Leptomeningeal enhancement in multiple sclerosis: a focus on patients treated with hematopoietic stem cell transplantation.

Background: Leptomeningeal enhancement (LME) is considered an MRI marker of leptomeningeal inflammation in inflammatory neurological disorders, including multiple sclerosis (MS). To our knowledge, no disease-modifying therapies (DMTs) have been demonstrated to affect LME number or morphology so far. Methods: Monocentric study investigating the frequency and number of LME in a cohort of people with (pw)MS who performed a 3 T brain MRI with a standardized protocol (including a post-contrast FLAIR sequence), and exploring the impact of autologous hematopoietic stem cell transplantation (AHSCT) on this marker. In a longitudinal pilot study, consecutive MRIs were also analyzed in a subgroup of pwMS, including patients evaluated both pre- and post-AHSCT. Results: Fifty-five pwMS were included: 24/55 (44%) had received AHSCT (AHSCT group) and 31 other treatments (CTRL group). At least one LME was identified in 19/55 (35%) cases (42 and 29% in the AHSCT and CTRL groups, respectively; p = 0.405). In the AHSCT group, LME number correlated with age at AHSCT (R = 0.50; p = 0.014), but not with age at post-treatment MRI. In the longitudinal pilot study (n = 8), one LME disappeared following AHSCT in 1/4 patients, whereas LME number was unchanged in the remaining four pwMS from the CTRL group. Discussion: These results suggest that AHSCT may affect development and persistence of LME, strengthening the indication for early use of effective therapies bioavailable within the central nervous system (CNS), and therefore potentially targeting compartmentalized inflammation.

Trajectory-driven computational analysis for element characterization in Trypanosoma cruzi video microscopy.

Optical microscopy videos enable experts to analyze the motion of several biological elements. Particularly in blood samples infected with Trypanosoma cruzi (T. cruzi), microscopy videos reveal a dynamic scenario where the parasites' motions are conspicuous. While parasites have self-motion, cells are inert and may assume some displacement under dynamic events, such as fluids and microscope focus adjustments. This paper analyzes the trajectory of T. cruzi and blood cells to discriminate between these elements by identifying the following motion patterns: collateral, fluctuating, and pan-tilt-zoom (PTZ). We consider two approaches: i) classification experiments for discrimination between parasites and cells; and ii) clustering experiments to identify the cell motion. We propose the trajectory step dispersion (TSD) descriptor based on standard deviation to characterize these elements, outperforming state-of-the-art descriptors. Our results confirm motion is valuable in discriminating T. cruzi of the cells. Since the parasites perform the collateral motion, their trajectory steps tend to randomness. The cells may assume fluctuating motion following a homogeneous and directional path or PTZ motion with trajectory steps in a restricted area. Thus, our findings may contribute to developing new computational tools focused on trajectory analysis, which can advance the study and medical diagnosis of Chagas disease.

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer: A Nonrandomized Controlled Trial.

Importance: The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies. Objective: To evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC. Design, Setting, and Participants: This nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months). Intervention: Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy. Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported. Results: Overall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects. Conclusions and Relevance: These findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.

A method to comprehensively identify germline SNVs, INDELs and CNVs from whole exome sequencing data of BRCA1/2 negative breast cancer patients.

In the rapidly evolving field of genomics, understanding the genetic basis of complex diseases like breast cancer, particularly its familial/hereditary forms, is crucial. Current methods often examine genomic variants-such as Single Nucleotide Variants (SNVs), insertions/deletions (Indels), and Copy Number Variations (CNVs)-separately, lacking an integrated approach. Here, we introduced a robust, flexible methodology for a comprehensive variants' analysis using Whole Exome Sequencing (WES) data. Our approach uniquely combines meticulous validation with an effective variant filtering strategy. By reanalyzing two germline WES datasets from BRCA1/2 negative breast cancer patients, we demonstrated our tool's efficiency and adaptability, uncovering both known and novel variants. This contributed new insights for potential diagnostic, preventive, and therapeutic strategies. Our method stands out for its comprehensive inclusion of key genomic variants in a unified analysis, and its practical resolution of technical challenges, offering a pioneering solution in genomic research. This tool presents a breakthrough in providing detailed insights into the genetic alterations in genomes, with significant implications for understanding and managing hereditary breast cancer.

