Guide Therapy Decisions Research Articles

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

Association of Serial High-Sensitivity Cardiac Troponin T With Subsequent Cardiovascular Events in Patients Stabilized After Acute Coronary Syndrome

Studies have demonstrated an association between single measures of high-sensitivity troponin (hsTn) and future cardiovascular events in patients with chronic coronary syndromes. However, limited data exist regarding the association between changes in serial values of hsTn and subsequent cardiovascular events in this patient population. To evaluate the association between changes in high-sensitivity troponin T (hsTnT) and subsequent cardiovascular events in patients stabilized after acute coronary syndrome (ACS). This is a secondary analysis from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a randomized clinical trial of ezetimibe vs placebo on a background of simvastatin in 18 144 patients hospitalized for an ACS across 1147 sites in 39 countries. The current biomarker substudy includes the 6035 participants consenting to the biomarker substudy with available hsTnT at months 1 and 4. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed from February 28, 2021, through August 14, 2022. The outcomes of interest were cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure (HHF). Associations of absolute and relative changes in hsTnT between month 1 and month 4 as a function of the starting month 1 hsTnT and the composite outcome were examined using landmark analyses. Of 6035 patients in this analysis (median [IQR] age, 64 [57-71]), 1486 (24.6%) were female; 361 (6.0%) were Asian; 121 were (2.0%) Black; 252 (4.2%) were Spanish descent; 4959 were (82.2%) White; and 342 (5.7%) reported another race (consolidated owing to small numbers), declined to respond, or were not asked to report race owing to regulatory prohibitions. Most patients (4114 [68.2%]) had stable hsTnT values (change <3 ng/L), with 1158 (19.2%) and 763 (12.6%) having changes of 3 to less than 7 ng/L and 7 ng/L or more, respectively. After adjustment for clinical risk factors and stratification by the starting month 1 hsTnT level, an absolute increase in hsTnT of 7 ng/L or more was associated with a more than 3-fold greater risk of the composite outcome (adjusted hazard ratio [aHR], 3.33; 95% CI, 1.99-5.57; P < .001), whereas decreases of 7 ng/L or more were associated with similar to lower risk (aHR, 0.51; 95% CI, 0.26-1.03; P = .06) compared with stable values. There was a stepwise association moving from larger absolute decreases (aHR, 0.51; 95% CI, 0.26-1.03) to larger absolute increases (aHR, 3.33; 95% CI, 1.99-5.57) in hsTnT with future risk of the composite outcome (P trend <.001). A similar association was observed when analyzed on the basis of relative percent and continuous change. Among stable patients post-ACS, changes in hsTnT were associated with a gradient of risk of subsequent cardiovascular events across the range of starting hsTnT values. Serial assessment of hsTnT may refine risk stratification with the potential to guide therapy decisions in this patient population. ClinicalTrials.gov Identifier: NCT00202878.

Role of multi detector computed tomography (MDCT) in evaluation and management of blunt abdominal trauma

Background: The majority of all blunt and penetrating body injuries are abdominal injuries. Computed tomography is a significant and quick technology that provides information on the kind of abdominal damage quickly and aids in patient care in accordance with that information. The current study's objectives were to assess the value of Multidetector Computed Tomography (MDCT) in identifying intra-abdominal injuries in patients with acute abdominal trauma and to give knowledge that might precisely guide therapy decisions (non- operative versus operative). and to compare the computed tomography (CT) results to either clinical observation, a further CT scan (if necessary), or the results of surgery (wherever applicable). Objectives: To examine the utility of multidetector computed tomography (MDCT) in detecting intra-abdominal injuries in patients with blunt abdominal trauma and providing information to define the role of therapy (operative versus conservative). Materials and Methods: This two-year prospective study looked at 50 patients who had suffered blunt abdominal trauma. The MDCT findings were compared to clinical outcomes, follow-up CT scans (if needed), and surgical outcomes (whichever applicable). Results: Motor vehicular accidents were the commonest cause of abdomen blunt injury (68%). Abdominal injury was present in 38 (76%) patients and hemoperitoneum was seen on CT scan in 33 patients (85.8%). In 27 patients, hemoperitoneum was associated with solid organ injury. The commonest injury was splenic injury. In 6 patients (15.8%) who underwent surgery, CT findings of hemoperitoneum and solid organ injury were verified, and bowel injury was shown to be the origin of isolated hemoperitoneum in two cases. The CT scan was 100% accurate in detecting hemoperitoneum. During the follow-up period, all conservatively handled cases recovered without incident. As a result, OIS grading appeared to predict care methods in the majority of patients in this study's overall analysis of solid organ injuries, with the exception of those with bowel and mesenteric injuries. Conclusion: In the diagnosis and management of blunt abdominal trauma, CT is the imaging modality of choice. Keywords: Computed tomography; Blunt Abdominal Trauma; Organ Injury Scaling (OIS); splenic injury; liver injury, road traffic accidents.

