Rare Subgroups Research Articles

Community organization and network complexity and stability: contrasting strategies of prokaryotic versus eukaryotic microbiomes in the Bohai Sea and Yellow Sea.

Unraveling the effects of spatial gradients on microbiome assembly and association is a challenging topic that remains understudied in the coastal ecosystem. Here, we aimed to investigate the effects of spatial variation on the network complexity and stability of plankton microbiomes in the Bohai Sea and Yellow Sea. These seas serve as spawning and nursery grounds for economically important fisheries valued at billions of dollars annually. Environmental heterogeneity structures microbial communities into distinct spatial patterns, leading to complex direct/indirect relationships and broader ecological niches of bacterioplankton compared to microeukaryotic communities. Interestingly, salinity gradients positively influenced the richness of rare subgroups of bacterioplankton, while the rare microeukaryotic subgroups showed an opposite trend. Abundant subgroups of prokaryotic/eukaryotic microbiomes exhibited greater environmental niche breadth and lower phylogenetic distance compared to the rare subgroups. Stochastic processes contributed greatly to microbiome dynamics, and deterministic processes governed the bacterioplankton organization with a lower phylogenetic turnover rate. Compared to microeukaryotes, bacterioplankton exhibit higher network modularity, complexity, and robustness and lower fragmentation, and vulnerability. These observations offer vital insights into the anti-interference ability and resistance of plankton microbiomes in response to environmental gradients in terms of organization and survival strategy as well as their adaptability to environmental disturbances.IMPORTANCEAn in-depth understanding of community organization and stability of coastal microbiomes is crucial to determining the sustainability of marine ecosystems, such as the Bohai Sea and Yellow Sea. Distinct responses between prokaryotic and eukaryotic microbiomes to spatial heterogeneity were observed in terms of geographical distribution, phylogenetic distance, niche breadth, and community assembly process. Environmental variations are significantly correlated with the dynamics of rare eukaryotic plankton subcommunities compared to prokaryotic plankton subcommunities. Deterministic processes shaped prokaryotic plankton community organization with a lower phylogenic turnover rate. Rare subgroups had noticeably higher phylogenetic distance and lower niche breadth than the corresponding abundant subgroups. Prokaryotic microbiomes had higher molecular network complexity and stability compared to microeukaryotes. Results presented here show how environmental gradients alter both the geographical characteristics of the microbial organization in coastal seas and also their co-occurrence network complexity and stability and thus have critical implications for nutrient and energy cycling.

Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D.

Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib. Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children. A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children. This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

The genomic landscape of 2,023 colorectal cancers

Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2–9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichiacolipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11–13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

Two cases of atrial myxoma with calcification and ossification as the main features

BackgroundCardiac myxomas are the most common type of primary cardiac tumors in adults, but they can have variable features that make them difficult to diagnose. We report two cases of atrial myxoma with calcification or ossification, which are rare pathological subgroups of myxoma.Case presentationA 47-year-old woman and a 35-year-old man presented to our hospital with different symptoms. Both patients had a history of chronic diseases. Transthoracic and transesophageal echocardiography revealed a mass in the left or right atrium, respectively, with strong echogenicity and echogenic shadows. The masses were suspected to be malignant tumors with calcification or ossification. Contrast transthoracic echocardiography(cTEE) showed low blood supply within the lesions. The patients underwent surgical resection of the atrial mass, and the pathology confirmed myxoma with partial ossification or massive calcification.ConclusionWe report two rare cases of atrial myxoma with calcification or ossification and analyze their ultrasonographic features. Transthoracic echocardiography and cTEE can provide valuable information for the diagnosis and management of such mass. However, distinguishing calcification and ossification in myxoma from calcification in malignant tumors is challenging. More studies are needed to understand the pathogenesis and imaging characteristics of these myxoma variants.

