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BACKGROUND AND AIM: Patients with autoimmune inflammatory rheumatic disease (AIIRD) are at higher risk of severe infections because of their underlying diseases and immunosuppression. Our objective was to elucidate the epidemiological and clinical characteristics of patients with AIIRD presenting with COVID-19 and their relation to disease severity. We explored whether variables, including underlying diagnosis, disease-modifying antirheumatic drugs (DMARDs) and COVID-19 vaccine status, were associated with more severe forms of COVID-19 infection. METHODS: Between 1 January 2020 and 30 June 2022, 151 patients with AIIRD and COVID-19 infection were analysed using a binary regression model and a multinomial regression model. RESULTS: The average age was 61.5 years, and average Charlson Comorbidity Index (CCI) was 2.1; 106 (70.2%) patients were diagnosed with rheumatoid arthritis (RA), and 70 (46.4%) patients were receiving prednisolone. In the multivariable logistic regression model, ages between 50 and 69 years (odds ratio (OR) = 5.85; 95% confidence interval (CI) = 1.35-25.25) and older than 70 years (OR = 5.29; 95% CI = 1.21-23.14), prior prednisolone treatment (OR = 7.09; 95% CI = 2.63-19.11) and vaccination status including one and two doses (OR = 0.19; 95% CI = 0.05-0.69) and three and four doses (OR = 0.09; 95% CI = 0.02-0.35) were all statistically significant factors related to changes in the severity level of COVID-19. CONCLUSION: Severity of COVID-19 infection in patients with AIIRD is affected by age, background steroid use and vaccination status. Factors including sex, comorbidity, diagnosis of AIIRDs and use of DMARDs, including conventional synthetic, biologics and targeted DMARDs, were not significantly associated with COVID-19 severity.
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Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30-0.81); ctDNA- patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40-2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.
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OBJECTIVES: Although genetic testing (GT) is universally recommended for patients with epithelial ovarian cancer (EOC), rates are low (34%). In 1/2019, we implemented mainstreaming-GT in parallel with tumor testing via MSK-IMPACT within oncology clinics. We sought to determine GT rates pre/post-mainstreaming and patient characteristics associated with GT. METHODS: Patients with newly diagnosed EOC seen at our institution from 7/1/2015-3/31/2022 were included. Clinical data were abstracted including social determinants of health (SDOH) variables, race/ethnicity, marital status, insurance, language, comorbidities, employment, and Yost index, a measure of socioeconomic status. GT rates were calculated overall and pre-/post-mainstreaming (1/2019). Logistic regression models were fit to identify variables associated with GT. RESULTS: Of 1742 patients with EOC, 1591 (91%) underwent GT. Rates of GT increased from 87% to 95% after mainstreaming (p < 0.001). Among 151 patients not undergoing GT, major reasons were lack of provider recommendation (n = 76, 50%) and logistical issues (n = 38, 25%) with few declining (n = 14, 9%) or having medical complications preventing GT (n = 7, 4.6%). High-grade serous histology, advanced stage (III/IV), and having a spouse/partner were associated with increased GT uptake (p < 0.01). Among SDOH variables, there were no differences by insurance, Yost score, language, comorbidities, employment, or race/ethnicity. In multivariable models, likelihood of GT increased with mainstreaming, even after adjustment for histology, stage, and marital status (OR 3.77; 95% CI: 2.56-5.66). CONCLUSIONS: Mainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non-high-grade serous histology, and early-stage disease, representing potential areas for future interventions.