The DKTK EXLIQUID consortium – exploiting liquid biopsies to advance cancer precision medicine for molecular tumor board patients

Abstract Testing for genetic alterations in tumor tissue allows clinicians to identify patients who most likely will benefit from molecular targeted treatment. EXLIQUID – exploiting liquid biopsies to advance cancer precision medicine – investigates the potential of additional non-invasive tools for guiding therapy decisions and monitoring of advanced cancer patients. The term “liquid biopsy” (LB) refers to non-invasive analysis of tumor-derived circulating material such as cell-free DNA in blood samples from cancer patients. Although recent technological advances allow sensitive and specific detection of LB biomarkers, only few LB assays have entered clinical routine to date. EXLIQUID is a German Cancer Consortium (DKTK)-wide joint funding project that aims at establishing LBs as a minimally-invasive tool to analyze molecular changes in circulating tumor DNA (ctDNA). Here, we present the structure, clinical aim, and methodical approach of the new DKTK EXLIQUID consortium. Within EXLIQUID, we will set up a multicenter repository of high-quality LB samples from patients participating in DKTK MASTER and local molecular tumor boards, which use molecular profiles of tumor tissues to guide targeted therapies. We will develop LB assays for monitoring of therapy efficacy by the analysis of tumor mutant variants and tumor-specific DNA methylation patterns in ctDNA from these patients. By bringing together LB experts from all DKTK partner sites and exploiting the diversity of their particular expertise, complementary skills and technologies, the EXLIQUID consortium addresses the challenges of translating LBs into the clinic. The DKTK structure provides EXLIQUID a unique position for the identification of liquid biomarkers even in less common tumor types, thereby extending the group of patients benefitting from non-invasive LB testing. Besides its scientific aims, EXLIQUID is building a valuable precision oncology cohort and LB platform which will be available for future collaborative research studies within the DKTK and beyond.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Malassezia species: the need to establish epidemiological cutoff values.

Malassezia species causes skin disorders to systemic infections. Epidemiological cutoff value (ECV) allows for differentiation of wild-type and non wild-type isolates. Based on MIC data of 160 isolates we propose tentative ECVs for three Malassezia species. ECVs are useful in surveillance and guide therapy decisions.

Abstract 2773: 3D Predict™, an analytically and clinically validated platform for evidence-based functional precision medicine

Abstract Treatment paradigms for cancer patients have evolved as technology has advanced. Initial treatment guidelines were developed from probability-based assessments of the likelihood of groups of patients to respond to a compound. Biomarkers such as HER2 further added to the strength of therapy direction. The advent of next-generation sequencing (NGS) facilitated the use of gene mutations to direct patients to targeted chemotherapies. The one thing in common for each of these methods is a lack of functional assessment of each patient’s own tumor cells when in direct contact with the therapy being considered. Advanced live cell preservation methods combined with innovative cell culture techniques have facilitated a new paradigm for guiding therapy decisions. 3D Predict™ uses 3D cell culture to place each patient’s own tumor cells into direct contact with a panel of potential therapies. Individual response dynamics to each therapy are assessed thereby producing a patient-specific therapeutic response prediction. 95% of samples are successfully assayed with both response and non-response predictions being useful in therapy guidance, and data is returned within 7 business days of a patient’s surgical resection providing results within an actionable window. This platform has been analytically validated for use in high-grade gliomas (HGG) and ovarian cancer, it has been clinically validated in both HGG and ovarian cancer, and it is commercially available for use in HGG. 3D Predict™ Glioma, when judged against clinical outcomes, is 85% accurate in the prediction of response to temozolomide for newly diagnosed patients and has been shown to more than double the progression-free survival of relapsed patients in the clinical study 3D-PREDICT (NCT03561207). When the ovarian assay is judged against clinical outcomes, it is 89% accurate in the prediction of response to carboplatin/paclitaxel for newly diagnosed patients. Here we present the continued growth of the 3D Predict™ pipeline, including validation in rare cancers, breast cancer, and non-small cell lung cancer and the adaptation of the platform for the use of single core biopsies. Utilization of the 3D Predict™ platform can help patients with tumor types that have little to no guidance metrics for treatment decisions, improve the accuracy of biomarker-based direction, and increase the precision of NGS-based response predictions. Citation Format: Melissa Rayner, Katherine Miles, Kimberly Burgess, Taylor Brooks, Ashley K. Elrod, Natalie A. Williams, Jeremy Stuart, Lillia Holmes, Teresa M. DesRochers. 3D Predict™, an analytically and clinically validated platform for evidence-based functional precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2773.

