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We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3–4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229–0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation. • Efficacy and safety of chemotherapy plus durvalumab with or without tremelimumab were studied in PROC without HRR mutation. • Addition of tremelimumab improved progression-free survival on multivariable Cox HR analysis. • Biomarkers were explored with immunohistochemistry and whole-exome and transcriptome sequencing. • Mutation in MUC16 and high EPCAM were associated with favorable response in the overall cohort. • Arm-specific biomarker in tremelimumab group were EPCAM expression and matrix remodeling score. [ABSTRACT FROM AUTHOR]

Objectives: AMBITION is a multi-center, open-label, five-arm, uncontrolled, umbrella trial in platinum-resistant ovarian cancer patients (NCT03699449). Here, we present an exploratory analysis of clinical and molecular characteristics associated with the benefit of two olaparib-based regimens in the homologous recombination repair (HRR) gene mutation cohort. Methods: Between December 2018 and October 2020, 30 patients who had mutations in HRR genes were randomized, and received either olaparib 200mg bid + cediranib 30mg QD (arm 1; n =16) or olaparib 300mg bid + durvalumab 1500mg q4w (arm 2; n =14). From the pre-treatment biopsy (n =22) and archival (n =8) tumor samples, next-generation whole-exome and whole-transcriptomic sequencing were conducted. We also evaluated tumor immunologic signatures, including the PD-L1 (SP263) assay and tumor-infiltrating lymphocytes (TILs). Clinical and molecular features were compared between responders and non-responders. Results: Arms 1 and 2 showed an acceptable objective response rate at 50.0% and 42.9%, respectively. The responders (n =14) had 12.4 months of a median duration of response. Overall, no differences in serum CA-125 levels, ECOG performance status, histologic subtype, prior lines of therapy, and last treatment-free interval were observed between the responders and non-responders. Intratumoral TILs and stromal TILs were also similar between the responders and non-responders. While all responders had BRCA1/2 mutations, 54.5% of non-responders had BRCA1/2 mutations. DNA damage repair pathways were enriched in the responders. Especially, enrichment of DNA mismatch repair and nucleotide excision repair pathways were associated with prolonged progression-free survival (PFS). In arm 1, cell cycle pathway enrichment significantly improved PFS (p =0.006), but PD-L1 expression did not. In arm 2, patients with PD-L1 ≥1% of tumor cells showed significantly better PFS than those with PD-L1 <1% (p =0.027), and the responders had a significantly higher level of myeloid-derived suppressor cell recruiting score than the non-responders (p =0.041). Conclusions: Responders in the randomly assigned arms 1 and 2 of AMBITION showed distinct molecular features. Based on integrative molecular analyses, pre-treatment identification of responders to the olaparib doublet treatment for platinum-resistant ovarian cancer might be possible. [Display omitted] [ABSTRACT FROM AUTHOR]

Intratumor heterogeneity within individual cancer tissues underlies the numerous phenotypes of cancer. Tumor subclones ultimately affect therapeutic outcomes due to their distinct molecular features. Drug-resistant subclones are present at a low frequency in tissues at the time of biopsy, but can also arise as a result of acquired somatic mutations. A number of different approaches have been utilized to understand the nature of intratumor heterogeneity. Clonal analysis using whole exome or genome sequencing data can help monitor subclones in the context of tumor progression. Multiregional biopsies permit the molecular characterization of subclones within tumors. Deep sequencing has also provided researchers with the ability to measure the low allele fraction variant within a small number of cells. Ultimately, single-cell sequencing will enable the identification of every minor population within a tumor microenvironment. In the clinical context, the ability to identify and monitor the subclonal architecture of a tumor is valuable for the development of precise cancer therapeutic methods. [ABSTRACT FROM AUTHOR]

A single tumor biopsy specimen is typically used in cancer genome studies. However, it may represent incompletely the underlying mutational and transcriptional profiles of tumor biology. Multi-regional biopsies have the advantage of increased sensitivity for genomic profiling, but they are not cost-effective. The concept of an alternative method such as the pooling of multiple biopsies is a challenge. In order to determine if the pooling of distinct regions is representative at the genomic and transcriptome level, we performed sequencing of four regional samples and pooled samples for four cancer types including colon, stomach, kidney and liver cancer. Subsequently, a comparative analysis was conducted to explore differences in mutations and gene expression profiles between multiple regional biopsies and pooled biopsy for each tumor. Our analysis revealed a marginal level of regional difference in detected variants, but in those with low allele frequency, considerable discrepancies were observed. In conclusion, sequencing pooled samples has the benefit of detecting many variants with moderate allele frequency that occur in partial regions, but it is not applicable for detecting low-frequency mutations that require deep sequencing. [ABSTRACT FROM AUTHOR]