Considerations for pooling real-world data as a comparator cohort to a single arm trial: a simulation study on assessment of heterogeneity

BackgroundNovel precision medicine therapeutics target increasingly granular, genomically-defined populations. Rare sub-groups make it challenging to study within a clinical trial or single real-world data (RWD) source; therefore, pooling from disparate sources of RWD may be required for feasibility. Heterogeneity assessment for pooled data is particularly complex when contrasting a pooled real-world comparator cohort (rwCC) with a single-arm clinical trial (SAT), because the individual comparisons are not independent as all compare a rwCC to the same SAT. Our objective was to develop a methodological framework for pooling RWD focused on the rwCC use case, and simulate novel approaches of heterogeneity assessment, especially for small datasets.MethodsWe present a framework with the following steps: pre-specification, assessment of dataset eligibility, and outcome analyses (including assessment of outcome heterogeneity). We then simulated heterogeneity assessments for a binary response outcome in a SAT compared to two rwCCs, using standard methods for meta-analysis, and an Adjusted Cochran’s Q test, and directly comparing the individual participant data (IPD) from the rwCCs.ResultsWe found identical power to detect a true difference for the adjusted Cochran’s Q test and the IPD method, with both approaches superior to a standard Cochran’s Q test. When assessing the impact of heterogeneity in the null scenario of no difference between the SAT and rwCCs, a lack of statistical power led to Type 1 error inflation. Similarly, in the alternative scenario of a true difference between SAT and rwCCs, we found substantial Type 2 error, with underpowered heterogeneity testing leading to underestimation of the treatment effect.ConclusionsWe developed a methodological framework for pooling RWD sources in the context of designing a rwCC for a SAT. When testing for heterogeneity during this process, the adjusted Cochran’s Q test matches the statistical power of IPD heterogeneity testing. Limitations of quantitative heterogeneity testing in protecting against Type 1 or Type 2 error indicate these tests are best used descriptively, and after careful selection of datasets based on clinical/data considerations. We hope these findings will facilitate the rigorous pooling of RWD to unlock insights to benefit oncology patients.

P49 Epidemiology of skin cancer by ethnicity in England, 2013–2020: a cohort study

Abstract Skin cancer rates are increasing worldwide and predominantly affect people of white ethnicity. Although less common, skin cancers in people with skin of colour (SOC) are more likely to experience diagnostic delays and higher mortality. High-quality epidemiological data on skin cancers in SOC are limited. SOC and skin phototype are not recorded in registry data; however, the ethnic group can be used as a somewhat limited proxy. The aim of this retrospective national cancer registry cohort study was to describe skin cancer epidemiology by the ethnic group. We identified a cohort of patients diagnosed with skin cancer in England (2013–2020) from the National Disease Registration Service (NDRS). The ethnic group is routinely recorded as self-reported during hospital visits in Patient Administration System and Hospital Episode Statistics datasets collected by the NDRS. We analysed data by the broad ethnic group [White, Asian (excluding Chinese), Black, Chinese, mixed, other, unknown]. We report counts, incidence, stage at presentation (melanoma only), referral pathway, anatomical location and geographical variation. The first basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) per patient were reported. More cases of skin cancers were diagnosed in Asian ethnicities than in Black and Chinese ethnicities, except for melanoma, which was more frequently diagnosed in Black ethnicities. Of 713 615 BCCs, 571 396 (80.1%) were reported in White, 799 (0.1%) in Asian, 634 (0.1%) in mixed, 413 (0.1%) in Black, 156 (0.02%) in Chinese and 3122 (0.4%) in people of ‘other’ ethnicities; 137 095 (19.2%) were of ‘unknown’ ethnicity. Of 244 072 cSCCs, 225 534 (92.4%) were in White, 609 (0.2%) in Asian, 354 (0.1%) in Black, 279 (0.1%) in mixed, 66 (0.03%) in Chinese and 1137 (0.5%) in people of ‘other’ ethnicity; 16 093 (6.6%) were of ‘unknown’ ethnicity. Of 111 676 melanomas, 102 273 (91.6%) were in White, 199 (0.2%) in Black, 180 (0.2%) in Asian, 125 (0.1%) in mixed, 25 (0.02%) in Chinese and 695 (0.6%) in ‘other’ ethnicities; 8179 (7.3%) were of ‘unknown’ ethnicity. This is the first national study of skin cancer types by ethnicity in England. National datasets allow for the better evaluation of rare subgroups of patients. The main limitation is the high proportion of unknown ethnicity reporting, which is higher for keratinocyte cancers than for other cancers, presumably due to their automated processing and lack of data sources (i.e. inpatient or multidisciplinary team datasets). These data will support a better understanding of unmet clinical needs in underserved populations.