Ongoing Clinical Trials and Future Research Scenarios of Circulating Tumor DNA for the Treatment of Metastatic Colorectal Cancer.

Liquid biopsy using circulating tumor DNA (ctDNA) has emerged as a minimally invasive, timely approach to provide molecular diagnosis and monitor tumor evolution in patients with cancer. Since the molecular landscape of metastatic colorectal cancer (mCRC) is substantially heterogeneous and dynamic over space and time, ctDNA holds significant advantages as a biomarker for this disease. Numerous studies have demonstrated that ctDNA broadly recapitulates the molecular profile of the primary tumor and metastases, and have mainly focused on the genotyping of RAS and BRAF, that is propaedeutic for anti-EGFR treatment selection. However, ctDNA soon broadened its scope towards the assessment of early tumor response, as well as the identification of drug resistance biomarkers to drive potential molecular actionability. In this review article, we provide an overview of the current state-of-the-art of this methodology and its applications, focusing on ongoing clinical trials that employ ctDNA to prospectively guide treatment in patients with mCRC.

Clinicopathological characterisation of MTAP alterations in gastrointestinal cancers.

BACKGROUND: Methylthioadenosine phosphorylase (MTAP) is an essential metabolic enzyme in the purine and methionine salvage pathway. In cancer, MTAP gene copy number loss (MTAP loss) confers a selective dependency on the related protein arginine methyltransferase 5. The impact of MTAP alterations in gastrointestinal (GI) cancers remains unknown although hypothetically druggable. Here, we aim to investigate the prevalence, clinicopathological features and prognosis of MTAP loss GI cancers. METHODS: Cases with MTAP alterations were retrieved from The Cancer Genome Atlas (TCGA) and a real-world cohort of GI cancers profiled by next-generation sequencing. If MTAP alterations other than loss were found, immunohistochemistry was performed. Finally, we set a case-control study to assess MTAP loss prognostic impact. RESULTS: Findings across the TCGA dataset (N=1363 patients) and our cohort (N=508) were consistent. Gene loss was the most common MTAP alteration (9.4%), mostly co-occurring with CDKN2A/B loss (97.7%). Biliopancreatic and gastro-oesophageal cancers had the highest prevalence of MTAP loss (20.5% and 12.7%, respectively), being mostly microsatellite stable (99.2%). In colorectal cancer, MTAP loss was rare (1.1%), while most MTAP alterations were mutations (5/7, 71.4%); among the latter, only MTAP-CDKN2B truncation led to protein loss, thus potentially actionable. MTAP loss did not confer worse prognosis. CONCLUSIONS: MTAP alterations are found in 5%-10% of GI cancers, most frequently biliopancreatic and gastro-oesophageal. MTAP loss is the most common alteration, identified almost exclusively in MSS, CDKN2A/B loss, upper-GI cancers. Other MTAP alterations were found in colorectal cancer, but unlikely to cause protein loss and drug susceptibility.

BlinkBoard: Guiding and monitoring circuit assembly for synchronous and remote physical computing education.

Motivated by the necessity of guiding and monitoring students when assembling electronic circuits during in-class activities, we propose BlinkBoard, an augmented breadboard that enhances synchronous and remote physical computing classes. BlinkBoard uses LEDs placed on each row of a breadboard to guide, via four distinct blinking patterns, how to place and connect components and wires. It also uses a set of Input/Output pins to sense voltage levels or to generate voltage output at user-specified rows. Our hardware uses an open protocol of JSON commands and responses that can be used directly via a command line interface to control the hardware. Alternatively, these commands can be issued within a front-end graphical application hosted on a computer for a more user-friendly interface, and to ensure bidirectional and real-time communication between the instructor's guiding and monitoring panel, and all the students' remote BlinkBoards. The BlinkBoard hardware is affordable and simple, partially due to a customized circuit configured via a hardware description language that handles the LEDs' patterns with minimal load on the Arduino microcontroller. Finally, we briefly show BlinkBoard in use during a workshop with high-school students and an undergraduate design course.

Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells.

The bacterial genotoxin colibactin promotes colorectal cancer (CRC) tumorigenesis, but systematic assessment of its impact on DNA repair is lacking, and its effect on response to DNA-damaging chemotherapeutics is unknown. We find that CRC cell lines display differential response to colibactin on the basis of homologous recombination (HR) proficiency. Sensitivity to colibactin is induced by inhibition of ATM, which regulates DNA double-strand break repair, and blunted by HR reconstitution. Conversely, CRC cells chronically infected with colibactin develop a tolerant phenotype characterized by restored HR activity. Notably, sensitivity to colibactin correlates with response to irinotecan active metabolite SN38, in both cell lines and patient-derived organoids. Moreover, CRC cells that acquire colibactin tolerance develop cross-resistance to SN38, and a trend toward poorer response to irinotecan is observed in a retrospective cohort of CRCs harboring colibactin genomic island. Our results shed insight into colibactin activity and provide translational evidence on its chemoresistance-promoting role in CRC.

The role of anti-EGFR rechallenge in metastatic colorectal cancer, from available data to future developments: A systematic review.

Despite recent molecular and immunological advancements, prognosis of metastatic colorectal cancer (mCRC) patients remains poor. In this context, several retrospective and phase II studies suggested that after failure of an upfront anti-EGFR based regimen, a subset of patients can still benefit from further anti-EGFR blockade. Several translational studies involving circulating tumor DNA (ctDNA) analysis demonstrated that cancer clones harboring mutations driving anti-EGFR resistance, which can arise under anti-EGFR agents selective pressure, often decay after anti-EGFR discontinuation potentially restoring sensitivity to this therapeutic strategy. Accordingly, several retrospective analyses and a recent prospective trial demonstrated that ctDNA RAS and BRAF wild-type mCRC patients are those benefitting the most from anti-EGFR rechallenge. Indeed, in molecularly selected patients, anti-EGFR rechallenge strategy achieved up to 30 % response rate, with a progression free survival longer than 4 months and an overall survival longer than 1 year, which favorably compared with other standard therapeutic options available for heavily pretreated patients. Anti-EGFR is also well tolerated with no unexpected toxicities compared to the upfront setting. However, several open questions remain to be addressed towards a broader applicability of anti-EGFR strategy in the everyday clinical practice such as the identification of the best rechallenge regimen, the right placement in mCRC therapeutic algorithm, the best ctDNA screening panel. In our systematic review, we revised available data from clinical trials assessing anti-EGFR rechallenge activity in chemo-refractory mCRC patients, discussing as well potential future scenarios and development to implement this therapeutic approach. Particularly, we discussed the role of ctDNA as a safe, timely and comprehensive tool to refine patient's selection and the therapeutic index of anti-EGFR rechallenge.

Young-onset colorectal cancer: treatment-related nausea, vomiting and diarrhoea.

OBJECTIVES: Early-onset colorectal cancer (EO-CRC) incidence is increasing, raising a clinical challenge. Clinicians tend to treat EO-CRC patients with more intensive regimens despite the lack of survival benefits, based on an age-related bias. Limited evidence is available regarding treatment-related toxicities in this peculiar subset of patients. METHODS: We performed a literature search in MEDLINE/PubMed, EMBASE and Scopus, looking for reporting of nausea, vomiting and diarrhoea occurring in patients with EO-CRC, defined by age lower than 50 years old at initial diagnosis, while receiving anticancer treatment. RESULTS: 2318 records were screened and 9 full-text articles were considered eligible for inclusion for a total of 59 783 patients (of whom 8681 EO-CRC patients). We found nausea and vomiting occurring at higher incidence among EO-CRC compared with older patients, while no difference was reported as for diarrhoea. Peritoneal involvement, age younger than 40, female gender, suboptimal adherence to guidelines and oxaliplatin might represent potential risk factors for increased nausea and vomiting in patients with EO-CRC. CONCLUSION: EO-CRC patients experience more nausea and vomiting but equal or less diarrhoea compared with older patients. Adherence to clinical guidelines is recommended, and more data are warranted to assess if an enhanced antiemetic approach might be required, particularly in case of specific risk factors.