Summary Solanum lycopersicum (tomato) and its wild relatives harbor genetic diversity that yields heritable variation in fruit chemistry that could be exploited to identify genes regulating their synthesis and accumulation. Carotenoids, for example, are essential in plant and animal nutrition, and are the visual indicators of ripening for many fruits, including tomato. Whereas carotenoid synthesis is well characterized, factors regulating flux through the pathway are poorly understood at the molecular level. To exploit the impact of tomato genetic diversity on carotenoids, Solanum pennellii introgression lines were used as a source of defined natural variation and as a resource for the identification of candidate regulatory genes. Ripe fruits were analyzed for numerous fruit metabolites and transcriptome profiles generated using a 12 000 unigene oligoarray. Correlation analysis between carotenoid content and gene expression profiles revealed 953 carotenoid-correlated genes. To narrow the pool, subnetwork analysis of carotenoid-correlated transcription revealed 38 candidates. One candidate for impact on trans-lycopene and β-carotene accumulation was functionally charaterized, SlERF6, revealing that it indeed influences carotenoid biosynthesis and additional ripening phenotypes. Reduced expression of SlERF6 by RNAi enhanced both carotenoid and ethylene levels during fruit ripening, demonstrating an important role for SlERF6 in ripening, integrating the ethylene and carotenoid synthesis pathways. [ABSTRACT FROM AUTHOR]

Abstract: Human papillomaviruses (HPVs) are small DNA tumor viruses which infect epithelial tissues and induce hyperproliferative lesions. Infection by high-risk genital HPVs is associated with the development of anogenital cancers. Classification of risk types is important in understanding the mechanisms in infection and in developing novel instruments for medical examination such as DNA microarrays. The sequence-based classification methods are useful in classifying risk types by considering residues in conserved positions. In this paper, we present a machine learning approach to the classification of HPV risk types by using the protein sequences. Our approach is based on the hidden Markov model and the kernel method. The former searches informative subsequence positions and the latter computes efficiently to classify protein sequences. In the experiments, the classifier predicted four unknown HPV types exactly. An additional result shows that the kernel-based classifiers learned with more informative subsequences outperform the classifiers learned with the whole sequence or random subsequences. [Copyright &y& Elsevier]

Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E−06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed. [ABSTRACT FROM AUTHOR]

Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E−06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed. [ABSTRACT FROM AUTHOR]

Background: The immunogenomic changes triggered by concurrent chemoradiation therapy (CCRT), a standard neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC), are unknown. We aimed to analyze the early immunogenomic changes in ESCC induced by CCRT and to correlate them with clinical outcomes. Methods: We collected biopsy samples from 40 patients with ESCC and the surgical candidates were treated with 5-fluorouracil (5-FU)/Cisplatin and concurrent radiation therapy. Endoscopic biopsy was performed before and after one treatment cycle of 5-FU/Cisplatin and 5 to 18 fractions of radiation. We analyzed immunogenomic changes using paired whole-exome sequencing (n = 29) and paired whole-transcriptome sequencing (WTS, n = 23). Multiplex immunohistochemistry (IHC) was conducted in four representative pair samples. Results: Fourteen out of 23 WTS samples (60.8%) showed increased immune scores after CCRT, as calculated by ESTIMATE. The rate of progression-free survival was higher in patients with increased immune scores compared with the remaining patients (83.1% vs. 57.1%, p = 0.25). Tumor mutation burden and neoantigen load were significantly reduced after CCRT (p < 0.001). We observed no specific correlation with non-synonymous mutations and no changes in the single-nucleotide variant spectrum after CCRT. Post-CCRT samples were enriched in gene sets related to immune signaling pathways, such as interferon gamma signaling and CD28 co-stimulation. Multiplex IHC showed an incremental trend in the proportion of CD4 positive cells in cytokeratin positive region after CCRT. However, CD8, CD20, FOXP1, PD-L1 showed no definitive trend. Proportion of immune cells calculated by CIBERSORT, showed that significant increase in neutrophils after CCRT. Conclusions: We have comprehensively analyzed the early immunogenomic changes induced in ESCC by CCRT and correlated them with clinical outcomes. Our results provide a potential basis for combining immunotherapy with CCRT for the treatment of ESCC. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian carcinoma (HGSOC) is a fatal gynecological malignancy. Somatic recombination occurring during T-cell receptor (TCR) development results in TCR diversity, and the TCR repertoire, thus produced, is associated with immune response. This study analyzed the difference in the TCR repertoire and their prognostic significance in 51 patients with HGSOC. The patient's clinical characteristics, gene expression pattern, TCR clonotypes, and degree of tumor-infiltrating leukocytes (TILs) were analyzed, and the patients were divided into groups depending on their recurrence pattern, tumor-infiltrating leukocyte (TIL) score, and homologous recombinant repair pathway deficiency (HRD)-associated mutations. The TCR repertoire was low in patients with recurrence and showed the expansion of eight TCR segments. Interestingly, a few genes correlated with the TCRs also showed a difference in expression according to the prognosis. Among them, seven genes were related to immune responses and KIAA1199 was up-regulated in ovarian cancer. Our study shows that the differences in the TCR repertoire in patients with ovarian cancer and their associated immune pathways could affect the prognosis of HGSOC. [ABSTRACT FROM AUTHOR]