Stratified split sampling of electronic health records

Although superficially similar to data from clinical research, data extracted from electronic health records may require fundamentally different approaches for model building and analysis. Because electronic health record data is designed for clinical, rather than scientific use, researchers must first provide clear definitions of outcome and predictor variables. Yet an iterative process of defining outcomes and predictors, assessing association, and then repeating the process may increase Type I error rates, and thus decrease the chance of replicability, defined by the National Academy of Sciences as the chance of “obtaining consistent results across studies aimed at answering the same scientific question, each of which has obtained its own data.”[1] In addition, failure to account for subgroups may mask heterogeneous associations between predictor and outcome by subgroups, and decrease the generalizability of the findings. To increase chances of replicability and generalizability, we recommend using a stratified split sample approach for studies using electronic health records. A split sample approach divides the data randomly into an exploratory set for iterative variable definition, iterative analyses of association, and consideration of subgroups. The confirmatory set is used only to replicate results found in the first set. The addition of the word ‘stratified’ indicates that rare subgroups are oversampled randomly by including them in the exploratory sample at higher rates than appear in the population. The stratified sampling provides a sufficient sample size for assessing heterogeneity of association by testing for effect modification by group membership. An electronic health record study of the associations between socio-demographic factors and uptake of hepatic cancer screening, and potential heterogeneity of association in subgroups defined by gender, self-identified race and ethnicity, census-tract level poverty and insurance type illustrates the recommended approach.

Data Challenges for Externally Controlled Trials: Viewpoint.

The preferred evidence of a large randomized controlled trial is difficult to adopt in scenarios, such as rare conditions or clinical subgroups with high unmet needs, and evidence from external sources, including real-world data, is being increasingly considered by decision makers. Real-world data originate from many sources, and identifying suitable real-world data that can be used to contextualize a single-arm trial, as an external control arm, has several challenges. In this viewpoint article, we provide an overview of the technical challenges raised by regulatory and health reimbursement agencies when evaluating comparative efficacy, such as identification, outcome, and time selection challenges. By breaking down these challenges, we provide practical solutions for researchers to consider through the approaches of detailed planning, collection, and record linkage to analyze external data for comparative efficacy.

Method considerations and study protocol for a Nordic multi-centre prospective study on outcomes in rare paediatric epilepsy surgery subgroups.

Epilepsy surgery is a therapeutic option for selected children with drug-resistant epilepsy. Children who are surgical candidates have a high prevalence of neurodevelopmental comorbidities. There is a lack of adequately sized prospective studies in a number of rare surgical subgroups, especially of outcome domains such as cognitive level and health-related quality-of-life. In this article, we describe method considerations and a study protocol for a Nordic population-based multi-centre follow-up programme covering seizure as well as non-seizure outcomes in children aged <4 years undergoing resective epilepsy surgery and children aged ≤18 years undergoing hemispherotomy, callosotomy or surgery for hypothalamic hamartoma.

Mother-newborn ABO group discrepancy caused by a rare BW.17 variant

Several ABO gene mutations are known to determine rare subgroups: these ABO variants are often responsible for weak or null phenotypes and may cause an incorrect determination of the serotype. Here we describe for the first time the phenotypic discrepancy of a rare B allele within the same Caucasian family that depends on the co-inheritance with A or H antigen. Blood samples from newborns, mothers, and grandmothers were analysed through routine serotype and genotype testing. Blood compatibility test was performed for red blood cells or serum of the grandmother. ABO exons were investigated through PCR and sanger sequencing. According to serology, the phenotype of the mother was AB, while it was O for the newborn. Genotype analysis confirmed that the mother was AB, while the newborn was found to be B. Sanger sequencing revealed the presence of a rare mutation in both individuals (784 G>A, D262N), corresponding to the ABO*BW.17 allele. The grandmother was found to have the same genotype/serotype of the newborn. Crossmatch testing suggested that subjects with this genotype/serotype might be considered O donors and recipients.

