Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.

BACKGROUND: British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS: A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION: Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).

Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering.

Developmental stuttering is a speech disorder characterized by disruption in the forward movement of speech. This disruption includes part-word and single-syllable repetitions, prolongations, and involuntary tension that blocks syllables and words, and the disorder has a life-time prevalence of 6-12%. Within Vanderbilt's electronic health record (EHR)-linked biorepository (BioVU), only 142 individuals out of 92,762 participants (0.15%) are identified with diagnostic ICD9/10 codes, suggesting a large portion of people who stutter do not have a record of diagnosis within the EHR. To identify individuals affected by stuttering within our EHR, we built a PheCode-driven Gini impurity-based classification and regression tree model, PheML, by using comorbidities enriched in individuals affected by stuttering as predicting features and imputing stuttering status as the outcome variable. Applying PheML in BioVU identified 9,239 genotyped affected individuals (a clinical prevalence of ∼10%) for downstream genetic analysis. Ancestry-stratified GWAS of PheML-imputed affected individuals and matched control individuals identified rs12613255, a variant near CYRIA on chromosome 2 (B = 0.323; p value = 1.31 × 10-8) in European-ancestry analysis and rs7837758 (B = 0.518; p value = 5.07 × 10-8), an intronic variant found within the ZMAT4 gene on chromosome 8, in African-ancestry analysis. Polygenic-risk prediction and concordance analysis in an independent clinically ascertained sample of developmental stuttering cases validate our GWAS findings in PheML-imputed affected and control individuals and demonstrate the clinical relevance of our population-based analysis for stuttering risk.

Nanoplastics Detected in Commercial Sea Salt.

People of all ages consume salt every day, but is it really just salt? Plastic nanoparticles [nanoplastics (NPs)] pose an increasing environmental threat and have begun to contaminate everyday salt in consumer goods. Herein, we developed a combined surface enhanced Raman scattering (SERS) and stimulated Raman scattering (SRS) approach that can realize the filtration, enrichment, and detection of NPs in commercial salt. The Au-loaded (50 nm) anodic alumina oxide substrate was used as the SERS substrate to explore the potential types of NP contaminants in salts. SRS was used to conduct imaging and quantify the presence of the NPs. SRS detection was successfully established through standard plastics, and NPs were identified through the match of the hydrocarbon group of the nanoparticles. Simultaneously, the NPs were quantified based on the high spatial resolution and rapid imaging of the SRS imaging platform. NPs in sea salts produced in Asia, Australasia, Europe, and the Atlantic were studied. We estimate that, depending on the location, an average person could be ingesting as many as 6 million NPs per year through the consumption of sea salt alone. The potential health hazards associated with NP ingestion should not be underestimated.

Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

OPINION STATEMENT: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

A CT-based radiomics classification model for the prediction of histological type and tumour grade in retroperitoneal sarcoma (RADSARC-R): a retrospective multicohort analysis.

