Clinical Risk Status Research Articles

Predictive significance of intraprostatic volumetric parameters derived from early and standard time 68Ga-PSMA PET/CT images in newly diagnosed prostate cancer patients.

To investigate the relationship between intraprostatic 68Ga-prostate-specific membrane antigen (PSMA) uptake values and volumetric parameters derived from early pelvic and standard-time whole-body 68Ga-PSMA PET/computed tomography (CT) images in untreated prostate cancer (PCa) patients, and to assess the predictive significance of these data in relation to disease prognosis, comparing them with the Gleason score, clinical risk classification and the presence of metastatic disease detected in 68Ga-PSMA PET/CT imaging. Eighty-one newly diagnosed PCa patients underwent early phase pelvic imaging at the 5th minute and standard time whole-body imaging at the 60th minute. Various threshold values were used in intraprostatic delineations to compute maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), intraprostatic PSMA tumor volume and intraprostatic total lesion PSMA uptake. Correlations between early and standard time measurements, as well as changes in SUV parameters over time, were examined. The association of these values with Gleason score, clinical risk status (National Comprehensive Cancer Network), and metastatic disease was explored. SUVmax measurements from both early and standard time images distinguished all three groups (clinical risk scores, Gleason score and metastatic group), with standard imaging demonstrating statistical superiority in receiver operating characteristic analyses. Strong correlations were observed between early and standard-time PET parameters. Changes in intraprostatic SUVmax and SUVmean values over time did not exhibit predictive value. Although intraprostatic PSMA PET parameters generally aligned at both early and standard times, parameters obtained from standard time images showed more robust correlations with clinical risk scores, Gleason score and metastasis status in newly diagnosed, untreated PCa patients.

First Blood: Pre-Therapy BRAFV600E+ PBMC Identifies a Novel Clinical Risk Category for Patients with LCH

Purpose: Langerhans Cell Histiocytosis (LCH) is a myeloproliferative neoplasia driven by somatic mutations in the mitogen-activated protein kinases pathway (MAPK). LCH has historically been clinically staged as “high risk” (e.g. liver, spleen and/or bone marrow involvement, HR) or “low risk” (LR) due relative to risk of death in earlier trials. However, clinical staging is complicated by different sensitivities of imaging and, more recently, molecular analyses. We previously identified that BRAFV600E allele in peripheral blood mononuclear cells (PBMC) in patients with HR LCH, which supported a model of LCH arising from hematopoietic myeloid precursors. To determine the clinical significance of somatic lesion BRAFV600E mutations as well as ability to detect pre-therapy BRAFV600E+ PBMC at diagnosis, we analyzed an extended cohort of LCH patients with longitudinal clinical evaluations. Methods: Genomic DNA was isolated from 366 lesion biopsies and the PBMCs of 294 patients with active LCH before initial therapy. The percentage of PBMC with the BRAFV600E allele in patients was determined by quantitative polymerase chain reaction. Lesion genotype and ability to detect pre-therapy BRAFV600E in PBMC were correlated with clinical features including i) clinical risk status, ii) extent of disease (single lesion vs multifocal; single system vs multisystem), iii) response to therapy, v) and time to relapse were analyzed using a chi-square test. Fluorescence-activated cell sorting (FACS), DNA amplification and subsequent qPCR was performed on 15 pretherapy BRAFV600E+ blood samples to explore the relationship between different myeloid lineages (CD3, CD19, CD56, CD14, CD16, CD11c) and extent of LCH disease. Survival proportions were calculated using the Kaplan-Meier (product limit) method and a log-rank (Mantel-Cox) test was used to calculate the significance of the difference between survival curves. Results: Median age was 3.01 years (range 3.6 days to 21.5 years), 58.5% of the patients were male (41.5% female), and 15.4% had HR disease (84.6% LR). Among patients with LR disease, 33.0% had multisystem, 23.1% had multi-focal single system, and 44.0% had single lesions. Lesion genotypes were 51.9% BRAFV600E and 49.1% not BRAFV600E. BRAFV600E in LCH lesions was associated with lower age at diagnosis and higher prevalence of HR disease. However, after a median follow-up time of 1.6 years (range 1 month to 8.5 years) there was no difference in EFS between BRAFV600E and alternative mutations (p=0.35). Notably, for the entire cohort, presence of BRAFV600E in diagnostic PBMC was highly associated with younger patients, clinical HR disease and risk of developing LCH-associated neurodegeneration (LCH-ND). For patients with BRAFV600E+ lesions, 32.5% had detectable BRAF V600E in pre-therapy PBMC: 100% of HR, 52.6% of multisystem LR, 18.4% of multi-focal single system LR and 0% of single lesion. Further, after a median follow-up time of 2.0 years (range 1 month to 9,1 years) clinical LR PBMC BRAFV600E+ represented a group at higher risk of treatment failure compared to BRAFV600E-neg LR (p=0.01). BRAFV600E alleles were present in PBMC at diagnosis in all of the sorted myeloid populations, with consistent enrichment in myeloid dendritic cells and monocytes. There was no significant correlation between BRAFV600E allele burden (percentage of BRAFV600E+ PBMC) and clinical risk, and no significant differences in the distribution of allele burden within lineages. Conclusion: Ability to detect pretherapy BRAFV600E+ represents an important clinical biomarker for patients with LCH. Results from this study support the potential for pre-therapy PBMC BRAFV600E to predict clinical risks, inform pathogenic mechanisms in LCH, and identify LR PBMC BRAFV600E+ as a novel clinical risk group. We hypothesize that persistence of hematopoietic clones and circulating myeloid precursors may underlie the increased risks of treatment failure and development of LCH-ND in patients previously presumed to have “low risk” disease.