Abnormal DNA Damage Response Suggests Novel Fingerprint of Relapse in Acute Monocytic Leukemia Post Transplantation

Background The heterogeneity of acute myeloid leukemia plays an important role in the development of drug resistance. Minimal residual disease is the major cause of relapse for the patients who already received chemotherapy and stem cell transplantation. Some rare subgroups of leukemia cells harboring relapse-inducing genes were selected after chemotherapy. To unravel intra-tumoral heterogeneity and selective drug-resistance, single-cell RNA sequencing (scRNA-seq) was already performed on many solid tumors and blood cancer to achieve the high-resolution transcriptomic profiling on individual cells from a larger heterogeneous population. However, the mechanism underlying the reason of leukemia heterogeneity is still not validated. Methods Since single-cell suspension was obtained from bone marrow of acute myeloid leukemia samples, we used the 10x Genomics Chromium platform to capture transcriptomes of single cells on barcoded mRNA capture beads for massively parallel scRNA-seq. Data processing followed by Cell Ranger software pipeline to demultiplex cellular barcodes, and map reads to the genome and transcriptome hg38 using the STAR aligner. Unique molecular identifier (UMI) count matrix and quality control was performed using Seurat. The t-SNE map was calculated using Rtsne package. The related genes were overexpressed or knockdown in Thp1 cell line to investigate their roles in DNA damage response. Results We analyzed transcriptome data from above 50K single leukemia bone marrow cells across 3 patients during newly diagnosed, complete remission and relapse stages. These 3 patients belong to M4 or M5, according to French-American-British classification. The genotyping of them exhibited positive WT1-ABL, and negative for c-Kit, NPM1, FLT3-ITD and FL3-TKD. To define the landscape of cellular heterogeneity and its association with outcome in an unbiased manner, we performed unsupervised machine learning algorithm on near 50K single cells from leukemia bone marrow and identify one robust 14-cluster solution (from 0 to 13, Figure 1A) and the hallmark genes within each clusters (Figure 1B). The pattern exhibits distinct distribution on different stages (Figures 1C), indicating intra-tumoral heterogeneity during leukemia progression. The cluster 0 mainly contains newly diagnosed cells. Within cluster 0, several hallmark genes (Figure 2A), such as LILRB2(Leukocyte immunoglobulin like receptor 2) and TNFAIP2(TNF alpha induced protein 2) were already reported to be associated with AML. Interestingly, the subpopulation of PTAFR (Platelet-activating factor receptor) highly expressing cells were identified in newly diagnosed group, though whether PTAFR can induce acute myeloid leukemia is still elusive. Cells expressing these genes rarely occur at relapse region (Figure 1C), implying that these genes may be not related to relapse. However, cells expressing genes, such as RPS4Y1(Ribosomal protein S4, Y isoform 1), CDKN2A, KLF1 or GATA1 were mainly distributed in relapse group, and rare cells can be found in newly diagnosed group, implying that these genes may have potential role in chemotherapy resistance, and subclones expressing these genes expanded during leukemia progression. The high expression of KLF1 as erythropoietic transcription factor and GATA1 was associated with AML. Higher levels of GATA1 expression had poor outcomes. Next, we found these genes were associated with abnormal DNA damage response, which contributes to leukemia heterogeneity. These genes can regulate the pathway of DNA damage repair as the switch between NHEJ (Non-Homologous End Joining) and HR (Homologous recombination). Conclusion The application of scRNA-seq in cancer has been relatively limited in patients who achieve remission and appear relapse after therapy. We analyze heterogeneity of acute myeloid leukemia during progression and identify novel relapse subgroups in these heterogeneous populations. Our results show a greater degree of heterogeneity in AML tumor samples during leukemia progression, compared to traditional bulk RNA-seq, and highlights the potential of single-cell RNA-seq to identify novel subgroups in AML related to relapse, demonstrating the value of single-cell analysis for AML. Furthermore, we illustrate the roles of relapse-related genes in regulating DNA damage response, which facilitate better understanding of leukemia heterogeneity.