BACKGROUND: Retroperitoneal sarcomas are tumours with a poor prognosis. Upfront characterisation of the tumour is difficult, and under-grading is common. Radiomics has the potential to non-invasively characterise the so-called radiological phenotype of tumours. We aimed to develop and independently validate a CT-based radiomics classification model for the prediction of histological type and grade in retroperitoneal leiomyosarcoma and liposarcoma. METHODS: A retrospective discovery cohort was collated at our centre (Royal Marsden Hospital, London, UK) and an independent validation cohort comprising patients recruited in the phase 3 STRASS study of neoadjuvant radiotherapy in retroperitoneal sarcoma. Patients aged older than 18 years with confirmed primary leiomyosarcoma or liposarcoma proceeding to surgical resection with available contrast-enhanced CT scans were included. Using the discovery dataset, a CT-based radiomics workflow was developed, including manual delineation, sub-segmentation, feature extraction, and predictive model building. Separate probabilistic classifiers for the prediction of histological type and low versus intermediate or high grade tumour types were built and tested. Independent validation was then performed. The primary objective of the study was to develop radiomic classification models for the prediction of retroperitoneal leiomyosarcoma and liposarcoma type and histological grade. FINDINGS: 170 patients recruited between Oct 30, 2016, and Dec 23, 2020, were eligible in the discovery cohort and 89 patients recruited between Jan 18, 2012, and April 10, 2017, were eligible in the validation cohort. In the discovery cohort, the median age was 63 years (range 27-89), with 83 (49%) female and 87 (51%) male patients. In the validation cohort, median age was 59 years (range 33-77), with 46 (52%) female and 43 (48%) male patients. The highest performing model for the prediction of histological type had an area under the receiver operator curve (AUROC) of 0·928 on validation, based on a feature set of radiomics and approximate radiomic volume fraction. The highest performing model for the prediction of histological grade had an AUROC of 0·882 on validation, based on a radiomics feature set. INTERPRETATION: Our validated radiomics model can predict the histological type and grade of retroperitoneal sarcomas with excellent performance. This could have important implications for improving diagnosis and risk stratification in retroperitoneal sarcomas. FUNDING: Wellcome Trust, European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group, the National Institutes for Health, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

Patterns of failure in pediatric medulloblastoma and implications for hippocampal sparing.

BACKGROUND: Hippocampal avoidance (HA) has been shown to preserve cognitive function in adult patients with cancer treated with whole-brain radiation therapy for brain metastases. However, the feasibility of HA in pediatric patients with brain tumors has not been explored because of concerns of increased risk of relapse in the peri-hippocampal region. Our aim was to determine patterns of recurrence and incidence of peri-hippocampal relapse in pediatric patients with medulloblastoma (MB). METHODS AND MATERIALS: We identified pediatric patients with MB treated with protons between 2002 and 2016 and who had recurrent disease. To estimate the risk of peri-hippocampal recurrence, three hippocampal zones (HZs) were delineated corresponding to ≤5 mm (HZ-1), 6 to 10 mm (HZ-2), and >10 mm (HZ-3) distance of the recurrence from the contoured hippocampi. To determine the feasibility of HA, three standard-risk patients with MB were planned using either volumetric-modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) plans. RESULTS: Thirty-eight patients developed a recurrence at a median of 1.6 years. Of the 25 patients who had magnetic resonance imaging of the recurrence, no patients failed within the hippocampus and only two patients failed within HZ-1. The crude incidence of peri-hippocampal failure was 8%. Both HA-VMAT and HA-IMPT plans were associated with significantly reduced mean dose to the hippocampi (p < .05). HA-VMAT and HA-IMPT plans were associated with decreased percentage of the third and lateral ventricles receiving the prescription craniospinal dose of 23.4 Gy. CONCLUSIONS: Peri-hippocampal failures are uncommon in pediatric patients with MB. Hippocampal avoidance should be evaluated in a prospective cohort of pediatric patients with MB. PLAIN LANGUAGE SUMMARY: In this study, the patterns of disease recurrence in patients with a pediatric brain tumor known as medulloblastoma treated with proton radiotherapy were examined. The majority of failures occur outside of an important structure related to memory formation called the hippocampus. Hippocampal sparing radiation plans using proton radiotherapy were generated and showed that dose to the hippocampus was able to be significantly reduced. The study provides the rationale to explore hippocampal sparing in pediatric medulloblastoma in a prospective clinical trial.

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

BACKGROUND: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. METHODS: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. RESULTS: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. CONCLUSION: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.

The Hand and Wrist: AntImicrobials and Infection (HAWAII) trial.