Targeting HER2 heterogeneity in breast and gastrointestinal cancers.

About 20% of breast and gastric cancers and 3% of colorectal carcinomas overexpress the human epidermal growth factor receptor 2 (HER2) and are sensitive to HER2-directed agents. The expression of HER2 may differ within the same tumoral lesion (spatial intralesional heterogeneity), from different tumor locations (spatial interlesional heterogeneity), and throughout treatments (temporal heterogeneity). Spatial and temporal heterogeneity may impact on response and resistance to HER2-targeting agents and its prevalence and predictive role changes across HER2-overexpressing solid tumors. Therefore, the definition and the characterization of HER2 heterogeneity pose many challenges and its implementation as a reproducible predictive biomarker would help in guiding treatment modulation.

Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report.

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

What to do after immune-checkpoint inhibitors failure in advanced non-small cell lung cancer: an expert opinion and review.

INTRODUCTION: Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness. AREAS COVERED: Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov. EXPERT OPINION: The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.

Maxillary Sinus Elevation by Crestal Window: Influence of 3D Sinus Size on Bone Regeneration-A Retrospective Clinical and Histologic Evaluation.

This evaluation correlates maxillary sinus 3D morphology with bone regeneration. In 39 patients with crestal bone ≤ 2 mm, mineralized human bone allografts were used to augment the sinus floor through the crestal window sinus elevation approach. CBCT was used to measure the buccopalatal diameter (BPD), mesiodistal diameter (MDD), and hemi-ellipsoidal volume (Vh) in all sinuses. A bone core biopsy sample was taken at implant placement (4 to 5 months after sinus augmentation). Microradiographs of methacrylate-embedded sections were used to evaluate the amounts of bone, residual graft, and soft tissue. All 51 implants placed in the 39 patients successfully osseointegrated. A linear regression analysis showed that as BPD, MMD, and Vh increased, the amount of bone gain decreased and the amount of soft tissue increased (P < .05). The amount of residual graft was little affected by sinus morphology. Microradiographic data were grouped into four different sinus types (from small to great) using BPD and Vh medians. The best amount of bone formation was achieved in the narrow and short sinus type, while no great differences were found in the remaining three sinus types. Understanding of 3D sinus cavity morphology, especially the buccopalatal diameter and mesiodistal dimensions, is fundamental for achieving the best possible sinus augmentation outcomes.

Circulating Tumor DNA to Drive Treatment in Metastatic Colorectal Cancer.

In the evolving molecular treatment landscape of metastatic colorectal cancer (mCRC), the identification of druggable alterations is pivotal to achieve the best therapeutic opportunity for each patient. Because the number of actionable targets is expanding, there is the need to timely detect their presence or emergence to guide the choice of different available treatment options. Liquid biopsy, through the analysis of circulating tumor DNA (ctDNA), has proven safe and effective as a complementary method to address cancer evolution while overcoming the limitations of tissue biopsy. Even though data are accumulating regarding the potential for ctDNA-guided treatments applied to targeted agents, still major gaps in knowledge exist as for their application to different areas of the continuum of care. In this review, we recapitulate how ctDNA information could be exploited to drive different targeted treatment strategies in mCRC patients, by refining molecular selection before treatment by addressing tumor heterogeneity beyond tumor tissue biopsy; longitudinally monitoring early-tumor response and resistance mechanisms to targeted agents, potentially leading to tailored, molecular-driven, therapeutic options; guiding the molecular triage towards rechallenge strategies with anti-EGFR agents, suggesting the best time for retreatment; and providing opportunities for an "enhanced rechallenge" through additional treatments or combos aimed at overcoming acquired resistance. Besides, we discuss future perspectives concerning the potential role of ctDNA to fine-tune investigational strategies such as immuno-oncology.