GIST avancées : quels traitements en 2022 ?

Gastrointestinal stromal tumors (GIST) are rare digestive tumors. Activating KIT mutations are the most common molecular alteration in these patients, identified in approximately 70% of cases, followed by PDGFRA mutations (10-15%), of which the D842V mutation accounts for most cases. Succinate dehydrogenase (SDH) deficiency and alterations involving NF1, BRAFV600E, RAS or NTRK genes are rare molecular subgroups. In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively. Two new compounds have recently been evaluated in patients with advanced GIST. Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments. Avapritinib is now the recommended first-line treatment in this subgroup and may represent an additional option, whose place remains to be clarified, in pre-treated patients without D842V mutations. Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.

HGG-14. Molecular characterization of unique biological subgroups among H3 wild type high-grade gliomas

INTRODUCTION: Paediatric high-grade gliomas (HGG) are characterised by the aggressive biological behaviour with dismal prognosis of long-term survival 10-15%. Current molecular-biological diagnostic approaches allow for more precise characterization and determination of new unique subgroups of HGG. Our aim was to identify novel and rare HGG subgroups within our institution cohort. PATIENTS AND METHODS: Our reference centre patients′ cohort consisted of 97 clinically annotated patients with HGG diagnosed between 2000 and 2021. Sanger sequencing was used for screening of the most common HGG-related oncogenic drivers; furthermore we employed whole genome methylation array (Illumina Infinium MethylationEPIC BeadChip) and for selected samples RNA sequencing and expression profiling. RESULTS: Based on H3 status and previous radiotherapy we separated our HGG cases into the RIG, H3mut and H3wt groups. In contrast to H3mut(n=35) and RIG(n=11) that were uniformly fatal, H3wt group contained a proportion of long-term survivors. In the H3wt group we found patients carrying driver mutations in IDH1/2 (n=2) and BRAFV600E (7). Five young patients (under 3) consisted of 3 infant hemispheric gliomas (with NTRK and ROS1 fusions), one gliomatosis cerebri and one brainstem anaplastic astrocytoma with MYB/QKI fusion. We also identified a rare EWSR1-PATZ1 gene fusion in one patient. Importantly, long-term survivors recruited from these subgroups. On the contrary, four cases of MYCN GBM with poor prognosis presented in various locations: one disseminated, one gliomatosis cerebri and two with hemispheric tumour. We identified one patient with “hypermutated” glioblastoma and used targeted therapy with Nivolumab. In three samples of our patients with thalamic glioblastomas, we detected “loss of H3K27-trimethylation” caused by EZHIP overexpression. These tumours proved to be very aggressive with early metastatic recurrence and dismal prognosis. SUMMARY: Detailed characterization of H3 wild-type HGG is very important for further understanding of their biological behaviour, diagnostics, prognostication and identification of therapeutic targets.

Uncommon EGFR mutations in lung carcinoma: features and treatment outcomes in a retrospective French cohort.