BACKGROUND: Hand trauma, comprising injuries to both the hand and wrist, affects over five million people per year in the NHS, resulting in 250 000 operations each year. Surgical site infection (SSI) following hand trauma surgery leads to significant morbidity. Triclosan-coated sutures may reduce SSI in major abdominal surgery but have never been tested in hand trauma. Feasibility needs to be ascertained before a definitive trial can be delivered in hand trauma. METHODS: A multicentre feasibility RCT of antimicrobial sutures versus standard sutures involving adults undergoing surgery for hand trauma to evaluate feasibility for a definitive trial. Secondary objectives were incidence of SSI in both groups, hand function measured with patient-reported outcome measures, health-related quality of life and change in employment. Randomization was performed on a 1:1 basis, stratified by age of the patient and whether the injury was open or closed, using a secure, centralized, online randomization service. Participants were blinded to allocation. RESULTS: 116 participants were recruited and randomized (60 intervention, 56 control). Of 227 screened, most were eligible (89.5 per cent), and most who were approached agreed to be included in the study (84.7 per cent). Retention was low: 57.5 per cent at 30 days, 52 per cent at 90 days and 45.1 per cent at 6 months. Incidence of SSI was >20 per cent in both groups. Hand function deteriorated after injury but recovered to near pre-injury levels during the study period. CONCLUSIONS: Risk of SSI after hand trauma is high. A definitive RCT of antimicrobial sutures in hand trauma surgery is feasible, if retention is improved. TRIAL REGISTRATION: ISRCTN10771059.

Ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor after treatment with imatinib: a plain language summary of the phase 3 INTRIGUE trial.

WHAT IS THIS SUMMARY ABOUT?: This document presents a patient-friendly summary of the phase 3 INTRIGUE clinical trial results, which were published in the Journal of Clinical Oncology in August 2022. A phase 3 trial is a study that tests the safety of a proposed treatment and how well it works compared with a standard treatment or a treatment with no active ingredient (also called a placebo). The aim of the INTRIGUE trial was to understand whether treatment with a drug called ripretinib (brand nameQINLOCK®) was superior to treatment with sunitinib (brand name SUTENT®) in participants with advanced gastrointestinal stromal tumor (also known as GIST) who cannot tolerate or whose disease progressed beyond first-line treatment with imatinib (brand name GLEEVEC®). The INTRIGUE trial included 453 participants with advanced GIST who had previously been treated with a tyrosine kinase inhibitor (also known as a TKI) medicine called imatinib. For patients with advanced GIST who cannot tolerate or whose disease progresses while taking imatinib, the recommended second-line TKI medicine is sunitinib. The recommended third-line TKI medicine is called regorafenib (brand name STIVARGA®). Ripretinib is currently the only medication approved for adults with advanced GIST who have previously been treated with 3 or more TKIs (fourth-line). WHAT WERE THE RESULTS?: The trial showed that ripretinib did not significantly increase the time that participants survived without their cancer getting worse (progression-free survival or PFS) over sunitinib. However, participants treated with ripretinib had similar PFS to those treated with sunitinib. Importantly, treatment with ripretinib resulted in fewer severe adverse events, or side effects, compared with sunitinib, and participants reported better quality of life with ripretinib compared with sunitinib. WHAT DO THE RESULTS MEAN?: Treatment with ripretinib, after imatinib stops working or can no longer be tolerated, provided similar PFS for participants with advanced GIST and had fewer severe adverse events compared with sunitinib. Sunitinib is the only medication currently approved for use as a second-line treatment in patients with advanced GIST previously treated with imatinib. With more investigation, ripretinib could be a treatment option for these patients. Patients should always talk to their medical team before making any decisions about their treatment.

Psychological and social challenges of patients with locally advanced and metastatic gastrointestinal stromal tumours (GIST) on long-term treatment with tyrosine kinase inhibitors: a qualitative study with patients and medical oncologists.