Gene expression profiles in clinically T1-2N0 ER+HER2− breast cancer patients treated with breast-conserving therapy: their added value in case sentinel lymph node biopsy is not performed

PurposeOmitting sentinel lymph node biopsy (SLNB) in breast cancer treatment results in patients with unknown positive nodal status and potential risk for systemic undertreatment. This study aimed to investigate whether gene expression profiles (GEPs) can lower this risk in cT1-2N0 ER+ HER2– breast cancer patients treated with BCT.MethodsPatients were included if diagnosed between 2011 and 2017 with cT1-2N0 ER+ HER2– breast cancer, treated with BCT and SLNB, and in whom GEP was applied. Adjuvant chemotherapy recommendations based on clinical risk status (Dutch breast cancer guideline of 2020 versus PREDICT v2.1) with and without knowledge on SLNB outcome were compared to GEP outcome. We examined missing adjuvant chemotherapy indications, and the number of GEPs needed to identify one patient at risk for systemic undertreatment.ResultsOf 3585 patients, 2863 (79.9%) had pN0 and 722 (20.1%) pN + disease. Chemotherapy was recommended in 1354 (37.8% guideline-2020) and 1888 patients (52.7% PREDICT). Eliminating SLNB outcome (n = 722) resulted in omission of chemotherapy recommendation in 475 (35.1% guideline-2020) and 412 patients (21.8% PREDICT). GEP revealed genomic high risk in 126 (26.5% guideline-2020) and 82 patients (19.9% PREDICT) in case of omitted chemotherapy recommendation in the absence of SLNB. Extrapolated to the whole group, this concerns 3.5% and 2.3%, respectively, resulting in the need for 28–44 GEPs to identify one patient at risk for systemic undertreatment.ConclusionIf no SLNB is performed, clinical risk status according to the guideline of 2020 and PREDICT predicts a very low risk for systemic undertreatment. The number of GEPs needed to identify one patient at risk for undertreatment does not justify its standard use.

Clinical application of the 21-gene oncotype recurrence score in an older cohort: A single center experience