BackgroundThe best management for rare epidermal growth factor receptor (EGFR) mutations in advanced non-small cell lung carcinoma (NSCLC) remains uncertain. The literature indicates that response to usual treatment could differ in certain subgroups such as exon 20 insertion/duplication (E20ID), other single uncommon mutation (OSUM), and EGFR complex mutation (ECM).MethodsIn this observational, regional, multi-center, retrospective study, we gathered data on uncommon EGFR mutations in NSCLC from 2007 to 2021. We analyzed patient characteristics, prognostic factors and treatment outcomes [objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS)].ResultsAmong 119 patients with an uncommon EGFR mutant, 34 harbored E20ID, 23 ECM, and 62 OSUM. There were significantly more non-smokers in E20ID. Female gender and performance status <2 were associated with a better prognosis. Among the 97 metastatic patients with available data for 1st line treatment, median estimated OS was 21 months (95% CI: 18–31 months), with better non-significant OS for ECM. Median estimated PFS was 7 months (95% CI: 4–9 months). We found significant differences in ORR, DCR and PFS favoring 1st line chemotherapy for E20ID, whereas the outcomes for OSUM and ECM were more favorable for tyrosine kinase inhibitor (TKI) (mainly 2nd and 3rd generation).ConclusionsThere were variations in treatment outcomes among subgroups in our cohort. Exon 20 insertions showed better ORR and PFS with 1st line chemotherapy compared to TKI. Conversely, other rare EGFR mutations including ECM had better ORR and PFS with TKI than chemotherapy. There was no significant difference in OS among treatment groups overall or within rare mutation subgroups.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

A novel fusion between CDC42BPB and ALK in a patient with quadruple wild‐type gastrointestinal stromal tumor

BackgroundGastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor in gastrointestinal tract, with striking features of morphology and immunohistochemistry. But GISTs in pregnancy could seldom be found. Pathogenic activating mutations of the proto‐oncogene KIT and PDGFRA are detected in majority GISTs, and adjuvant imatinib therapy targeting KIT and PDGFRA mutations is recommended for patients with high‐risk GIST. However, some rare subgroups with distinct molecular features remain uncovered and more therapeutic targets need to be revealed.MethodsThe DNA/RNA samples were detected using the NGS‐based YuanSu450 gene panel. After identifying the CDC42BPB‐ALK fusion by NGS, this novel fusion was further confirmed by Sanger sequencing. Subsequently, FISH analysis was performed using the Vysis ALK Break Apart FISH Probe kit to testify the ALK status. ALK protein expression was confirmed by IHC (D5F3 and 5A4).ResultsHerein, we reported the first case of quadruple wild‐type (WT) GIST with ALK‐CDC42BPB fusion and ALK (D5F3) overexpression. In this study, we described a 33‐year‐old pregnant patient in lactation who had a massive space occupying lesion (with the maximum diameter of 22 cm) in the stomach and was eventually diagnosed as quadruple WT GIST (KIT WT/PDGFRA WT/SDH WT/RAS‐P WT).ConclusionWe unexpectedly found that this GIST patient showed ALK (D5F3) overexpression and harbored a novel fusion CDC42BPB exon 24‐ALK in exon 20.

Standardizing registry data to the OMOP Common Data Model: experience from three pulmonary hypertension databases

BackgroundThe Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) can be used to transform observational health data to a common format. CDM transformation allows for analysis across disparate databases for the generation of new, real-word evidence, which is especially important in rare disease where data are limited. Pulmonary hypertension (PH) is a progressive, life-threatening disease, with rare subgroups such as pulmonary arterial hypertension (PAH), for which generating real-world evidence is challenging. Our objective is to document the process and outcomes of transforming registry data in PH to the OMOP CDM, and highlight challenges and our potential solutions.MethodsThree observational studies were transformed from the Clinical Data Interchange Standards Consortium study data tabulation model (SDTM) to OMOP CDM format. OPUS was a prospective, multi-centre registry (2014–2020) and OrPHeUS was a retrospective, multi-centre chart review (2013–2017); both enrolled patients newly treated with macitentan in the US. EXPOSURE is a prospective, multi-centre cohort study (2017–ongoing) of patients newly treated with selexipag or any PAH-specific therapy in Europe and Canada. OMOP CDM version 5.3.1 with recent OMOP CDM vocabulary was used. Imputation rules were defined and applied for missing dates to avoid exclusion of data. Custom target concepts were introduced when existing concepts did not provide sufficient granularity.ResultsOf the 6622 patients in the three registry studies, records were mapped for 6457. Custom target concepts were introduced for PAH subgroups (by combining SNOMED concepts or creating custom concepts) and World Health Organization functional class. Per the OMOP CDM convention, records about the absence of an event, or the lack of information, were not mapped. Excluding these non-event records, 4% (OPUS), 2% (OrPHeUS) and 1% (EXPOSURE) of records were not mapped.ConclusionsSDTM data from three registries were transformed to the OMOP CDM with limited exclusion of data and deviation from the SDTM database content. Future researchers can apply our strategy and methods in different disease areas, with tailoring as necessary. Mapping registry data to the OMOP CDM facilitates more efficient collaborations between researchers and establishment of federated data networks, which is an unmet need in rare diseases.