External validation of a clinical prediction tool for the use of manual therapy for patients with temporomandibular disorders: a protocol for a prospective observational study.

INTRODUCTION: Clinical guidelines recommend conservative treatment for the management of temporomandibular disorders (TMD), and manual therapy directed to temporomandibular structures is commonly applied to reduce pain and improve function. In a recent prospective study, we developed a clinical prediction tool based on an array of predictors to identify people with TMD who are likely to experience significant pain relief and functional improvements following a programme of manual therapies (MTP) applied to temporomandibular structures. The purpose of this study is to externally validate in a different sample (temporal validation) the prediction model obtained in the initial study. METHODS/ANALYSIS: This observational prospective study will recruit a cohort of 120 adults with TMD from a Dental Hospital in Italy. The intervention will be an MTP consisting of four sessions (once per week) of manual therapy applied to temporomandibular structures. Candidate predictors included in the predictive model will be pain intensity during mouth opening, treatment expectations, number of pain locations, central sensitisation, TMD pain duration and maximal mouth opening. Outcome measures (i.e., pain intensity, functional improvement) will be collected before starting the MTP, after the last session and after 1 month (2 months from baseline). A reduction of pain intensity by at least 30% will be considered a good outcome. External validity of the prediction model will be evaluated after the last session by measuring its calibration, discrimination and overall fit. Additionally, the performance of the model will be evaluated considering the clinical outcomes collected 1 month after the last MTP session. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy. The results will be submitted for publication in a peer-reviewed journal, and the prediction model will be implemented in a web-based calculator to facilitate its use by clinicians. TRIAL REGISTRATION NUMBER: NCT03990662.

Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study.

BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.

Conventional and Advanced Magnetic Resonance Imaging Assessment of Non-Enhancing Peritumoral Area in Brain Tumor.

The non-enhancing peritumoral area (NEPA) is defined as the hyperintense region in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images surrounding a brain tumor. The NEPA corresponds to different pathological processes, including vasogenic edema and infiltrative edema. The analysis of the NEPA with conventional and advanced magnetic resonance imaging (MRI) was proposed in the differential diagnosis of solid brain tumors, showing higher accuracy than MRI evaluation of the enhancing part of the tumor. In particular, MRI assessment of the NEPA was demonstrated to be a promising tool for distinguishing high-grade gliomas from primary lymphoma and brain metastases. Additionally, the MRI characteristics of the NEPA were found to correlate with prognosis and treatment response. The purpose of this narrative review was to describe MRI features of the NEPA obtained with conventional and advanced MRI techniques to better understand their potential in identifying the different characteristics of high-grade gliomas, primary lymphoma and brain metastases and in predicting clinical outcome and response to surgery and chemo-irradiation. Diffusion and perfusion techniques, such as diffusion tensor imaging (DTI), diffusional kurtosis imaging (DKI), dynamic susceptibility contrast-enhanced (DSC) perfusion imaging, dynamic contrast-enhanced (DCE) perfusion imaging, arterial spin labeling (ASL), spectroscopy and amide proton transfer (APT), were the advanced MRI procedures we reviewed.

BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as "benign." However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer. SIGNIFICANCE: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Rendering Perceived Terrain Stiffness in VR Via Preload Variation Against Body-Weight.

PreloadStep is a novel platform that creates the illusion of walking on different types of terrain in Virtual Reality without requiring users to wear any special instrumentation. PreloadStep works by compressing a set of springs between two plates, with the amount of compression determining the perceived stiffness of the virtual terrain. The platform can render perception of stiffness by applying preload forces up to 824 N in different portions of the terrain, capable of changing stiffness illusion even while a user is standing on it. The effectiveness of PreloadStep was tested in two perception studies (perception thresholds and haptic-visual congruence studies) and an example application, with the results indicating that it is a promising method for creating engaging virtual terrain experiences.