BackgroundIn early luminal breast cancer, the Oncotype DX® Recurrence Score (RS) prognostic and predictive value with regards to chemotherapy (CHT) application benefit has been broadly validated. In older patients its value has not been deeply addressed. This study aimed to evaluate the benefits of RS testing and to look at differences in treatment allocation for these patients when compared with younger ones. MethodsWe included data from consecutive patients with early luminal HER2-negative breast cancer, treated between 2010 and 2022 at the University Hospital Basel and Cantonal Hospital Baselland, Switzerland. The older cohort included 63 (19%) patients aged ≥70, and the younger cohort 263 (81%) patients aged <70. ResultsOlder breast cancer patients had more co-morbidities (N = 36, 57% vs. N = 92, 35%, p = 0.002) and a higher clinical risk status (N = 49, 78% vs. N = 155, 59%; p = 0.01) when compared to younger patients. Histopathologic characteristics were significantly different between the two cohorts. Although older patients had a higher clinical risk status (78% vs. 59%) (p = 0.01), most of them (74%) received no CHT. Specifically, adjuvant CHT was administered less frequently in older than in younger patients (13% vs. 22%; p = 0.01). Moreover, older patients were less likely to complete CHT (>4 cycles: 78% vs. 97%). ConclusionBreast cancer patients aged ≥70 have higher clinical risk status, more co-morbidities, higher clinical stage (driven by larger tumor size), and more often RS ≥26. However, they receive fewer adjuvant RT and CHT than those aged <70. RS maintains its independent prognostic value in older patients. However, assessing the predictive value of additional CHT benefit remains challenging due to significant differences in CHT administration. Although therapy decision-making in older patients with breast cancer still follows RS-based guidelines, clinical practice indicates an individualized treatment approach.

PD10-01 ASSOCIATIONS BETWEEN PROSTATE MRI AND GENOMIC TESTING AND TREATMENT INTENSIFICATION AMONG PATIENTS WITH LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD10-01 ASSOCIATIONS BETWEEN PROSTATE MRI AND GENOMIC TESTING AND TREATMENT INTENSIFICATION AMONG PATIENTS WITH LOCALIZED PROSTATE CANCER Michael Leapman, Rong Wang, Jessica Long, Preston Sprenkle, Xiaomei Ma, and Cary Gross Michael LeapmanMichael Leapman More articles by this author , Rong WangRong Wang More articles by this author , Jessica LongJessica Long More articles by this author , Preston SprenklePreston Sprenkle More articles by this author , Xiaomei MaXiaomei Ma More articles by this author , and Cary GrossCary Gross More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003250.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate magnetic resonance imaging (MRI) and tissue-based gene expression (genomic) tests improve local staging and estimates of disease prognosis, however clinical management associated with their use in the real-world setting is not well understood. METHODS: We performed a retrospective cohort study of Medicare beneficiaries diagnosed with clinically localized prostate cancer in 2013-2017 and treated with prostate radiation or radical prostatectomy in the Surveillance Epidemiology and End-Results (SEER)-Medicare database. We identified prostate MRI and genomic tests using specific administrative claims codes. The primary study outcome was treatment intensification, defined as any use of androgen deprivation therapy (ADT) for prostate radiation or pelvic lymph node dissection (PLND) for radical prostatectomy, respectively. We assessed the associations between patient-level receipt of prostate MRI and genomic testing and treatment intensification via multivariable logistic regressions, adjusting for clinical and sociodemographic factors, and further stratifying the analyses by D’Amico clinical risk status. RESULTS: We identified 26,017 patients meeting inclusion criteria, including 2,822 (11%) with low, 17,651 (68%) with intermediate and 4,664 (18%) with high-risk prostate cancer. In the overall cohort, receipt of prostate MRI (odds ratio [OR], 1.76 95% confidence interval [CI] 1.65-1.88, p<0.001) was associated with increased odds of treatment intensification, while genomic testing was not associated (OR 0.86, 95% CI 0.73-1.01, p=0.07). Prostate MRI was associated with increased odds of intensified treatment in all risk strata, while genomic testing was associated with lower odds of intensified treatment in the high-risk subset only (OR 0.59, 95% CI 0.35-1.00, p=0.048). By specific treatments, prostate MRI was associated with increased odds of PLND (OR 2.54, 95% CI 2.24-2.87) and ADT (OR 1.37, 95% CI 1.26-1.48) across all risk strata, while genomic testing was associated with decreased odds of PLND (OR 0.67, 95% CI 0.54-0.83) and ADT (OR 0.55, 95% CI 0.41-0.76). This analysis is limited by the absence of MRI and genomic testing results. CONCLUSIONS: We identified distinct patterns of management associated with prostate MRI and genomic testing in localized prostate cancer. These findings suggest the need for additional information about the independent role of diagnostic technologies in decision-making. Source of Funding: William O. Seery Foundation, Patterson Trust Mentored Research AwardNIH/National Cancer Institute © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e326 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Leapman More articles by this author Rong Wang More articles by this author Jessica Long More articles by this author Preston Sprenkle More articles by this author Xiaomei Ma More articles by this author Cary Gross More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract P5-14-13: Benefits of Oncotype DX genomic screening in a geriatric vs. non-geriatric cohort. Analyzing key factors in therapy decision making process