Subject(s)
Carcinoma, Ovarian Epithelial , Genetic Testing , Ovarian Neoplasms , Humans , Female , Middle Aged , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/pathology , Genetic Testing/statistics & numerical data , Genetic Testing/methods , Ovarian Neoplasms/genetics , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , Aged , Adult , Patient Acceptance of Health Care/statistics & numerical dataABSTRACT
OBJECTIVE: To gain consensus on the definitions and descriptions of the domains of the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials evaluating shared decision making (SDM) interventions. METHODS: Following the OMERACT Handbook methods, our Working Group (WG), comprised of 90 members, including 17 patient research partners (PRPs) and 73 clinicians and researchers, had six virtual meetings in addition to email exchanges to develop draft definitions and descriptions. The WG then conducted an international survey of its members to gain consensus on the definitions and descriptions. Finally, the WG members had virtual meetings and e-mail exchanges to review survey results and finalize names, definitions and descriptions of the domains. RESULTS: WG members contributed to developing the definitions. Fifty-two members representing four continents and 13 countries completed the survey, including 15 PRPs, 33 clinicians and 37 researchers. PRPs and clinicians/researchers agreed with all definitions and descriptions with agreements ranging from 87% to 100%. Respondents suggested wording changes to the names, definitions and descriptions to better reflect the domains. Discussions led to further simplification and clarification to address common questions/concerns about the domains. CONCLUSION: Our WG reached consensus on the definitions and descriptions of the domains of the core domain set for rheumatology trials of SDM interventions. This step is crucial to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set. CLINICAL SIGNIFICANCE: The current study provides consensus-based definitions and descriptions for the domains of the OMERACT core domain set for shared decision making interventions from patients/caregivers, clinicians and researchers. This is a crucial step to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set for trials of SDM interventions.
Subject(s)
Rheumatology , Humans , Consensus , Decision Making, Shared , Outcome Assessment, Health CareABSTRACT
Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.
Subject(s)
Lung Neoplasms , Protein-Tyrosine Kinases , Male , Humans , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MutationABSTRACT
A man in his 30s, who presented with fevers and a diffuse purpuric rash, developed sudden-onset visual loss on day 2. He was unable to perceive light in either eye. Examination by a neurologist confirmed cortical blindness, and the MRI showed subtle juxtacortical infarcts and leptomeningeal enhancement in the occipital region. Further history taken in the patient's native language revealed a history of untreated systemic lupus erythematosus. A diagnosis of central nervous system lupus was made and he was treated promptly with pulse methylprednisolone and cyclophosphamide. His vision gradually improved to 80% on day 10 and eventually returned to baseline. He continued with high-dose prednisolone and monthly cyclophosphamide for 6 months and remained on hydroxychloroquine and mycophenolate mofetil with no relapses. This case shows the importance of approaching the uncommon but potentially dangerous issue of acute visual loss with a broad differential.
Subject(s)
Blindness, Cortical , Lupus Erythematosus, Systemic , Lupus Vasculitis, Central Nervous System , Male , Humans , Lupus Vasculitis, Central Nervous System/drug therapy , Blindness, Cortical/etiology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Methylprednisolone/therapeutic use , Cyclophosphamide/therapeutic use , Vision Disorders/drug therapyABSTRACT
High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFß signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.
Subject(s)
Immune Evasion , Mutation , Ovarian Neoplasms , Female , Humans , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/immunology , Cystadenocarcinoma, Serous/pathology , Homologous Recombination , Immune Evasion/genetics , Ovarian Neoplasms/genetics , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Tumor Microenvironment , Transforming Growth Factor beta , Genes, BRCA1 , Genes, BRCA2ABSTRACT
The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/genetics , Mutation , Tumor BurdenABSTRACT
Immunotherapy is used to treat almost all patients with advanced non-small cell lung cancer (NSCLC); however, identifying robust predictive biomarkers remains challenging. Here we show the predictive capacity of integrating medical imaging, histopathologic and genomic features to predict immunotherapy response using a cohort of 247 patients with advanced NSCLC with multimodal baseline data obtained during diagnostic clinical workup, including computed tomography scan images, digitized programmed death ligand-1 immunohistochemistry slides and known outcomes to immunotherapy. Using domain expert annotations, we developed a computational workflow to extract patient-level features and used a machine-learning approach to integrate multimodal features into a risk prediction model. Our multimodal model (area under the curve (AUC) = 0.80, 95% confidence interval (CI) 0.74-0.86) outperformed unimodal measures, including tumor mutational burden (AUC = 0.61, 95% CI 0.52-0.70) and programmed death ligand-1 immunohistochemistry score (AUC = 0.73, 95% CI 0.65-0.81). Our study therefore provides a quantitative rationale for using multimodal features to improve prediction of immunotherapy response in patients with NSCLC using expert-guided machine learning.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Radiology , Humans , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Lung Neoplasms/diagnostic imaging , Programmed Cell Death 1 Receptor/therapeutic use , GenomicsABSTRACT
We describe the first case of antisynthetase syndrome (ASS) with antibodies to anti-glycyl tRNA synthetase (EJ-1) with antiphospholipid syndrome (APLS). A 66-year-old man presented with progressive dyspnoea, fever, dry cough and proximal muscle weakness over several months on a background of cryptogenic organizing pneumonia. Examination revealed bibasal fine chest crackles, proximal muscle weakness of the upper and lower limbs, digital skin thickening and facial telangiectasias. Creatine kinase was elevated and autoimmune screening was positive for anti-EJ-1, anti-beta-2-glycoprotein, anti-Ro and anti-La antibodies. Computed tomography of the chest revealed a usual interstitial pneumonia pattern and a ventilation-perfusion scan demonstrated scintigraphic evidence of bilateral pulmonary emboli. A diagnosis of ASS and APLS was made. Immunosuppressive therapy including pulsed methylprednisolone, rituximab and mycophenolate was commenced with improvement in symptoms. This case highlights the importance of evaluation for ASS in idiopathic interstitial pneumonia, and APLS in ASS patients.