Background: Recurrent glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor that is resistant to existing treatments. Recently, we reported that activated autologous natural killer (NK) cell therapeutics induced a marked increase in survival of some patients with recurrent GBM. Methods: To identify biomarkers that predict responsiveness to NK cell therapeutics, we examined immune profiles in tumor tissues using NanoString nCounter analysis and compared the profiles between 5 responders and 7 non-responders. Through a three-step data analysis, we identified three candidate biomarkers (TNFRSF18, TNFSF4, and IL12RB2) and performed validation with qRT-PCR. We also performed immunohistochemistry and a NK cell migration assay to assess the function of these genes. Results: Responders had higher expression of many immune-signaling genes compared with non-responders, which suggests an immune-active tumor microenvironment in responders. The random forest model that identified TNFRSF18, TNFSF4, and IL12RB2 showed a 100% accuracy (95% CI 73.5–100%) for predicting the response to NK cell therapeutics. The expression levels of these three genes by qRT-PCR were highly correlated with the NanoString levels, with high Pearson's correlation coefficients (0.419 (TNFRSF18), 0.700 (TNFSF4), and 0.502 (IL12RB2)); their prediction performance also showed 100% accuracy (95% CI 73.54–100%) by logistic regression modeling. We also demonstrated that these genes were related to cytotoxic T cell infiltration and NK cell migration in the tumor microenvironment. Conclusion: We identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor. [ABSTRACT FROM AUTHOR]

The risk of chromosomal abnormalities in the child increases with increasing maternal age. Although non-invasive prenatal testing (NIPT) is a safe and effective prenatal screening method, the accuracy of the test results needs to be improved owing to various testing conditions. We attempted to achieve a more accurate and robust prediction of chromosomal abnormalities by combining multiple methods. Here, three different methods, namely standard Z-score, normalized chromosome value, and within-sample reference bin, were used for 1698 reference and 109 test samples of whole-genome sequencing. The logistic regression model combining the three methods achieved a higher accuracy than any single method. In conclusion, the proposed method offers a promising approach for increasing the reliability of NIPT. [ABSTRACT FROM AUTHOR]

Biogenesis of the primary cilium, a cellular organelle mediating various signaling pathways, is generally coordinated with cell cycle exit/re-entry. Although the dynamic cell cycle-associated profile of the primary cilium has been largely accepted, the mechanism governing the link between ciliogenesis and cell cycle progression has been poorly understood. Using a human genome-wide RNAi screen, we identify genes encoding subunits of the spliceosome and proteasome as novel regulators of ciliogenesis. We demonstrate that 1) the mRNA processing-related hits are essential for RNA expression of molecules acting in cilia disassembly, such as AURKA and PLK1, and 2) the ubiquitin–proteasome systems (UPS)-involved hits are necessary for proteolysis of molecules acting in cilia assembly, such as IFT88 and CPAP. In particular, we show that these screen hit-associated mechanisms are crucial for both cilia assembly and cell cycle arrest in response to serum withdrawal. Finally, our data suggest that the mRNA processing mechanism may modulate the UPS-dependent decay of cilia assembly regulators to control ciliary resorption-coupled cell cycle re-entry. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy (NAC) induced a dynamic change in the TIME that increased the level of immune infiltration, leading to a high number of CD8 T cells with enhanced immune activity. However, increased immune infiltration and immune activity did not present any survival benefit, probably due to concomitant immunosuppression associated with an increase in the proportion of Foxp3+ regulatory T cells. Our results could provide therapeutic strategies to improve the survival benefit from immunotherapies in an NAC setting. The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer. [ABSTRACT FROM AUTHOR]