Abstract Introduction In early luminal HER2 negative breast cancer Oncotype DX® Recurrence-Score (RS) has been broadly validated in pre- and postmenopausal patients and can predict prognosis and benefit of chemotherapy. Its value in elderly breast cancer populations has not been deeply addressed. This study analyses clinical and pathologic factors, RS distribution and outcomes in an elderly vs. non-elderly breast cancer population with the purpose of establishing RS added value to the therapy decision-making process in a geriatric cohort. Methods This is a retrospective analysis of available data from patients with early luminal HER2 negative breast cancer treated at the University Hospital Basel and the Cantonal Hospital Baselland between 2010 and 2022. Cohort A (A) consists of patients &amp;lt; 70 years old and cohort B (B) of patients aged ≥70 years. At moment of decision for adjuvant treatment all patients had known RS result. Results A and B included 266 (81%) and 60 (19%) patients, respectively. The median age in A was 55.2 and in B, 74 years. The following clinical and pathologic factors were different in B vs. A: co-morbidities (55 % vs. 35%, p=0.005), BMI (BMI≥25 (overweight vs. normal, p=0.023), tumor size (31.3 mm vs 23.6 mm p=0.021). Geriatric patients also tended to have a clinically higher risk status (83% vs. 70%; p=0.05). There was a trend for a higher mastectomy rate in B vs. A (41.7% vs. 29%, p=0.065), significantly less radiotherapy use (65% vs. 81%, p=0.009) and more osteo-oncologic treatment (61% vs 43%, p=0.013). RS distribution was not significantly different between cohorts (A vs. B was: RS 1-15: 44.3% vs 41.7%, RS 16-25 41.2% vs 35% and RS≥26 14.5% vs 23.3%; p=0.234). Adjuvant chemotherapy was performed in 11.5% of B and 22.9% of A (p=0.116) and adjuvant endocrine therapy in 98.3% of B vs. 93.5% of A (p=p=0.214). Tumor board suggested systemic treatment was not implemented in 22% vs 15 %, (B vs. A; p =0.087). With a median follow-up of 36.6 months, recurrence rate was higher, but not statistically significant in B vs. A (10% vs 6%, p=0.259). Relapse rate was higher with RS≥26 vs. RS 0-25 (13.5% in B vs. 5.7% in A; p=0.043). Conclusions Older breast cancer patients tend to have higher clinical risk status, more co-morbidities and higher BMI. RS distribution was not significantly different between the two cohorts, however higher RS did pose a higher relapse rate for older patients in our cohort. Although RS based guidelines, still apply in therapy decision making in the case of geriatric breast cancer patients, clinical practice points to a rather individualized treatment in which all clinical and pathological factors are weighted. Citation Format: Elena D Chiru, Cvetka Grasic Kuhar, Anton Oseledchyk, Christian Kurzeder, Marcus Vetter. Benefits of Oncotype DX genomic screening in a geriatric vs. non-geriatric cohort. Analyzing key factors in therapy decision making process [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-13.

32O 5-year (y) overall survival (OS) with maintenance olaparib (ola) plus bevacizumab (bev) by clinical risk in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial

In the PAOLA-1/ENGOT-ov25 trial, adding maintenance ola to bev improved progression-free survival in homologous recombination deficiency-positive (HRD+; tumour BRCA1/2 mutation [tBRCAm] and/or genomic instability) pts with newly diagnosed AOC at higher and lower risk of progression by disease stage and surgical status. Greatest benefits were seen in lower-risk pts (Harter et al. Gynecol Oncol 2022). Here, we analysed 5-y OS according to clinical risk and HRD status. Pts in response after first-line platinum-based chemotherapy + bev were randomized 2:1 to ola (300 mg bid; up to 24 months [mo]) + bev (15 mg/kg q3w; up to 15 mo) or placebo [pbo] + bev. This post hoc exploratory analysis evaluated OS in pts classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by HRD status. 537 pts were randomized to ola + bev and 269 to pbo + bev (median OS follow-up 61.7 and 61.9 mo, respectively). Of 806 randomized pts, 595 (74%) were classified as higher risk and 211 (26%) as lower risk. At final data cutoff (22 March 2022), OS events had occurred in 377 higher-risk pts (data maturity 63%) and 69 lower-risk pts (data maturity 33%). OS was prolonged with ola + bev in higher- and lower-risk pts with a tBRCAm or who were HRD+. No OS benefit was seen in HRD− pts in any clinical risk subgroup. Subsequent PARP inhibitor therapy was received by 19.5% and 19.6% of ola + bev pts, and 45.9% and 45.2% of pbo + bev pts, in higher- and lower-risk groups, respectively.Table: 32OHRD statusHigher risk (n=595)Lower risk (n=211)No. of events/no. of pts (%)5-y OS rate† (%)No. of events/no. of pts (%)5-y OS rate† (%)Ola + bevPbo + bevOla + bevPbo + bevOla + bevPbo + bevOla + bevPbo + bevFull analysis set249/399 (62)128/196 (65)38.535.339/138 (28)30/73 (41)72.758.3HRD+*82/177 (46)53/89 (60)55.242.211/78 (14)16/43 (37)88.361.3tBRCAm43/109 (39)29/55 (53)65.248.35/48 (10)8/25 (32)91.466.1HRD−116/144 (81)46/62 (74)18.226.324/48 (50)12/23 (52)48.048.5HRD status by Myriad MyChoice HRD Plus assay; tBRCAm status by central labs.*HRD+ defined as a tBRCAm and/or genomic instability score of ≥42 on the Myriad MyChoice HRD Plus assay; †Kaplan–Meier estimates. Open table in a new tab HRD status by Myriad MyChoice HRD Plus assay; tBRCAm status by central labs. *HRD+ defined as a tBRCAm and/or genomic instability score of ≥42 on the Myriad MyChoice HRD Plus assay; †Kaplan–Meier estimates. This post hoc analysis of 5-y OS suggests that adding maintenance ola to bev should be considered for all HRD+ pts with newly diagnosed AOC, irrespective of their clinical risk status. Particular benefit was observed in HRD+ lower-risk pts who achieved 5-y OS rates of 88.3%.

Heart Rate Variability Impairment Is Associated with Right Ventricular Overload and Early Mortality Risk in Patients with Acute Pulmonary Embolism.

The association between heart rate variability (HRV) and mortality risk of acute pulmonary embolism (APE), as well as its association with right ventricular (RV) overload is not well established. We performed an observational study on consecutive patients with confirmed APE. In the first 48 h after admission, 24 h Holter monitoring with assessment of time-domain HRV, echocardiography and NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurement were performed in all participants. We pre-examined 166 patients: 32 (20%) with low risk of early mortality, 65 (40%) with intermediate-low, 65 (40%) with intermediate-high, and 4 (0.02%) in the high risk category. The last group was excluded from further analysis due to sample size, and finally, 162 patients aged 56.3 ± 18.5 years were examined. We observed significant correlations between HRV parameters and echocardiographic signs of RV overload. SDNN (standard deviation of intervals of all normal beats) correlated with echocardiography-derived RVSP (right ventricular systolic pressure; r = -0.31, p = 0.001), TAPSE (tricuspid annulus plane systolic excursion; r = 0.21, p = 0.033), IVC (inferior vena cava diameter; r = -0.27, p = 0.002) and also with NT-proBNP concentration (r = -0.30, p = 0.004). HRV indices were also associated with APE risk stratification, especially in the low-risk category (r = 0.30, p = 0.004 for SDNN). Univariate and multivariate analyses confirmed that SDNN values were associated with signs of RV overload. In conclusion, we observed a significant association between time-domain HRV parameters and echocardiographic and biochemical signs of RV overload. Impaired HRV parameters were also associated with worse a clinical risk status of APE.

Predictive Value of Circulating Tumor Cells Based on Subtraction Enrichment for Recurrence Risk in Stage II Colorectal Cancer.