Tracking C-type lectin-like receptor positive leukemic stem cells to determine therapeutic efficacy in acute myeloid leukemia.

e19011 Background: Although the importance of leukemia stem cells (LSC) in disease course of acute myeloid leukemia (AML) is well established in basic research, detecting and tracking LSC is seldom adopted in routine clinical practice. This is partly due to difficulty in tracking LSC in routine clinical practice and the paucity of evidence to support the benefit of detecting LSC in guiding clinical practice. Recently, a functional LSC population has been methodically characterized immunophenotypically, and the C-type lectin-like receptor (CLL1; aka CD371) has been shown to be widely expressed on LSC but not on normal hematopoietic stem cells (HSC). We postulate that CLL1 can be used to track LSC in a clinical setting and by analyzing changes in the LSC Compartment, we may be better able to assess response to therapy. Methods: Bone marrow samples from non-M3 CD34+ AML patients that were positive for CLL1 expression were included. Flow cytometry data were retrospectively analyzed for CLL1 percent positivity in the HSC compartment, which was defined as the CD34+CD38low/- fraction. A chart review was conducted to determine correlation between CLL1 positive LSC compartment change and clinical outcome. Statistical analysis was performed using GraphPad Prism version 9. Results: From 12/2018 to 12/2021, 49 AML cases with both pre- and post-treatment data from a single institution, were identified for the study. Among them, fourteen patients with CLL1 positivity higher than 50% were analyzed for CLL1+/HSC fractional change between pre- and post-treatment. We found that 6 of these 14 patients with significant reduction in CLL1+/HSC achieved longer remission, while the other 8 patients with no significant decrease in the CLL1+/HSC fraction demonstrated no or only a temporary remission. Importantly, several cases of patients with significant reduction in CLL1 positive cells will be presented to highlight the fact that LSC fractional change was more accurate in evaluating therapeutic effects and more predictive of clinical outcome than traditional morphology and flow cytometric analysis. This may even alter interpretation of specific treatment outcomes by predicting, for example, the brief nature that can be expected from certain remissions. Lastly, the CLL1+/HSC compartment in the peripheral blood is highly correlated with that of the bone marrow, indicating future feasibility of tracking LSC fractional change non-invasively to guide therapeutic decisions. Conclusions: CLL1 as a LSC marker is readily applicable to the clinical setting. Tracking LSC before and after AML treatment provides critical information regarding therapeutic effects that can sometimes be missed by traditional morphological and flow cytometric analysis. Thus, measuring changes in the LSC compartment using CLL1 analysis should be incorporated routinely in clinical practice to guide therapy decisions.

P141 What are the predictors of fragility fracture in patients with low body mass index: an observational cohort study