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Biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) have been an important advance in the management of inflammatory arthritis, but are expensive medications, carry a risk of infection and other adverse effects, and are often perceived as a burden by patients. We used GRADE methodology to develop recommendations for dose reduction and discontinuation of b/tsDMARD in people with rheumatoid arthritis (RA), axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA) who have achieved a low disease activity state or remission. The recommendations form part of the Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis, an NHMRC-endorsed 'living' guideline, in which recommendations are updated in near real-time as new evidence emerges. Conditional recommendations were made in favour of dose reduction in RA and AxSpA but not in PsA. Abrupt discontinuation of b/tsDMARD is not recommended in any of the three diseases.
Subject(s)
Antirheumatic Agents , Arthritis, Psoriatic , Arthritis, Rheumatoid , Biological Products , Humans , Arthritis, Psoriatic/drug therapy , Biological Products/therapeutic use , Australia , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/chemically inducedABSTRACT
PURPOSE: To evaluate the effect of postoperative topical prednisolone acetate and difluprednate on surgical outcomes of Ahmed glaucoma valve (AGV) implantation. DESIGN: Retrospective, comparative case series. PARTICIPANTS: The study population consisted of 102 eyes of 90 patients, including 52 eyes that received 1% prednisolone acetate (Pred Forte [PF]; Allergan Inc) and 50 eyes that received 0.05% difluprednate (Durezol [DZ]; Novartis Inc). METHODS: The medical records of consecutive patients who underwent AGV implantation at the University of California, San Francisco, were retrospectively reviewed. Patients in the PF group received 1% prednisolone acetate 6 to 8 times per day tapered over 5 to 6 months postoperatively, and patients in the DZ group received 0.05% difluprednate 4 times daily tapered over 4 months postoperatively. MAIN OUTCOME MEASURES: Intraocular pressure (IOP), number of glaucoma medications, visual acuity (VA), postoperative complications, and the rate of treatment success. RESULTS: At 1 year, the IOPs (mean ± standard deviation) were 12.4 ± 3.7 mmHg in the DZ group and 13.0 ± 4.0 mmHg in the PF group (P = 0.49). The numbers of glaucoma medications were 0.72 ± 0.71 in the DZ group and 1.09 ± 0.91 in the PF group (P = 0.04), with reductions from baseline of 2.5 ± 1.0 glaucoma medications in the DZ group and 1.8 ± 1.6 glaucoma medications in the PF group (P = 0.01). The logarithm of the minimum angle of resolution VAs (mean ± standard deviation) were 0.55 ± 0.80 in the DZ group and 0.59 ± 0.65 in the PF group after 1 year of follow-up (P = 0.81). The cumulative probabilities of success were 95.8% in the DZ group and 93.5% in the PF group at 1 year (P = 0.61). Postoperative complications occurred in 4 eyes (7.7%) in the DZ group and 6 eyes (12%) in the PF group (P = 0.52). CONCLUSIONS: After 1 year, postoperative treatment with 0.05% difluprednate after AGV implantation resulted in a similar IOP, with the use of fewer glaucoma medications, compared with postoperative treatment with 1% prednisolone acetate. The rates of treatment success and surgical complications were comparable between the 2 groups during the first year of follow-up.