Current guidelines recommend adjuvant chemotherapy (ACT) for stage II colorectal cancer (CRC) patients by using clinical high risk factors, with which circulating tumor cells (CTCs) were not considered. Here, an assessment to detect CTCs based on subtraction enrichment mediated by magnetic beads conjugated with CD45, immunofluorescence staining of CK, and fluorescence in situ hybridization of CEP8 is established. Both CEP8- and CK-positive CTCs have the potential to improve the risk stratification of stage II CRC patients. Patients with preoperative CTCs of ≥4 had a significantly higher recurrence risk than those with preoperative CTCs of <4 in two external validation cohorts (P < 0.0001). In the subgroup with clinical high risk, when preoperative CTCs were <4, patients did not benefit from ACT (P = 0.5764); however, when preoperative CTCs were ≥4, patients received benefit from ACT (P = 0.0064). Additionally, regardless of clinical risk status and preoperative CTC levels, if postoperative CTC levels were ≥4 for more than three consecutive time points (monitoring time interval, 2-6 months), the recurrence rate was 100%. Our findings suggested that the subtraction enrichment of CTCs could provide a reliable method to stratify the recurrence risk and make therapeutic decisions after surgery in stage II CRC patients.

The Investigation of Cognitive Functions and Clinical High Risk Status for Psychosis in First-Degree Relatives of Patients with Substance Induced Psychotic Disorder

IntroductionThe etiology of substance-induced psychotic disorder (SIPD) is an important research area to study.ObjectivesIt is aimed to investigate clinical risk status for psychosis, schizotypal features and neurocognitive functions in siblings of the patients who have been diagnosed as SIPD and who have no family history of psychotic spectrum disorder.MethodsThis study included 41 healthy siblings of patients who have been diagnosed as SIPD according to DSM-V and 41 healthy controls without family history of psychiatric disorders (matched on age, gender, and years of education). The data collected with sociodemographic and clinical data form, Digid Span Test, Trail Making Test A, Trail Making Test B, Verbal Fluency Test and Stroop Test, Comprehensive Assesment of At-Risk Mental States (CAARMS) and Structured Interview for Schizotypy-Revised.ResultsIt is determined that %41.5 of siblings and %7.3 of healthy controls are in one of the clinical high risk groups for psychosis according to CAARMS. There is significant difference in Trail Making Test A error and Trail Making Test B error and correction, verbal fluency test- lexical fluency-perseveration mean scores between siblings of patients and healthy controls.ConclusionsSiblings of patients with SIPD have more schizotypal features than healthy control group and they take part more frequent in one of high risk group for psychosis. Schizotypal features are known as trait factor and show genetic predisposition. Siblings who are in high risk groups have more schizotypal features and it may point that predisposition to psychosis is more related to underlying genetic predisposition than environmental factors and social stressors.DisclosureNo significant relationships.

Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial.

500 Background: Gene signatures have proven successful in identifying patients with a low risk of distant recurrence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was established within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggesting that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who participated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profiling revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were ≥50 years, 81% had tumors &lt; 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant systemic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%.[Table: see text]

Advanced molecular pathology for rare tumours: A national feasibility study and model for centralised medulloblastoma diagnostics.

AimsApplication of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array).MethodsThis nationwide trial in medulloblastoma (<80 UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin‐fixed, paraffin‐embedded tumour material were co‐submitted from 135 patients (16 referral centres).ResultsComplete CPR diagnostics were successful for 88% (120/135). Inadequate sampling was the most common cause of failure; biomaterials were typically suitable for methylation‐array (129/135, 94%), but frozen tissues commonly fell below RNA‐seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results; fluorescent in‐situ hybridisation most accurately identified high‐risk MYC/MYCN amplification (20/135, 15%), while combined methods (CTNNB1/chr6 status, methylation‐array subgrouping) best defined favourable‐risk WNT tumours (14/135; 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk‐status for 29% of patients.ConclusionNational real‐time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk‐status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker‐driven routine diagnostics and clinical/research studies.

Emergent Stenting for Obstructive Nephrolithiasis During the COVID-19 Pandemic Compared to the Prepandemic Era.

COVID-19 has rapidly evolved into a global pandemic. In an attemp to reduce transmission, patients were advised to avoid in-person medical evaluations when possible. Accordingly, we hypothesize that fewer patients have sought care and undergone treatment for emergent urological conditions such as nephrolithiasis. We performed a retrospective chart review of patients undergoing emergent ureteral stent placement for obstructive nephrolithiasis from March 15, 2020 through May 31, 2020 and compared them to similar patients from a year earlier. We found that notably fewer patients underwent emergent stent placement during the COVID-19 era and that these patients were notably sicker. These findings suggest that indirect sequelae of the pandemic include delays in seeking care for conditions unrelated to the virus. Strategies such as increased use of in-office stenting and improved patient counseling may help reduce delays in care and improve clinical outcomes for patients with nephrolithiasis during subsequent peaks in the ongoing pandemic.

