Meningioma is a common incidental finding, and clinical course varies based on anatomical location. The aim of this sub-analysis of the IMPASSE study was to compare the outcomes of patients with an incidental frontobasal meningioma who underwent active surveillance to those who underwent upfront stereotactic radiosurgery (SRS). Data were retrospectively collected from 14 centres. The active surveillance (n = 28) and SRS (n = 84) cohorts were compared unmatched and matched for age, sex, and duration of follow-up (n = 25 each). The study endpoints included tumor progression, new symptom development, and need for further intervention. Tumor progression occurred in 52.0% and 0% of the matched active surveillance and SRS cohorts, respectively (p < 0.001). Five patients (6.0%) treated with SRS developed treatment related symptoms compared to none in the active monitoring cohort (p = 0.329). No patients in the matched cohorts developed symptoms attributable to treatment. Three patients managed with active surveillance (10.7%, unmatched; 12.0%, matched) underwent an intervention for tumor growth with no persistent side effects after treatment. No patients subject to SRS underwent further treatment. Active monitoring and SRS confer a similarly low risk of symptom development. Upfront treatment with SRS improves imaging-defined tumor control. Active surveillance and SRS are acceptable treatment options for incidental frontobasal meningioma. Full article

GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuro–ectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelial–mesenchymal transition. Since GD3 and GD2 levels are directly linked to GD3 synthase expression and activity, targeting GD3 synthase appears to be a promising strategy through which to interfere with ganglioside-associated malignant properties. We review here the current knowledge on GD3 synthase expression and regulation in cancers, and the consequences of complex ganglioside expression on cancer cell signaling and properties, highlighting the relationships between GD3 synthase expression and epithelial–mesenchymal transition and stemness. Different strategies were used to modulate GD3 synthase expression in cancer cells in vitro and in animal models, such as inhibitors or siRNA/lncRNA, which efficiently reduced cancer cell malignant properties and the proportion of GD2 positive cancer stem cells, which are associated with high metastatic properties, resistance to therapy, and cancer relapse. These data show the relevance of targeting GD3 synthase in association with conventional therapies, to decrease the number of cancer stem cells in tumors. Full article

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of <8%. PDAC is characterised by desmoplasia with an abundant extracellular matrix (ECM) rendering current therapies ineffective. Monocarboxylate transporters (MCTs) are key regulators of cellular metabolism and are upregulated in different cancers; however, their role in PDAC desmoplasia is little understood. Here, we investigated MCT and ECM gene expression in primary PDAC patient biopsies using RNA-sequencing data obtained from Gene Expression Omnibus. We generated a hypernetwork model from these data to investigate whether a causal relationship exists between MCTs and ECMs. Our analysis of stromal and epithelial tissues (n = 189) revealed nine differentially expressed MCTs, including the upregulation of SLC16A2/6/10 and the non-coding SLC16A1-AS1, and 502 ECMs, including collagens, laminins, and ECM remodelling enzymes (false discovery rate < 0.05). A causal hypernetwork analysis demonstrated a bidirectional relationship between MCTs and ECMs; four MCT and 255 ECM-related transcripts correlated with 90% of the differentially expressed ECMs (n = 376) and MCTs (n = 7), respectively. The hypernetwork model was robust, established by iterated sampling, direct path analysis, validation by an independent dataset, and random forests. This transcriptomic analysis highlights the role of MCTs in PDAC desmoplasia via associations with ECMs, opening novel treatment pathways to improve patient survival. Full article