PURPOSE: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of locally advanced and metastatic gastrointestinal stromal tumours (GISTs). Patients are experiencing prolonged survival but often at the expense of their health-related quality of life. It is not only the physical side effects that impact GIST patients' daily lives but also the psychological and social challenges they have to deal with. This qualitative study aimed to explore the psychological and social life challenges of GIST patients with locally advanced and metastatic disease on ≥ 5 years TKI treatment. METHODS: Semi-structured interviews with 15 locally advanced and/or metastatic GIST patients and 10 medical oncologists with experience of delivering care to this specific patient group were conducted. Thematic analysis was used to interpret the data. RESULTS: Psychological challenges expressed by participants concerned fears, scanxiety, negative change in emotion and mood, doubts about their treatment and follow-up, living with uncertainty, lack of understanding from others or healthcare professionals, and constantly being reminded of their illness. Challenges regarding social health included financial difficulties, challenges in relationships, concerns about fertility and parenting, work, and impact on social activities. CONCLUSION: The reported psychological and social challenges can significantly hamper the overall quality of life of GIST patients. Some challenges were clearly underreported and hardly recognized by medical oncologist, as they may tend to focus on the physical side effects and clinical outcomes of treatment. Therefore, it is essential to take the patient's perspective into account in research and clinical practice to ensure optimal care for this patient group.

Validation of a novel risk score to predict early and late recurrence in solitary fibrous tumour.

BACKGROUND: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. METHODS: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. RESULTS: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and SalasOS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. CONCLUSIONS: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.

KIT-Associated Familial GIST Syndrome: Response to Tyrosine Kinase Inhibitors and Implications for Risk Management.

Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.

Immunotherapy of sarcomas with modified T cells.

PURPOSE OF REVIEW: To summarize the development of modified T-cell therapies in sarcomas and discuss relevant published and ongoing clinical trials to date. RECENT FINDINGS: Numerous clinical trials are underway evaluating tumor-specific chimeric antigen receptor T cells and high affinity T-cell receptor (TCR)-transduced T cells in sarcomas. Notably, translocation-dependent synovial sarcoma and myxoid/round cell liposarcoma are the subject of several phase II trials evaluating TCRs targeting cancer testis antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen-A4 (MAGE A4), and response rates of up to 60% have been observed for NY-ESO-1 directed, modified T cells in synovial sarcoma. Challenges posed by modified T-cell therapy include limitations conferred by HLA-restriction, non-immunogenic tumor microenvironments (TME), aggressive lymphodepletion and immune-mediated toxicities restricting coinfusion of cytokines. SUMMARY: Cellular therapy to augment the adaptive immune response through delivery of modified T cells is an area of novel therapeutic development in sarcomas where a reliably expressed, ubiquitous target antigen can be identified. Therapeutic tools to improve the specificity, signaling, proliferation and persistence of modified TCRs and augment clinical responses through safe manipulation of the sarcoma TME will be necessary to harness the full potential of this approach.

Promoting informed prostate cancer screening decision-making for African American men in a community-based setting.

PURPOSE: Current screening guidelines for prostate cancer (PCa) encourage men to make individual screening decisions after consulting with their primary care provider to weigh the risks and benefits of undergoing prostate specific antigen (PSA) testing, but many men at high risk of PCa diagnosis (notably African American men) are more likely to be uninsured and lack a primary care provider. An academic-community partnership redesigned its community-based screening program to ensure access to services for African American men, incorporating a session with a trained clinical educator in community settings, designed to increase knowledge and promote informed decision-making regarding PSA testing. This study evaluated effects of the intervention on decision-making outcomes. METHODS: To evaluate program efficacy, 88 men completed pre- and post-test surveys assessing outcomes of interest. RESULTS: Participants' knowledge, beliefs, attitudes, anxiety levels, and self-efficacy all improved from pre- to post-test at a statistically significant level. Most notably participants' awareness that PCa is often not life-threatening, and watchful waiting is a reasonable treatment option increased after the encounter. More than half of the study sample felt they had received enough knowledge to make an informed decision about whether the PSA test was right for them. CONCLUSION: Our findings show the program had positive effects on men's ability to make informed decisions about PCa screening and demonstrate that educational outreach programs with an emphasis on informed decision-making can effectively balance screening guidelines with the needs of underserved populations in community settings to improve outcomes.

Machine learning for rhabdomyosarcoma histopathology.

Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly among histologic types of RPS, with implications for management. The Transatlantic Australasian RPS Working Group (TARPSWG) published a consensus approach to primary RPS, and to complement this, one for recurrent RPS in 2016. Since then, additional studies have been published, and collaborative discussion is ongoing to address the clinical challenges of local recurrence in RPS. METHODS: An extensive literature search was performed, and the previous consensus statements for recurrent RPS were updated after review by TARPSWG members. The search included the most common RPS histologic types: liposarcoma, leiomyosarcoma, solitary fibrous tumor, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor. RESULTS: Recurrent RPS management was evaluated from diagnosis to follow-up evaluation. For appropriately selected patients, resection is safe. Nomograms currently are available to help predict outcome after resection. These and other new findings have been combined with expert recommendations to provide 36 statements, each of which is attributed a level of evidence and grade of recommendation. In this updated document, more emphasis is placed on histologic type and clarification of the intent for surgical treatment, either curative or palliative. Overall, the fundamental tenet of optimal care for patients with recurrent RPS remains individualized treatment after multidisciplinary discussion by an experienced team with expertise in RPS. CONCLUSIONS: Updated consensus recommendations are provided to help guide decision-making for treatment of locally recurrent RPS and better selection of patients who would potentially benefit from surgery.

Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial.

BACKGROUND: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.

On the road to improved outcomes by capturing leiomyosarcoma patients' views.

An international collaborative project set up as a 'priority setting partnership' used a questionnaire to capture the views of patients, carers and clinicians about the sarcoma research agenda. Responses from 25 patients with leiomyosarcoma (LMS) in eight countries provided useful insight from the patient's perspective. Unmet needs identified by patients were in the areas of: LMS-specific trial design; exploring new therapeutic avenues; avoiding morcellation; exploring the immune system in LMS; investigating circulating tumor DNA; implementing molecular characterization of LMS; conducting basic research and a translational pipeline; evaluating imaging modalities; improving early diagnosis; identifying patient-reported outcomes; improving communication, information and support; and addressing survivorship and end-of-life care. Each of the unmet needs is described in more detail.

Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval.

Over the past 20 years, the management of gastrointestinal stromal tumors has acted as an important model in the advancement of molecularly targeted therapies for solid tumors. The success of imatinib has established it as a lasting therapy in the management of early-stage and advanced disease in the first-line setting. Imatinib resistance inevitably develops, resulting in the need for further lines of therapy. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor, specifically developed to target both primary and secondary KIT and PDGFRα resistance mutations. Herein, the authors discuss the molecular rationale, the preclinical evidence and the clinical use of ripretinib in the treatment of gastrointestinal stromal tumors in the advanced stages of disease.

KIT Exon 9-Mutated Gastrointestinal Stromal Tumours: Biology and Treatment.

BACKGROUND: The majority of gastroinstestinal stromal tumours (GISTs) harbour oncogenic mutations in the gene encoding for the tyrosine kinase (TK) KIT. The most common mutations are found in exon 11, followed by mutations in exon 9. The latter mutations are associated more frequently with GISTs in extra-gastric locations and with a more aggressive clinical behaviour. SUMMARY: Here, we review the unique and often poorly recognized molecular, biological, and clinical characteristics that differentiate KIT exon 9-mutant GISTs from other GIST subtypes. In particular, KIT exon 9 mutations are associated to KIT mutants with retained sensitivity to stimulation by stem cell factor and localization to the cell membrane. Moreover, KIT exon 9-mutant GISTs display significant activation of KIT-independent oncogenic pathways. These characteristics may explain the limited activity of the TK inhibitor imatinib in the adjuvant setting in KIT exon 9-mutant GISTs, as well as their lower sensitivity to standard dose imatinib in the advanced setting. In contrast, the multi-TK inhibitor sunitinib displays better activity in KIT exon 9-mutant GISTs compared to others. KEY MESSAGES: KIT exon 9-mutant GISTs represent a subtype of GIST distinct from other GISTs, including the more common KIT exon 11-mutant GISTs. A better understanding of the molecular biology and clinical behaviour of KIT exon 9-mutant GISTs may help identify more improved treatment options.