The Outcome of Acute Lymphoblastic Leukemia in 109 Adult Iraqi Patients.

While many studies addressed the outcome of adult ALL in developed Western countries, there is paucity of such prospective studies from developing Mediterranean ones. This is a prospective cohort study conducted at Hiwa Cancer Hospital in Sulaimani city and Nanakali Hospital in Erbil city-Kurdistan Iraq from March 2012 to August 2017. The main characteristics of adult ALL patients, type of therapy and risk factors were analyzed to assess their impact on treatment outcome and survival status. A total of 109 adult ALL patients were included with a median age of 24years and male to female ratio of 1.7:1. B-ALL accounted for 76.1% of the cases, while the rest were T-ALL. BCR-ABL rearrangement was encountered in 12% of B-ALL. Complete remission (CR) rate was 81.7%, the overall 5year survival (OS) was 38%, Relapse Free 5year Survival (RFS) was 49%. Younger adults (< 35years) had significantly higher CR rates and OS compared to the older group (P < 0.001 each). On the other hand, gender, high leucocyte count ≥ 50×109/L, immunophenotype (including B and T ALL subtypes), and clinical risk status did not predict a poor outcome. Multivariate analysis revealed that only age < 35years and BCR-ABL rearrangement were significantly associated with better OS. Despite some limitations, the outcomes of Iraqi adult ALL is comparable to those reported in Western developed countries, with particularly favorable outcomes in younger patients. The need to improve outcome in adult ALL remains an important priority in our country as it is throughout the world.

Complication rate among people with diabetes at low risk of foot ulceration in Fife, UK: an analysis of routinely collected data.

To estimate the rate at which people with diabetes and a low risk of foot ulceration change diabetic foot ulceration risk status over time, and to estimate the rate of ulceration, amputation and death among this population. We conducted an observational study of 10 421 people with diabetes attending foot screening in an outpatient setting in NHS Fife, UK, using routinely collected data from a national diabetes register, NHS SCI Diabetes. We estimated the proportion of people who changed risk status and the cumulative incidence of ulceration, amputation and death, respectively, among people with diabetes at low risk of diabetic foot ulceration at 2-year follow-up. At 2-year follow-up, 5.1% (95% CI 4.7, 5.6) of people with diabetes classified as low risk at their first visit had progressed to moderate risk. The cumulative incidence of ulceration, amputation and death was 0.4% (95% CI 0.3, 0.6), 0.1% (95% CI 0.1, 0.2) and 3.4% (95% CI 3.1, 3.8), respectively. At 2-year follow-up, 5% of people at low risk of diabetic foot ulceration changed clinical risk status and <1% of people experienced foot ulceration or amputation. These findings provide information which will help to inform the current debate regarding optimal foot screening intervals.

Clinical risk-based associations of lymph node dissection and detection of metastasis among men treated with radical prostatectomy.