Two-Stage Single-Arm Trials Are Rarely Analyzed Effectively or Reported Adequately.

PURPOSETwo-stage single-arm designs have historically been the most common design used in phase II oncology. They remain a mainstay today, particularly for trials in rare subgroups. Consequently, it is imperative such studies be designed, analyzed, and reported effectively. We comprehensively review such trials to examine whether this is the case.METHODSOncology trials that used Simon's two-stage design over a 5-year period were identified and reviewed. They were evaluated for whether they reported sufficient design (eg, required sample size) and analysis (eg, CI) details. Articles that did not adjust their inference for the incorporation of an interim analysis were also reanalyzed.RESULTSFour-hundred twenty-five articles were included. Of these, just 47.5% provided the five components that ensure design reproducibility. Only 1.2% and 2.1% reported an adjusted point estimate or CI, respectively. Just 55.3% provided the final stage rejection bound, indicating many trials did not test a hypothesis for their primary outcome. Trial reanalyses suggested reported point estimates underestimated treatment effects and reported CIs were too narrow.CONCLUSIONKey design details of two-stage single-arm trials are often unreported. Their inference is rarely performed such as to remove bias introduced by the interim analysis. These findings are particular alarming when considered against the growing trend in which nonrandomized trials make up a large proportion of all evidence on a treatment's effectiveness in a rare biomarker-defined patient subgroup. Future studies must improve the way they are analyzed and reported.

ASCO 2021—an update on metastastic colorectal cancer

SummaryThe 2021 ASCO Annual Meeting provided updates on novel therapies in rare subgroups of metastatic colorectal cancer, such as immunotherapy in microsatellite instable colorectal cancer and antibody–drug conjugate therapy in HER2-positive disease. Furthermore, the concept of anti-EGFR rechallenge therapy has received additional momentum with data from the CHRONOS trial in regard to treating patients in later lines as well as how to integrate analysis of circulating tumor DNA in clinical decision-making.

Refined prognostic staging for resected pancreatic cancer by modified stage grouping and addition of tumour grade

BackgroundWith changes in T and N categories the 8th edition of the AJCC/UICC TNM staging system for pancreatic cancer resulted in improved prognostic staging, but inconsistencies were observed with specific stage groups. Tumour grading remains disregarded in prognostic staging. We aimed to validate the current staging system and to investigate the possibility of further optimization by integration of grading. Methods1946 patients undergoing upfront surgical resection for pancreatic adenocarcinoma from 10/2001 to 12/2015 were identified from a prospective institutional database. Survival analyses based on the 8th UICC TNM edition were performed and rare TNM subgroups were reallocated based on survival. The impact of tumour grade on stage-specific survival was assessed and a TNMG staging system was developed. ResultsThe 8th UICC staging system accurately stratified prognosis except for comparable survival in stages IB (pT2N0M0) and IIA (pT3N0M0). Regrouping of pT3N0M0 and pT1N1M0 to IB and of pT1N2M0 to II resulted in a modified staging system with higher consistency. High tumour grade (G3&G4 vs G1&G2) was associated with a significantly shorter survival in all new stage groups except for stage IV modified UICC. A TNMG-based prognostic stage grouping in which high tumour grade results in grouping with tumours of the next higher pTNM-stage resulted in improvement of prognostication in non-metastatic pancreatic cancer. ConclusionsThe 8th edition of the UICC TNM staging system leaves room for improvement. A TNMG staging system with adjustments in group-allocation of specific rarely occurring pTNM subgroups and integration of tumour grade results in improved prognostic stratification.