Subject(s)
Glaucoma Drainage Implants , Glaucoma , Fluprednisolone/analogs & derivatives , Follow-Up Studies , Glaucoma/drug therapy , Glaucoma/surgery , Humans , Postoperative Complications , Prednisolone/analogs & derivatives , Retrospective Studies , Treatment OutcomeABSTRACT
Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
Subject(s)
Genomics , High-Throughput Nucleotide Sequencing , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Cohort Studies , Female , Humans , Male , Organ Specificity/genetics , Prospective StudiesABSTRACT
Reports suggest an increased risk of tuberculosis (TB) in people with chronic airway diseases (CADs) such as chronic obstructive pulmonary disease (COPD), but evidence has not been systematically reviewed. We performed a systematic review by searching MEDLINE and Embase for studies published from 1 January 1993 to 15 January 2021 reporting the association between the incident risk of TB in people with CADs (asthma, COPD and bronchiectasis). Two reviewers independently assessed the quality of individual studies. We included nine studies, with two from low-income high TB burden countries. Three cohort studies reported a statistically significant independent association between COPD and the risk of TB in high-income countries (n=711 389). Hazard ratios for incident TB ranged from 1.44 to 3.14 adjusted for multiple confounders including age, sex and comorbidity. There was large between-study heterogeneity (I2=97.0%) across studies. The direction of effect on the TB risk from asthma was inconsistent. Chronic bronchitis or bronchiectasis studies were limited. The small number of available studies demonstrated an increased risk of TB in people with COPD; however, the magnitude of the increase varies by setting and population. Data in high TB burden countries and for other CADs are limited.
Subject(s)
Asthma , Bronchiectasis , Pulmonary Disease, Chronic Obstructive , Tuberculosis , Asthma/epidemiology , Bronchiectasis/complications , Bronchiectasis/epidemiology , Humans , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/epidemiology , Tuberculosis/epidemiologyABSTRACT
Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
Subject(s)
Germ-Line Mutation , Neoplasms/genetics , Carcinogenesis/genetics , DNA Copy Number Variations , DNA Mismatch Repair/genetics , Genetic Predisposition to Disease , Heterozygote , Humans , PhenotypeABSTRACT
Background Patterns of metastasis in cancer are increasingly relevant to prognostication and treatment planning but have historically been documented by means of autopsy series. Purpose To show the feasibility of using natural language processing (NLP) to gather accurate data from radiology reports for assessing spatial and temporal patterns of metastatic spread in a large patient cohort. Materials and Methods In this retrospective longitudinal study, consecutive patients who underwent CT from July 2009 to April 2019 and whose CT reports followed a departmental structured template were included. Three radiologists manually curated a sample of 2219 reports for the presence or absence of metastases across 13 organs; these manually curated reports were used to develop three NLP models with an 80%-20% split for training and test sets. A separate random sample of 448 manually curated reports was used for validation. Model performance was measured by accuracy, precision, and recall for each organ. The best-performing NLP model was used to generate a final database of metastatic disease across all patients. For each cancer type, statistical descriptive reports were provided by analyzing the frequencies of metastatic disease at the report and patient levels. Results In 91 665 patients (mean age ± standard deviation, 61 years ± 15; 46 939 women), 387 359 reports were labeled. The best-performing NLP model achieved accuracies from 90% to 99% across all organs. Metastases were most frequently reported in abdominopelvic (23.6% of all reports) and thoracic (17.6%) nodes, followed by lungs (14.7%), liver (13.7%), and bones (9.9%). Metastatic disease tropism is distinct among common cancers, with the most common first site being bones in prostate and breast cancers and liver among pancreatic and colorectal cancers. Conclusion Natural language processing may be applied to cancer patients' CT reports to generate a large database of metastatic phenotypes. Such a database could be combined with genomic studies and used to explore prognostic imaging phenotypes with relevance to treatment planning. © RSNA, 2021 Online supplemental material is available for this article.