Abstract Background/Aims Low body mass index (BMI) is known to be associated with increased risk of fracture and therefore measurements of height and weight contribute towards the Fracture Risk Assessment Tool (FRAX) score, an estimation tool used to calculate approximate risk of fracture to guide therapy decisions. However, data is lacking on which measurement of bone mineral density is best in those that are underweight. Using a large population of patients with low BMI, we aimed to determine which measurement of bone mineral density (BMD) is the most accurate predictor of fragility fracture in this group of patients. We also aimed to explore the relationship of other traditional risk factors for fracture in this subpopulation. Methods Data on risk factors for osteoporosis and fragility fractures was collected on patients presenting for BMD estimation at a district general hospital in North West England between June 2004 and October 2016. All analysis was performed on those with low BMI, defined as &amp;lt; 18.5kg/m2. Firstly, univariate logistic regression was performed to assess risk of fracture using BMD for lumbar spine, femoral neck and total hip; as well as smoking, alcohol use, presence of rheumatoid arthritis, history of steroid use and history of hip fracture in a parent. Risk factors were defined as per FRAX. This was followed by multivariate regression of available risk factors, using the best BMD predictor identified from univariate analysis. All models were controlled for sex and age at first scan. Results for continuous variables are reported as beta coefficients and for categorical variables as odds ratios. All results are reported with 95% confidence intervals. Area under ROC curve for each model was calculated. Results 921 of 35,759 patients had a BMI of under 18.5 and were included in analysis. Of these, 88.4% were female, mean age at time of scan was 58.6 years. Results are shown in the table. Conclusion In those with low BMI, BMD of left total hip was the best predictor of fragility fracture. Smoking, alcohol use and history of hip fracture were also associated, but previous steroid use and diagnosis of rheumatoid arthritis was not. Disclosure S.D. Sharma: None. M. Bukhari: None.

Dual-Branch Convolutional Neural Network Based on Ultrasound Imaging in the Early Prediction of Neoadjuvant Chemotherapy Response in Patients With Locally Advanced Breast Cancer.

The early prediction of a patient’s response to neoadjuvant chemotherapy (NAC) in breast cancer treatment is crucial for guiding therapy decisions. We aimed to develop a novel approach, named the dual-branch convolutional neural network (DBNN), based on deep learning that uses ultrasound (US) images for the early prediction of NAC response in patients with locally advanced breast cancer (LABC). This retrospective study included 114 women who were monitored with US during pretreatment (NAC pre) and after one cycle of NAC (NAC1). Pathologic complete response (pCR) was defined as no residual invasive carcinoma in the breast. For predicting pCR, the data were randomly split into a training set and test set (4:1). DBNN with US images was proposed to predict pCR early in breast cancer patients who received NAC. The connection between pretreatment data and data obtained after the first cycle of NAC was considered through the feature sharing of different branches. Moreover, the importance of data in various stages was emphasized by changing the weight of the two paths to classify those with pCR. The optimal model architecture of DBNN was determined by two ablation experiments. The diagnostic performance of DBNN for predicting pCR was compared with that of four methods from the latest research. To further validate the potential of DBNN in the early prediction of NAC response, the data from NAC pre and NAC1 were separately assessed. In the prediction of pCR, the highest diagnostic performance was obtained when combining the US image information of NAC pre and NAC1 (area under the receiver operating characteristic curve (AUC): 0.939; 95% confidence interval (CI): 0.907, 0.972; F1-score: 0.850; overall accuracy: 87.5%; sensitivity: 90.67%; and specificity: 85.67%), and the diagnostic performance with the combined data was superior to the performance when only NAC pre (AUC: 0.730; 95% CI: 0.657, 0.802; F1-score: 0.675; sensitivity: 76.00%; and specificity: 68.38%) or NAC1 (AUC: 0.739; 95% CI: 0.664, 0.813; F1-score: 0.611; sensitivity: 53.33%; and specificity: 86.32%) (p<0.01) was used. As a noninvasive prediction tool, DBNN can achieve outstanding results in the early prediction of NAC response in patients with LABC when combining the US data of NAC pre and NAC1.

Drug Treatment of Hypercholesterolemia in Older Adults: Focus on Newer Agents.

There is increasing research interest in cholesterol-lowering therapy in older patients. The newer lipid-lowering agents (the proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors evolocumab and alirocumab; the PCSK9 synthesis inhibitor inclisiran, and the adenosine triphosphate–citrate lyase inhibitor bempedoic acid) might also provide more options for the future treatment of older patients. Data analyses of the phase III outcome trials of the PCSK9 inhibitors suggest that their clinical benefits are maintained at older ages and that there is no increased relative risk of adverse events in older patients; however, data from patients aged ≥ 75 years and particularly aged ≥ 85 years are limited, and the trials did not collect information on the frailty status of patients. Frailty is a predictor of adverse outcomes, including mortality, and might help guide therapy decisions. To date, no outcome data are available for cardiovascular endpoints for the low-density lipoprotein cholesterol-lowering drugs inclisiran and bempedoic acid. Except for the risk of gout and tendon rupture with bempedoic acid, which remains to be further characterized in larger populations, the safety profile of the novel lipid-lowering agents in older patients seems favorable. The newer lipid-lowering agents could be added to other lipid-lowering medication or used as an alternative treatment in older patients with documented statin intolerance (as is already recommended in guidelines for the PCSK9 inhibitors), such as myopathy. Especially in older patients needing high-intensity therapy despite polypharmacy or certain comedications, the absence of clinically relevant drug–drug interactions with the PCSK9 inhibitors and inclisiran might be an advantage.