Although the regulation of membrane receptor activation is known to be crucial for molecular signal transduction, the molecular mechanism underlying receptor activation is not fully elucidated. Here we study the physicochemical nature of membrane receptor behavior by investigating the characteristic molecular vibrations of receptor ligands using computational chemistry and informatics methods. By using information gain, t -tests, and support vector machines, we have identified highly informative features of adenosine receptor (AdoR) ligand and corresponding functional amino acid residues such as Asn (6.55) of AdoR that has informative significance and is indispensable for ligand recognition of AdoRs. These findings may provide new perspectives and insights into the fundamental mechanism of class A G protein-coupled receptor activation. [ABSTRACT FROM AUTHOR]

Background: Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear.Methods: We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation.Results: Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = - 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients.Conclusions: Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients. [ABSTRACT FROM AUTHOR]

Previous studies suggested that genetic, environmental factors and their interactions could affect body fat mass (BFM). However, studies describing these effects were performed at a single time point in a population. In this study, we investigated the interaction between genetic and environmental factors in affecting BFM and implicate the healthcare utilization of lifestyle modifications from a personalized and genomic perspective. We examined how nutritional intake or physical activity changes in the individuals affect BFM concerning the genetic composition. We conducted an observational study including 259 adult participants with single nucleotide polymorphism (SNP) genotyping and longitudinal lifestyle monitoring, including food consumption and physical activities, by following lifestyle modification guidance. The participants' lifelog data on exercise and diet were collected through a wearable device for 3 months. Moreover, we measured anthropometric and serologic markers to monitor their potential changes through lifestyle modification. We examined the influence of genetic composition on body fat reduction induced by lifestyle changes using genetic risk scores (GRSs) of three phenotypes: GRS-carbohydrate (GRS-C), GRS-fat (GRS-F), and GRS-exercise (GRS-E). Our results showed that lifestyle modifications affected BFM more significantly in the high GRS class compared to the low GRS class, indicating the role of genetic factors affecting the efficiency of the lifestyle modification-induced BFM changes. Interestingly, the influence of exercise modification in the low GRS class with active lifestyle change was lower than that in the high GRS class with inactive lifestyle change (P = 0.022), suggesting the implication of genetic factors for efficient body fat control. [ABSTRACT FROM AUTHOR]

Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Despite the increasing incidence of pathological stage T1 renal cell carcinoma (pT1 RCC), postoperative distant metastases develop in many surgically treated patients, causing death in certain cases. Therefore, this study aimed to create a radiomics model using imaging features from multiphase computed tomography (CT) to more accurately predict the postoperative metastasis of pT1 RCC and further investigate the possible link between radiomics parameters and gene expression profiles generated by whole transcriptome sequencing (WTS). Four radiomic features, including the minimum value of a histogram feature from inner regions of interest (ROIs) (INNER_Min_hist), the histogram of the energy feature from outer ROIs (OUTER_Energy_Hist), the maximum probability of gray-level co-occurrence matrix (GLCM) feature from inner ROIs (INNER_MaxProb_GLCM), and the ratio of voxels under 80 Hounsfield units (Hus) in the nephrographic phase of postcontrast CT (Under80HURatio), were detected to predict the postsurgical metastasis of patients with pathological stage T1 RCC, and the clinical outcomes of patients could be successfully stratified based on their radiomic risk scores. Furthermore, we identified heterogenous-trait-associated gene signatures correlated with these four radiomic features, which captured clinically relevant molecular pathways, tumor immune microenvironment, and potential treatment strategies. Our results of accurate surrogates using radiogenomics could lead to additional benefit from adjuvant therapy or postsurgical metastases in pT1 RCC. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the correlations between parameters of 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan and indices of genetic properties, heterogeneity index (HI), and tumor mutation burden (TMB), in patients with lung cancer.Methods: We produced 106 PET indices for each tumor site that underwent genomic analysis in a total of 176 study subjects (age, 62.0 ± 10.0 y; males, 68.2%), comprising 101 adenocarcinoma (ADC), 29 squamous cell carcinoma (SQCC), and 46 small cell lung cancer (SCLC) patients. We then examined the correlations of the PET parameters with genetic properties of HI and TMB, according to pathology and tumor site.Results: Comparisons between PET parameters and the genetic properties with false discovery rate (FDR) correction revealed that the surface standard uptake value (SUV) entropy of SUV statistics had a significant correlation with HI only in patients with SCLC who underwent a genetic test in lymph nodes (r = 0.592, p = 0.028), whereas PET parameters did not show a significant correlation with HI or TMB in patients with SCLC who underwent a genetic test in lung tissue. In patients with ADC and SQCC, there was no significant correlation between PET parameters and the genetic properties. Although SUVmax showed raw p values less than 0.05 in correlation with HI (r = 0.315, raw p = 0.048) and TMB (r = 0.206, raw p = 0.043) in ADC, and SUVpeak had a raw p value less than 0.05 in correlation with HI (r = 0.394, raw p = 0.046) in SQCC, these parameters were not significant when corrected by FDR.Conclusions: In this study, surface SUV entropy had a significant correlation with HI in SCLC. Regarding other PET parameters and tumors, no significant correlation with genetic parameters existed. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the dynamic changes of tumor immune microenvironment (TME) by evaluating lymphocyte infiltration before and after neoadjuvant chemotherapy (NACT) in patients with advanced-stage ovarian cancer. Methods: We conducted whole-transcriptome sequencing coupled with immunohistochemistry of 147 patients, including 140 pairs of serial tumor samples collected before NACT and at the time of interval debulking surgery (IDS). PD-L1 expression was determined by using a combined positive score (CPS). Tumor-infiltrating lymphocytes (TIL) were assessed by standardized methods according to the guidelines of the International TIL working group. Results: All the patients had high-grade serous carcinoma and were treated with platinum-based chemotherapy. High pre-NACT PD-L1 level (CPS ≥ 10%) was associated with worse progression-free survival (PFS, p < 0.001) and overall survival (OS, p = 0.038). High pre-NACT TIL level (>20%) was associated with better PFS (p = 0.039) and trend of better OS (p = 0.077). Post-NACT PD-L1 and TIL levels were not associated with survival outcomes. PD-L1 level (p = 0.001) and TIL level (p <0.001) were significantly increased before and after NACT. An increase in TIL in response to NACT was associated with shorter PFS compared to patients with decreased TIL levels (p = 0.020). A change in the PD-L1 level had no impact on the prognosis. In whole-transcriptome sequencing, stromal score (p = 8.6e-0.7), immune score (p = 4e-0.6), and CYT score (p = 2.1e-0.5) were significantly increased after NACT. Conclusions: Pre-NACT TIL level was associated with a survival benefit in advanced-stage ovarian cancer. By contrast, increased TIL level was an adverse prognostic factor for survival outcomes. Further research is needed to find a patient group that can benefit from immunotherapy in the NACT setting. [ABSTRACT FROM AUTHOR]

Background: Preoperative chemoradiotherapy (CRT) has become a widely used treatment for improving local control of disease and increasing survival rates of rectal cancer patients. We aimed to identify a set of genes that can be used to predict responses to CRT in patients with rectal cancer.Methods: Gene expression profiles of pre-therapeutic biopsy specimens obtained from 77 rectal cancer patients were analyzed using DNA microarrays. The response to CRT was determined using the Dworak tumor regression grade: grade 1 (minimal, MI), grade 2 (moderate, MO), grade 3 (near total, NT), or grade 4 (total, TO).Results: Top ranked genes for three different feature scores such as a p-value (pval), a rank product (rank), and a normalized product (norm) were selected to distinguish pre-defined groups such as complete responders (TO) from the MI, MO, and NT groups. Among five different classification algorithms, supporting vector machine (SVM) with the top 65 norm features performed at the highest accuracy for predicting MI using a 5-fold cross validation strategy. On the other hand, 98 pval features were selected for predicting TO by elastic net (EN). Finally we combined TO- and MI-finder models to build a three-class classification model and validated it using an independent dataset of rectal cancer mRNA expression.Conclusions: We identified MI- and TO-finders for predicting preoperative CRT responses, and validated these data using an independent public dataset. This stepwise prediction model requires further evaluation in clinical studies in order to develop personalized preoperative CRT in patients with rectal cancer. [ABSTRACT FROM AUTHOR]