In colorectal cancer, whereas mucinous adenocarcinoma (MAC) has several poor clinical prognostic factors compared to adenocarcinoma (AC), the prognosis of MAC remains controversial. We evaluated the prognosis of MAC without distant metastasis and the effects of adjuvant chemotherapy using health insurance registry data managed by South Korea. Patients with colorectal cancer between January 2014 and December 2016 were included (AC, 22,050 [96.8%]; MAC, 729 [3.2%]). We observed no difference in overall survival (OS) between AC and MAC in stages I and II. However, MAC showed a worse OS than AC in stage III disease, especially in patients administered chemotherapy (p < 0.001). These findings persisted after propensity score matching of clinical characteristics between AC and MAC. In addition, transcriptome analysis of The Cancer Genome Atlas (TCGA) data showed increased chemoresistance-associated pathways in MAC compared to AC. In consensus molecular subtypes (CMS) classification, unlike in AC, CMSs 1, 3, and 4 comprised most of MAC and the proportions of CMSs 3 and 4 increased with stage progression. These results suggest clues to overcome resistance to chemotherapy and develop targeted treatments in MAC. Full article

Immune checkpoint inhibitors (ICIs) harness the immune system and are the therapy of choice for multiple cancers. Although immunosuppressive agents such as steroids are also used in many cancers, it is unknown how their timing affects treatment outcomes. Thus, we investigated the relationship between the timing of steroid exposure preceding ICI administration and subsequent treatment outcomes in melanoma. This population-based study utilized the SEER-Medicare-linked database to identify patients diagnosed with melanoma between 1991 and 2015 and receiving ICIs between 2010 and 2016, examining last steroid exposure in the 12 months preceding ICI. The main outcome was all-cause mortality (ACM) after ICIs. Modifications of the Cox proportional hazards model were used to calculate time-dependent hazards. Of 1671 patients with melanoma receiving ICIs, 907 received steroids. Compared with no steroids, last steroid exposures ≤1 month and 1–3 months prior to ICIs were associated with a 126% and 51% higher ACM within 3 months post ICI initiation, respectively (hazard ratio (HR): 2.26, 95% CI: 1.65–3.08; and HR: 1.51, 95% CI: 1.01–2.27). Steroid exposure within 3 months of initiating ICIs was associated with increased mortality up to 6 months after ICI. Further investigation is warranted to elucidate mechanisms affecting outcomes due to steroids. Full article

In this position paper the Société Francophone d’OncoGériatrie (SOFOG; French-speaking oncogeriatric society), the Société Française de Pharmacie Oncologique (SFPO, French society for oncology pharmacy), the Groupe d’Investigateurs Nationaux pour l’Étude des Cancers de l’Ovaire et du sein (GINECO, National Investigators’ Group for Studies in Ovarian and Breast Cancer) and the Groupe Français de chirurgie Oncologique et Gynécologique (FRANCOGYN) propose a multi-disciplinary care planning of ovarian cancer in older patients. The treatment pathway is based on four successive decisional nodes (diagnosis, resectability assessment, operability assessment, adjuvant, and maintenance treatment decision) implying multidisciplinarity and adaptation of the treatment plan according to the patient’s geriatric covariates and her motivation towards treatment. Specific attention must be paid to geriatric intervention, supportive care and pharmaceutical conciliation. Studies are needed to prospectively evaluate the impact of geriatric vulnerability parameters at each step of the treatment agenda and the impact of geriatric interventions on patient outcomes. Full article

Liver transplantation (LT) is the only potentially curative option for children with unresectable hepatocellular carcinoma (HCC). We performed a systematic review of the MEDLINE, Scopus, Cochrane Library, and Web of Science databases (end-of-search date: 31 July 2020). Our outcomes were overall survival (OS) and disease-free survival (DFS). We evaluated the effect of clinically relevant variables on outcomes using the Kaplan–Meier method and log-rank test. Sixty-seven studies reporting on 245 children undergoing LT for HCC were included. DFS data were available for 150 patients and the 1-, 3-, and 5-year DFS rates were 92.3%, 89.1%, and 84.5%, respectively. Sixty of the two hundred and thirty-eight patients (25.2%) died over a mean follow up of 46.8 ± 47.4 months. OS data were available for 222 patients and the 1-, 3-, and 5-year OS rates were 87.9%, 78.8%, and 74.3%, respectively. Although no difference was observed between children transplanted within vs. beyond Milan criteria (p = 0.15), superior OS was observed in children transplanted within vs. beyond UCSF criteria (p = 0.02). LT can yield favorable outcomes for pediatric HCC beyond Milan but not beyond UCSF criteria. Further research is required to determine appropriate LT selection criteria for pediatric HCC. Full article