Cytomegalovirus-Positive Posner-Schlossman Syndrome: Impact on Corneal Endothelial Cell Loss and Retinal Nerve Fiber Layer Thinning

To report objective morphologic changes in cytomegalovirus (CMV)-positive Posner-Schlossman syndrome (PSS). Retrospective, consecutive case series. We reviewed the charts of patients with unilateral PSS tested positive for CMV by Goldmann-Witmer coefficients between 2007 and 2018 at our tertiary eye clinic. We report data on corneal endothelial cell (CEC) count, peripapillary retinal nerve fiber layer (RNFL), choroidal thickness (CT) using optical coherence tomography (OCT) as well as clinical findings and management. The unaffected eye served as control. Fifty-two eyes of 52 patients were included and followed for 32.8 ± 28.3 months. The peak intraocular pressure was 45 ± 11 mm Hg. The CEC (2241.7 ± 381.1 cells/mm2 vs 2529.4 ± 351.9 cells/mm2, P=.0004) and the global RNFL thickness (80.81 ± 21.01 µm vs 97.38 ± 9.75 µm, P=.0001) were significantly reduced, whereas CT was nonsignificantly higher (295.69 ± 45.46 µm vs 274.00 ± 67.85 µm, P=.156) in the affected eyes compared to the fellow eye. Forty (76.9%) patients were treated with oral valganciclovir (VGC), 2 (3.8%) with topical ganciclovir alone, and 10 (19.2%) received no antiviral therapy. Eight eyes (15.4%) underwent trabeculectomy with mitomycin C. After cessation of oral VGC, 23 patients (57.5%) had recurrences. In our cohort, CMV-positive PSS was often associated with RNFL thinning and CEC loss. Highly elevated intraocular pressures usually present the most relevant challenge. In conjunction with aqueous humor sampling, monitoring by OCT scans and endothelial microscopy may help to guide therapy decisions.

Optimal Urine Culture Diagnostic Stewardship Practice-Results from an Expert Modified-Delphi Procedure.

Urine cultures are nonspecific and often lead to misdiagnosis of urinary tract infection and unnecessary antibiotics. Diagnostic stewardship is a set of procedures that modifies test ordering, processing, and reporting in order to optimize diagnosis and downstream treatment. In this study, we aimed to develop expert guidance on best practices for urine culture diagnostic stewardship. A RAND-modified Delphi approach with a multidisciplinary expert panel was used to ascertain diagnostic stewardship best practices. Clinical questions to guide recommendations were grouped into three thematic areas (ordering, processing, reporting) in practice settings of emergency department, inpatient, ambulatory, and long-term care. Fifteen experts ranked recommendations on a 9-point Likert scale. Recommendations on which the panel did not reach agreement were discussed during a virtual meeting, then a second round of ranking by email was completed. After secondary review of results and panel discussion, a series of guidance statements was developed. One hundred and sixty-five questions were reviewed. The panel reaching agreement on 104, leading to 18 overarching guidance statements. The following strategies were recommended to optimize ordering urine cultures: requiring documentation of symptoms, sending alerts to discourage ordering in the absence of symptoms, and cancelling repeat cultures. For urine culture processing, conditional urine cultures and urine white blood cell count as criteria were supported. For urine culture reporting, appropriate practices included nudges to discourage treatment under specific conditions and selective reporting of antibiotics to guide therapy decisions. These 18 guidance statements can optimize use of urine cultures for better patient outcomes.

White Blood Cell Count (WBC) Levels Are Associated with Molecular Profiles and Are Independent Outcome Predictors in Acute Myeloid Leukemia (AML) Patients (Pts) (Alliance)

White Blood Cell Count (WBC) Levels Are Associated with Molecular Profiles and Are Independent Outcome Predictors in Acute Myeloid Leukemia (AML) Patients (Pts) (Alliance)

Image-Guided Biopsy for Relapsed Neuroblastoma: Focus on Safety, Adequacy for Genetic Sequencing, and Correlation of Tumor Cell Percent With Quantitative Lesion MIBG Uptake.