We hypothesized that adding durvalumab and tremelimumab to chemotherapy in advanced-stage epithelial ovarian cancer (aEOC) would increase progression-free survival (PFS) with minimal effects on safety. KGOG 3046 (NCT03899610) is a single-arm phase 2 study evaluating the combination of dual immune checkpoint inhibition and neoadjuvant chemotherapy (NAC) for the upfront treatment of aEOC. Patients with FIGO stage IIIC-IV EOC were offered three cycles of durvalumab (1500 mg), tremelimumab (75 mg) with chemotherapy for NAC followed by interval debulking surgery (IDS). After surgery, three cycles of durvalumab (1120 mg) and adjuvant chemotherapy followed by durvalumab maintenance (1120 mg [total 12 cycles]) were administered. During treatment, serial biopsies were performed at pre-treatment, IDS, and progression to identify immune biomarkers and changes in the tumor microenvironment. The primary endpoint was a 12 months PFS rate. Interim analysis was performed to evaluate outcomes after NAC (RECIST after NAC, R0 rate at IDS, the rate of CRS 3 at IDS, safety, a range of translational parameters) after all patients underwent IDS. A total of 23 patients were enrolled with a median age of 60 years (range:44-77 years). The majority were presented with high-grade serous carcinoma (87.0%) and stage IV disease (60.9%). After NAC, 3 patients experienced a complete response (13.0%) and 20 patients had a partial response (87.0%). At IDS, R0 resection was achieved in 17 patients (73.9%); 9 patients (39.1%) had a CRS of 3; pathologic complete remission was achieved in 4 patients (17.4%). A total of 2 patients (8.7%) delayed IDS due to grade 4 skin rash and pneumonitis, respectively. Skin rashes were the most common adverse events (56.5%) and grade ≥3 events occurred in 3 patients (13.0%), which completely resolved after steroid use. Treatment was associated with tumor microenvironment conversion to an "inflamed" phenotype, with a significant increase in cytolytic index (P=0.015), stromal score (P<0.001) and immune score (P=0.004) on whole-transcriptome sequencing. [Display omitted] These interim data highlight the clinical activity and a manageable toxicity profile for the addition of durvalumab and tremelimumab to NAC in aEOC. Additional correlative data will be presented at the meeting. This study is actively enrolling patients in an expansion cohort. [ABSTRACT FROM AUTHOR]

Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells. Targeted deep sequencing has been used widely as a diagnostic tool to identify actionable mutations in cancer patients. In this study, we evaluated the clinical utility of estimating tumor heterogeneity using targeted panel sequencing data. We investigated the prognostic impact of a tumor heterogeneity (TH) index on clinical outcomes, using mutational profiles from targeted deep sequencing data acquired from 1,352 patients across 8 cancer types. The TH index tended to be increased in high pathological stage disease in several cancer types, indicating clonal expansion of cancer cells as tumor progression proceeds. In colorectal cancer patients, TH index values also correlated significantly with clinical prognosis. Integration of the TH index with genomic and clinical features could improve the power of risk prediction for clinical outcomes. In conclusion, deep sequencing to determine the TH index could serve as a promising prognostic indicator in cancer patients. [ABSTRACT FROM AUTHOR]

Efficient isolation and genetic analysis of circulating tumor cells (CTCs) from cancer patients' blood is a critical step for clinical applications using CTCs. Here, we report a novel CTC-isolation method and subsequent genetic analysis. CTCs from the blood were complexed with magnetic beads coated with antibodies against the epithelial cell adhesion molecule (EpCAM) and separated vertically on a density-gradient medium in a modified well-plate. The recovery rate of model CTCs was reasonable and the cell purity was enhanced dramatically when compared to those parameters obtained using a conventional magnetic isolation method. CTCs were recovered from an increased number of patient samples using our magnetic system vs. the FDA-approved CellSearch system (100% vs. 33%, respectively). In 8 of 13 cases, targeted deep sequencing analysis of CTCs revealed private point mutations present in CTCs but not in matched tumor samples and white blood cells (WBCs), which was also validated by droplet digital PCR. Copy-number alterations in CTCs were also observed in the corresponding tumor tissues for some patients. In this report, we showed that CTCs isolated by the EpCAM-based method had complex and diverse genetic features that were similar to those of tumor samples in some, but not all, cases. [ABSTRACT FROM AUTHOR]