Subject(s)
Data Management/methods , Databases, Factual/statistics & numerical data , Electronic Health Records , Natural Language Processing , Neoplasms/epidemiology , Tomography, X-Ray Computed/methods , Feasibility Studies , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neoplasm Metastasis , Reproducibility of Results , Retrospective StudiesABSTRACT
PURPOSE: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations. RESULTS: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%-17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%-11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16-6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46-5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors. CONCLUSIONS: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.
Subject(s)
Carcinoma, Renal Cell/genetics , Genome , Kidney Neoplasms/genetics , Mutation , High-Throughput Nucleotide Sequencing , HumansABSTRACT
Purpose: To evaluate the inter- and intra-observer reliability of anterior chamber (AC) angle measurements obtained by swept-source optical coherence tomography (SS-OCT).Methods: Forty-eight consecutive patients diagnosed with primary angle closure suspect (PACS) were included. Three masked observers at different training levels (one glaucoma specialist, one ophthalmology resident, and one pre-medical college student) measured 192 SS-OCT images of the PACS patients. One observer (the glaucoma specialist) repeated measurements 1 week later. SS-OCT parameters included: Anterior segment volume, including corneal, AC, and iris volume; anterior segment dimensions, including AC depth and width (ACD, ACW), and lens vault (LV); and angle parameters, including angle opening distance (AOD), angle recess area (ARA), trabecular iris space area (TISA), and the trabecular iris angle (TIA). Intraclass correlation coefficients (ICCs) were used to measure reliability.Results: For inter-observer reproducibility, ICCs of corneal, AC, and iris volumes were 0.952 to 0.998. ICCs of ACD at all axes were above 0.989. ICCs of ACW and LV were smallest in the 90°-270° axis (0.751 and 0.768) but not significantly different from other axes. ARA, TISA, and TIA at all angles had significantly smallest ICCs 250 µm from the scleral spur compared with 500 µm and 750 µm. The ICCs comparing observers with different training levels had similar ranges and followed similar trends. For intra-observer repeatability, the smallest ICC was 0.843. Decreasing AC depth correlated with increased inter-observer reproducibility.Conclusions: We found excellent intra-observer repeatability for all SS-OCT parameters. Angle measurements have more variation among the observers when taken 250 µm from the scleral spur. Shallow AC might lead to more variability for angle parameters. Non-expert observers may be recruited for high-quality image grading with standard training.
Subject(s)
Anterior Chamber/diagnostic imaging , Glaucoma, Angle-Closure/diagnosis , Intraocular Pressure/physiology , Tomography, Optical Coherence/methods , Female , Glaucoma, Angle-Closure/physiopathology , Humans , Male , Middle Aged , Reproducibility of ResultsABSTRACT
PURPOSE: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer. METHODS: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined. RESULTS: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2, 75% of mismatch repair, 43% of PALB2, 35% of RAD51C/D, 24% of BRIP1, and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting. CONCLUSION: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.
Subject(s)
Germ-Line Mutation/genetics , Neoplasms/genetics , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
Mucinous carcinomas can arise in any organ with epithelial cells that produce mucus. While mucinous tumors from different organs are histologically similar, it remains to be elucidated whether they share molecular alterations. Here we analyzed a total of 902 patients across six cancer types by comparing mucinous and non-mucinous samples, integrating text mining of pathology reports, gene expression, methylation, mutational and copy-number profiling. We found that, in addition to genes involved in mucin processing and secretion, MUC2 up-regulation is a multi-cancer biomarker of mucinous histology and is regulated by DNA methylation in colorectal, breast and stomach cancer. The majority of carcinomas with mucinous differentiation had fewer DNA copy-number alterations than non-mucinous tumors. The tumor mutational burden was lower in breast and lung with mucinous differentiation compared to their non-mucinous counterparts. We found several differences in the frequency of oncogenic gene and pathway alterations between mucinous and non-mucinous carcinomas, including a lower frequency of p53 pathway alterations in colorectal and lung cancer, and a lower frequency of PI-3-Kinase/Akt pathway alterations in breast and stomach cancer with mucinous differentiation. This study shows that carcinomas with mucinous differentiation originating from different organs share transcriptomic and genomic similarities. These results might pave the way for a more biologically relevant taxonomy for these rare cancers.