Many novel therapies for relapsed and refractory neuroblastoma require tumor tissue for genomic sequencing. We analyze our experience with image-guided biopsy in these patients, focusing on safety, yield, adequacy for next-generation sequencing (NGS), and correlation of tumor cell percent (TC%) with quantitative uptake on 123I-meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography with computed tomography (SPECT/CT). An 11-year retrospective review of image-guided biopsy on 66 patients (30 female), with a median age of 8.7 years (range, 0.9-49 years), who underwent 95 biopsies (55 bone and 40 soft tissue) of relapsed or refractory neuroblastoma lesions was performed. There were seven minor complications (7%) and one major complication (1%). Neuroblastoma was detected in 88% of MIBG- or fluorodeoxyglucose-avid foci. The overall NGS adequacy was 69% (64% in bone and 74% in soft tissue, P = .37). NGS adequacy within neuroblastoma-positive biopsies was 88% (82% bone and 96% soft tissue, P = .11). NGS-adequate biopsies had a greater mean TC% than inadequates (51% v 18%, P = .03). NGS-adequate biopsies had a higher mean number of needle passes (7.5 v 3.4, P = .0002). The mean tissue volume from NGS-adequate soft-tissue lesions was 0.16 cm3 ± 0.12. Lesion:liver and lesion:psoas MIBG uptake ratios correlated with TC% (r = 0.74, r = 0.72, and n = 14). Mean TC% in NGS-adequate samples was 51%, corresponding to a lesion:liver ratio of 2.9 and a lesion:psoas ratio of 9.0. Thirty percent of biopsies showed an actionable ALK mutation or other therapeutically relevant variant. Image-guided biopsy for relapsed or refractory neuroblastoma was safe and likely to provide NGS data to guide therapy decisions. A lesion:liver MIBG uptake ratio of ≥ 3 or a lesion:psoas ratio of > 9 was associated with a TC% sufficient to deliver NGS results.

Seeding metastases: The role and clinical utility of circulating tumour cells.

Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for various solid cancers. Enumeration of CTCs from blood is becoming a common practice in informing prognosis and may guide therapy decisions. It is further recognized that enumeration alone does not capture perspective on the heterogeneity of tumours and varying functional abilities of the CTCs to interact with the secondary microenvironment. Characterizing the isolated CTCs further, in particular assessing their functional abilities, can track molecular changes in the disease progress. As a step towards identifying a suite of functional features of CTCs that could aid in clinical decisions, developing a CTC isolation technique based on extracellular matrix (ECM) interactions may provide a more solid foundation for isolating the cells of interest. Techniques based on size, charge, density, and single biomarkers are not sufficient as they underutilize other characteristics of cancer cells. The ability of cancer cells to interact with ECM proteins presents an opportunity to utilize their full character in capturing, and also allows assessment of the features that reveal how cells might behave at secondary sites during metastasis. This article will review some common techniques and recent advances in CTC capture technologies. It will further explore the heterogeneity of the CTC population, challenges they experience in their metastatic journey, and the advantages of utilizing an ECM-based platform for CTC capture. Lastly, we will discuss how tailored ECM approaches may present an optimal platform to capture an influential heterogeneous population of CTCs.

Treatment Paradigms for Older Adults with Pancreatic Cancer: a Nuanced Approach.

Pancreatic cancer is increasing in incidence in the USA. This disease disproportionately affects older adults, and as the percentage of adults > 65years old increases with the aging of the baby boomers, the prevalence is expected to rise over the coming decade. These patients are often more susceptible to disease-related symptoms and have less ability to withstand both cancer and treatment-related side effects. Therefore, it is imperative that treating physicians thoughtfully consider their recommended treatment approach towards this vulnerable patient population. This review focuses on the current state of research of older adults with pancreatic adenocarcinoma, highlighting deficiencies in the representation of this patient population in clinical trials. It is vital that the treating physicians take a nuanced approach towards therapy of localized and metastatic disease in geriatric patients. A one size fits all treatment algorithm is no longer appropriate in any cancer patient, let alone the elders who are particularly vulnerable to developing treatment-related toxicities. To help guide therapy decisions, it is important to perform a comprehensive geriatric assessment which may uncover unexpected frailty and lead to a change in the recommended treatment approach. In this way, we can support older adults during therapy for this aggressive malignancy and provide optimal care.