Soft-tissue sarcomas are biologically heterogenous tumors arising from connective tissues with over 100 subtypes. Although sarcomas account for <1% of all adult malignancies, retroperitoneal sarcomas are a distinct subgroup accounting for <10% of all sarcomatous tumors. There have been considerable advancements in the understanding and treatment of retroperitoneal sarcoma in the last decade, with standard treatment consisting of upfront primary surgical resection. The evidence surrounding the addition of radiation therapy remains controversial. There remains no standard with regards to systemic therapy, including immunotherapy. Adjunctive therapy remains largely dictated by expert consensus and preferences at individual centers or participation in clinical trials. In this 2021 review, we detail the anatomical boundaries of the retroperitoneum, clinical characteristics, contemporary standard of care and well as recent advancements in retroperitoneal sarcoma care. Ongoing international collaborations are encouraged to advance our understanding of this complex disease. Full article

The issue: Gliomas are primary tumors arising from supporting cells of the central nervous system (CNS), usually in the brain. The 2021 World Health Organization (WHO) classifies gliomas as adult-type diffuse gliomas or circumscribed astrocytic gliomas depending on their histology and molecular features. Spinal astrocytic gliomas are very rare, and nowadays no standard of therapy is available. Treatment options are limited: surgery is often not radical, and adjuvant therapies include mostly radiotherapy (RT) or systemic chemotherapy (CHT). There is lack of knowledge about the efficacy and safety of therapies and their multidisciplinary approaches. The aim of the review: A systematic review of the literature from January 2000 to June 2021 was performed, including both clinical trials and observational studies on histological adult primary spinal cord astrocytomas (SCA), with a minimum follow-up of 6 months and reporting the overall survival, progression-free survival or clinical neurological outcome after any therapeutic approach (surgery, RT or CHT). What are the main findings? A total of 1197 citations were identified by the Medline search and additional records; based on our inclusion criteria, 18 studies were included with a total of 285 adult patients. We documented the lack of any clinical trial. What are the conclusions? The available literature data are limited to series/retrospective studies, including heterogeneous patients, i.e., astrocytoma as well as ependymoma or pediatric/adult age, with scanty data on the outcomes of interest. No clinical trials have been run. Due to the rarity of this disease, multicentric clinical trials with molecular investigations are mandatory to better manage such a rare disease. Full article

Objective: To identify the most predictive parameters of ovarian malignancy and develop a machine learning (ML) based algorithm to preoperatively distinguish between a benign and malignant pelvic mass. Methods: Retrospective study of 70 predictive parameters collected from 140 women with a pelvic mass. The women were split into a 3:1 “training” to “testing” dataset. Feature selection was performed using Gini impurity through an embedded random forest model and principal component analysis. Nine unique ML classifiers were assessed across a variety of model-specific hyperparameters using 25 bootstrap resamples of the training data. Model predictions were then combined into an ensemble stack by LASSO regression. The final ensemble stack and individual classifiers were then applied to the testing dataset to assess model performance. Results: Feature selection identified HE4, CA125, and transferrin as three predictive parameters of malignancy. Assessment of the ensemble stack on the testing dataset outperformed all individual ML classifiers in predicting malignancy. The ensemble stack demonstrated an accuracy of 97.1%, a receiver operating characteristic (ROC) area under the curve (AUC) of 0.951, and a sensitivity of 93.3% with a specificity of 100%. Conclusions: Combining the measurement of three distinct biomarkers with the stacking of multiple ML classifiers into an ensemble can provide valuable preoperative diagnostic predictions for patients with a pelvic mass. Full article

