ICIs) is required to extend their clinical applicability to a broader spectrum of patients and cancer types. Numerous studies are presently investigating potential prognostic markers of responsiveness, the complex dynamics underlying the therapeutic and adverse effects of ICB, and tumor immune evasion throughout the course of immunotherapy. In this article, we have reviewed the extant literature elucidating the mechanisms underlying the response and resistance to ICB, with a particular emphasis on PD-1 and CTLA-4 pathway blockade in the context of anti-tumor immunity. Furthermore, we aimed to explore potential approaches to overcome cancer therapeutic resistance and develop a rational design for more personalized ICB-based combinational regimens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee and Kim.)

Recent years have seen cancer emerge as one of the leading cause of mortality worldwide with breast cancer being the second most common cause of death among women. Individuals harboring BRCA mutations are at a higher risk of developing breast and/ or ovarian cancers. This risk is much greater in the presence of germline mutations. BRCA1 and BRCA2 play crucial role in the DNA damage response and repair pathway, a function that is critical in preserving the integrity of the genome. Mutations that interfere with normal cellular function of BRCA not only lead to onset and progression of cancer but also modulate therapy outcome of treatment with platinum drugs. In this review, we discuss the structural and functional impact of some of the prevalent BRCA mutations in breast and ovarian cancers and their role in platinum therapy response. Understanding the response of platinum drugs in the context of BRCA mutations may contribute toward developing better therapeutics that can improve survival and quality of life of patients. [ABSTRACT FROM AUTHOR]

Introduction: As the top 3 cancer in terms of incidence and mortality, the first-line treatment for CRC includes FOLFOX, FOLFIRI, Cetuximab or immunotherapy. However, the drug sensitivity of patients to regimens is different. There has been increasing evidence that immune components of TME can affect the sensitivity of patients to drugs. Therefore, it is necessary to define novo molecular subtypes of CRC based on TME immune components, and screen patients who are sensitive to the treatments, to make personalized therapy possible., Methods: We analyzed the expression profiles and 197 TME-related signatures of 1775 patients using ssGSEA, univariate Cox proportional risk model and LASSO-Cox regression model, and defined a novo molecular subtype (TMERSS) of CRC. Simultaneously, we compared the clinicopathological factors, antitumor immune activity, immune cell abundance and differences of cell states in different TMERSS subtypes. In addition, patients sensitive to the therapy were screened out by correlation analysis between TMERSS subtypes and drug responses., Results: Compared with low TMERSS subtype, high TMERSS subtype has a better outcome, which may be associated to higher abundance of antitumor immune cell in high TMERSS subtype. Our findings suggested that the high TMERSS subtype may have a higher proportion of respondents to Cetuximab agent and immunotherapy, while the low TMERSS subtype may be more suitable for treatment with FOLFOX and FOLFIRI regimens., Discussion: In conclusion, the TMERSS model may provide a partial reference for the prognosis evaluation of patients, the prediction of drug sensitivity, and the implementation of clinical decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jun, Gao, Yu and Wang.)

Aim: In this study, we aimed to compare the diagnostic values of MRI and FDG-PET for the prediction of the response to neoadjuvant chemoradiotherapy (NACT) of patients with locally advanced Rectal cancer (RC)., Methods: Electronic databases, including PubMed, Embase, and the Cochrane library, were systematically searched through December 2021 for studies that investigated the diagnostic value of MRI and FDG-PET in the prediction of the response of patients with locally advanced RC to NACT. The quality of the included studies was assessed using QUADAS. The pooled sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), and the area under the ROC (AUC) of MRI and FDG-PET were calculated using a bivariate generalized linear mixed model, random-effects model, and hierarchical regression., Results: A total number of 74 studies with recruited 4,105 locally advanced RC patients were included in this analysis. The pooled sensitivity, specificity, PLR, NLR, and AUC for MRI were 0.83 (95% CI: 0.77-0.88), 0.85 (95% CI: 0.79-0.89), 5.50 (95% CI: 4.11-7.35), 0.20 (95% CI: 0.14-0.27), and 0.91 (95% CI: 0.88-0.93), respectively. The summary sensitivity, specificity, PLR, NLR and AUC for FDG-PET were 0.81 (95% CI: 0.77-0.85), 0.75 (95% CI: 0.70-0.80), 3.29 (95% CI: 2.64-4.10), 0.25 (95% CI: 0.20-0.31), and 0.85 (95% CI: 0.82-0.88), respectively. Moreover, there were no significant differences between MRI and FDG-PET in sensitivity ( P = 0.565), and NLR ( P = 0.268), while the specificity ( P = 0.006), PLR ( P = 0.006), and AUC ( P = 0.003) of MRI was higher than FDG-PET., Conclusions: MRI might superior than FGD-PET for the prediction of the response of patients with locally advanced RC to NACT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Lu and Liu.)