Prognostic biomarkers in pediatric pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive life-threatening disease of the pulmonary vasculature. Despite the introduction of targeted therapies, prognosis remains poor. In pediatric PAH, reliable prognostic biomarkers are needed to inform clinicians on disease progression and risk of mortality, in order to be able to assess the need for escalation of medical therapy, consider surgical options such as Pott's shunt and listing for (heart)-lung transplantation. This review provides an overview of prognostic biomarkers that are considered to carry potential for the clinical management of pediatric PAH. These include conventional physiological biomarkers [resting heart rate, heart rate variability (HRV), a child's growth], biomarkers of functional status [World Health Organization functional class, 6-minute walk distance (6MWD), parameters derived from cardiopulmonary exercise testing (CPET), daily physical activity level], electrocardiographic biomarkers, circulating serum biomarkers (natriuretic peptides, uric acid, neurohormones, inflammatory markers, and novel circulating biomarkers), and multiple hemodynamic biomarkers and imaging biomarkers [echocardiography and cardiac magnetic resonance (CMR)]. In recent years, many potential prognostic biomarkers have become available for the management of PAH in children. As the available prognostic biomarkers reflect different aspects of the disease process and functional implications, a multi-marker approach appears the most useful for guiding therapy decisions and improve outcome in pediatric PAH.

Preoperative clinical and tumor genomic features associated with pathologic lymph node metastasis in clinical stage I and II lung adenocarcinoma

While next-generation sequencing (NGS) is used to guide therapy in patients with metastatic lung adenocarcinoma (LUAD), use of NGS to determine pathologic LN metastasis prior to surgery has not been assessed. To bridge this knowledge gap, we performed NGS using MSK-IMPACT in 426 treatment-naive patients with clinical N2-negative LUAD. A multivariable logistic regression model that considered preoperative clinical and genomic variables was constructed. Most patients had cN0 disease (85%) with pN0, pN1, and pN2 rates of 80%, 11%, and 9%, respectively. Genes altered at higher rates in pN-positive than in pN-negative tumors were STK11 (p = 0.024), SMARCA4 (p = 0.006), and SMAD4 (p = 0.011). Fraction of genome altered (p = 0.037), copy number amplifications (p = 0.001), and whole-genome doubling (p = 0.028) were higher in pN-positive tumors. Multivariable analysis revealed solid tumor morphology, tumor SUVmax, clinical stage, SMARCA4 and SMAD4 alterations were independently associated with pathologic LN metastasis. Incorporation of clinical and tumor genomic features can identify patients at risk of pathologic LN metastasis; this may guide therapy decisions before surgical resection.

The mutational profile of immune surveillance genes in diagnostic and refractory/relapsed DLBCLs

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid neoplasm among adults,and approximately 30–40% of patients will experience relapse while 5–10% will suffer from primary refractory disease caused by different mechanisms, including treatment-induced resistance. For refractory and relapsed DLBCL (rrDLBCL) patients, early detection and understanding of the mechanisms controlling treatment resistance are of great importance to guide therapy decisions. Here, we have focused on genetic variations in immune surveillance genes in diagnostic DLBCL (dDLBCL) and rrDLBCL patients to elaborate on the suitability of new promising immunotherapies.MethodsBiopsies from 30 dDLBCL patients who did not progress or relapse during follow up and 17 rrDLBCL patients with refractory disease or who relapsed during follow up were analyzed by whole-exome sequencing, including matched individual germline samples to include only somatic genetic variants in downstream analysis of a curated list of 58 genes involved in major immune surveillance pathways.ResultsMore than 70% of both dDLBCLs and rrDLBCLs harbored alterations in immune surveillance genes, but rrDLBCL tumor samples have a lower number of genes affected compared to dDLBCL tumor samples. Increased gene mutation frequencies in rrDLBCLs were observed in more than half of the affected immune surveillance genes than dDLBCLs.ConclusionGenetic variants in the antigen-presenting genes affect a higher number of rrDLBCL patients supporting an important role for these genes in tumor progression and development of refractory disease and relapse.