Patients with metastatic soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options. Trabectedin is currently being investigated as a potential adjunct to immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify biomarkers that would be relevant to trials combining trabectedin with immunotherapy. We performed a single-center retrospective study of sarcoma patients treated with trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147 sarcoma patients treated with trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior chemotherapy regimens were more likely to stay on trabectedin longer (pairwise correlation = −0.17, p = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, p = 0.04, q = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells (p = 0.023, q = 0.058) and M2 macrophages (p = 0.03, q = 0.058). We found that the number of chemotherapy regimens prior to trabectedin negatively correlated with the number of trabectedin cycles received, suggesting that patients may benefit from receiving trabectedin earlier in their therapy course. The correlation of trabectedin outcomes with immune cell infiltrates supports the hypothesis that trabectedin may function as an immune modulator and supports ongoing efforts to study trabectedin in combination with immunotherapy. Furthermore, tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from trabectedin, which could guide clinicians in future treatment decisions. Full article

Background: Hepatitis C virus (HCV) has been shown to be associated with human papillomavirus (HPV)-positive head and neck cancers. However, studies regarding HPV infection and the risk of new-onset hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients are limited. We examined the risk of HCC in CHC patients with or without HPV infection. Methods: In total, 9905 CHC patients from 2000 to 2016 constituted the whole cohort. HPV was defined as being diagnosed after HCV. The CHC cohort with HPV (N = 1981) and age-, sex-, inception point-, comorbidity-, and medication-matched non-HPV (N = 7924) were followed up until HCC, death, or 2018. HCC patients were extracted from the Taiwan Registry for Catastrophic Illness Database. We adopted the propensity score match and inverse probability of treatment weighting (IPTW) to eliminate bias. Cox proportional hazard regression analyses were performed to calculate HCC risk. Results: After a full adjustment, HPV was not associated with HCC risk (aHR, 0.74; 95% CI, 0.58–0.96 in the main model, and aHR, 0.76; 95% CI, 0.66–0.87 in IPTW, respectively). Almost all subgroup analyses verified this finding (HRs < 1.0). Conclusions: Among CHC patients older than 18 years old, those with HPV infection were associated with a lower risk of subsequent HCC. Full article

Problem. Image biomarker analysis, also known as radiomics, is a tool for tissue characterization and treatment prognosis that relies on routinely acquired clinical images and delineations. Due to the uncertainty in image acquisition, processing, and segmentation (delineation) protocols, radiomics often lack reproducibility. Radiomics harmonization techniques have been proposed as a solution to reduce these sources of uncertainty and/or their influence on the prognostic model performance. A relevant question is how to estimate the protocol-induced uncertainty of a specific image biomarker, what the effect is on the model performance, and how to optimize the model given the uncertainty. Methods. Two non-small cell lung cancer (NSCLC) cohorts, composed of 421 and 240 patients, respectively, were used for training and testing. Per patient, a Monte Carlo algorithm was used to generate three hundred synthetic contours with a surface dice tolerance measure of less than 1.18 mm with respect to the original GTV. These contours were subsequently used to derive 104 radiomic features, which were ranked on their relative sensitivity to contour perturbation, expressed in the parameter η. The top four (low η) and the bottom four (high η) features were selected for two models based on the Cox proportional hazards model. To investigate the influence of segmentation uncertainty on the prognostic model, we trained and tested the setup in 5000 augmented realizations (using a Monte Carlo sampling method); the log-rank test was used to assess the stratification performance and stability of segmentation uncertainty. Results. Although both low and high η setup showed significant testing set log-rank p-values (p = 0.01) in the original GTV delineations (without segmentation uncertainty introduced), in the model with high uncertainty, to effect ratio, only around 30% of the augmented realizations resulted in model performance with p < 0.05 in the test set. In contrast, the low η setup performed with a log-rank p < 0.05 in 90% of the augmented realizations. Moreover, the high η setup classification was uncertain in its predictions for 50% of the subjects in the testing set (for 80% agreement rate), whereas the low η setup was uncertain only in 10% of the cases. Discussion. Estimating image biomarker model performance based only on the original GTV segmentation, without considering segmentation, uncertainty may be deceiving. The model might result in a significant stratification performance, but can be unstable for delineation variations, which are inherent to manual segmentation. Simulating segmentation uncertainty using the method described allows for more stable image biomarker estimation, selection, and model development. The segmentation uncertainty estimation method described here is universal and can be extended to estimate other protocol uncertainties (such as image acquisition and pre-processing). Full article

Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and poor overall prognosis compared to other cancers of the gastrointestinal tract. Owing to the rarity of the disease along with the paucity of high-quality tissue samples and preclinical models, little is known about the molecular alterations characteristic of SBA. This is reflected by the fact that the clinical management of SBA is primarily extrapolated from colorectal cancer (CRC). Recent advances in genomic profiling have highlighted key differences between these tumors, establishing SBA as a molecularly unique intestinal cancer. Moreover, comprehensive molecular analysis has identified a relatively high incidence of potentially targetable genomic alterations in SBA, predictive of response to targeted and immunotherapies. Further advances in our knowledge of the mutational and transcriptomic landscape of SBA, guided by an increased understanding of the molecular drivers of SBA, will provide opportunities to develop novel diagnostic tools and personalized therapeutic strategies. Full article

PIK3CA mutations are believed to contribute to the pathogenesis of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). This study aims to establish the frequency of PIK3CA mutations in a Portuguese HNSCC cohort and to determine their association with the HPV status and patient survival. A meta-analysis of scientific literature also revealed widely different mutation rates in cohorts from different world regions and a trend towards improved prognosis among patients with PIK3CA mutations. DNA samples were available from 95 patients diagnosed with HNSCC at the Portuguese Institute of Oncology in Lisbon between 2010 and 2019. HPV status was established based on viral DNA detected using real-time PCR. The evaluation of PIK3CA gene mutations was performed by real-time PCR for four mutations (H1047L; E542K, E545K, and E545D). Thirty-seven cases were found to harbour PIK3CA mutations (39%), with the E545D mutation (73%) more frequently detected. There were no significant associations between the mutational status and HPV status (74% WT and 68% MUT were HPV (+); p = 0.489) or overall survival (OS) (3-year OS: WT 54% and MUT 65%; p = 0.090). HPV status was the only factor significantly associated with both OS and disease-free survival (DFS), with HPV (+) patients having consistently better outcomes (3-year OS: HPV (+) 65% and HPV (−) 36%; p = 0.007; DFS HPV (+) 83% and HPV (−) 43%; p = 0.001). There was a statistically significant interaction effect between HPV status and PIK3CA mutation regarding DFS (Interaction test: p = 0.026). In HPV (+) patients, PIK3CA wild-type is associated with a significant 4.64 times increase in the hazard of recurrence or death (HR = 4.64; 95% CI 1.02–20.99; p = 0.047). Overall, PIK3CA gene mutations are present in a large number of patients and may help define patient subsets who can benefit from therapies targeting the PI3K pathway. The systematic assessment of PIK3CA gene mutations in HNSCC patients will require further methodological standardisation. Full article

Selecting a first-line (1L) maintenance option for ovarian cancer is challenging given the variety of therapies, differing trials, and the lack of head-to-head data for angiogenesis and poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, indirect treatment comparisons (ITCs) can aid treatment decision making. This study assessed the feasibility of two ITCs, a network meta-analysis (NMA) and a population-adjusted ITC (PAIC), comparing the efficacy of the PARP inhibitor niraparib in the PRIMA trial (NCT02655016) with other 1L maintenance treatments. A systematic literature review was conducted to identify trials using the Cochrane Handbook for Systematic Reviews of Interventions to assess differences in trial design, population characteristics, treatment arms, and outcome measures. All 12 trials identified were excluded from the NMA due to the absence of a common comparator and differences in survival measures and/or inclusion criteria. The PAIC comparing PRIMA and PAOLA-1 trials was also not feasible due to differences in inclusion criteria, survival measures, and the previous receipt of chemotherapy/bevacizumab. Neither ITC met recommended guidelines for analysis; the results of such comparisons would not be considered appropriate evidence when selecting 1L maintenance options in ovarian cancer. ITCs in this setting should be performed cautiously, as many factors can preclude objective trial comparisons. Full article