284 Background: Pelvic lymph node dissection (PLND) is recommended for most men at risk for lymph node involvement at the time of radical prostatectomy (RP) yet is frequently omitted. We aimed to examine the probability of PLND based on clinical risk status, and evaluate the impact of increasing lymph node yield on cancer detection rate across risk strata. Methods: We queried the National Cancer Database from 2004 to 2014 to identify patients with clinically localized PCa who underwent RP as their primary treatment. We extracted patient clinical and sociodemographic variables. Risk status was assessed using UCSF Cancer of the Prostate Risk Assessment (CAPRA) score. We fit conditional logistic regression models to estimate likelihood of PLND and incremental value of increasing lymph node count by risk strata. Results: We identified 698,728 men with PCa treated with RP including 380.201 (54.41%) whit PLND. Mean age at diagnosis was 62.6. PLND was omitted (Nx) in 56.1% of patients with low CAPRA-risk disease, 31.44% with intermediate and 24.72% high. Proportion of patients with &gt;30 lymph nodes removed decreased from 9.3% on 2004 to 3.64% on 2014. Adjusting for clinical and pathologic factors, treatment in a community versus academic (Odds Ratio, OR=1.62, 95% CI 1.59-1.66; P &lt;0.001) and black race (OR=1.13, 95% CI 1.09-1.17, P: 0.01) was associated with pNx status. Increasing lymph node count was independently associated with greater likelihood of detection of lymph node metastasis in all risk strata (11-20 nodes: OR: 3.13 , 95% CI 2.90-3.37, P&lt;0.001; 20-30 nodes: OR: 5.07 , 95% CI 4.50-5.73, P&lt;0.001; &gt;30 nodes OR: 6.58, 95% CI 5.38-8.05, P&lt;0.001) including patients with CAPRA-0 (11-20 nodes: OR: 3.28 , 95% CI 3.06-3.53, P&lt;0.001; 20-30 nodes: OR: 5.77, 95% CI 5.16-6.45, P&lt;0.001; &gt;30 nodes OR: 7.90, 95% CI 6.56-9.51, P&lt;0.001). Conclusions: PLND continues to be omitted in a substantial proportion of intermediate and high risk patients. Increasing lymph node yield was associated with greater odds of detecting lymph node metastasis in all groups of patients, including those at the lowest level of risk by clinical criteria.

Development and public release of a computerized adaptive (CAT) version of the Schizotypal Personality Questionnaire

One of the most widely used measures of psychosis-related symptoms and characteristics is the 74-item Schizotypal Personality Questionnaire (SPQ). Using multidimensional Item Response Theory (bifactor 2-parameter model), we calibrated SPQ items in a sample of 375 youths aged 9–24 years and constructed a fully functional computerized adaptive form of the SPQ on an open-source platform for public use. To assess validity, we used the above parameters to simulate CAT sessions in a separate validation sample (N = 100) using three test-length-based stopping rules: 8 items, 16 items, and 32 items. Those scores were then compared to full-form and SPQ-Brief scores on their abilities to predict psychosis or clinical risk status. Areas under the receiver operating characteristic curves indicated mediocre predictive ability, but did not differ among any of the forms, even when only eight adaptive items were administered. The Youden index for the 16-item adaptive version was higher than that for the 22-item SPQ-Brief. Classification accuracy for the full SPQ was 73% compared to 66% for the both the SPQ-Brief and adaptive versions (average of three stopping rules). The SPQ-CAT shows promise as a much shorter but valid assessment of schizotypy which can save time with minimal loss of information.

Alternative Response Criteria and Clinical Risk Factors for Assessing Tumor Response in Patients With Metastatic Renal Cell Carcinoma Who Are Receiving Salvage Therapy.

The purpose of this study is to compare the prognostic value of various solid tumor response criteria as well as the additive value of clinical risk factors in patients with advanced renal cell carcinoma (RCC). Two sets of CT scans (pretreatment scans and scans obtained 1-3.5 months after treatment) were reviewed for 57 patients with metastatic RCC treated with pazopanib in the salvage setting. Tumor response on the posttherapy scan was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) and Choi, modified Choi (mChoi), MASS (Morphology, Attenuation, Size, and Structure), and 10% threshold criteria. In addition, combined Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors plus imaging criteria were used to define response groups. Response evaluations using these criteria were correlated with overall survival (OS) and progression-free survival (PFS), with use of the log-rank test. Patients classified as having progressive disease (PD) on the basis of RECIST, mChoi, and MASS criteria had a significantly worse OS than patients with stable disease (SD) and partial response (PR). With the addition of MSKCC risk factors, all groups with PD defined by combined criteria had significantly worse OS. For 37 patients with no or one MSKCC risk factor, response groups defined by Choi, mChoi, MASS, and 10% threshold criteria did not differ in PFS or OS. However, among 20 patients with two to three MSKCC risk factors, those classified as having PR had longer PFS than did those with SD and had longer OS than did those with PD. For patients with advanced RCC for which prior therapies have failed, the prognostic value of various imaging-based tumor response criteria differs on the basis of the MSKCC clinical risk status.

Impairments of motor function among children with a familial risk of schizophrenia or bipolar disorder at 7 years old in Denmark: an observational cohort study

Owing to the genetic overlap between schizophrenia and bipolar disorder, we aimed to assess domain-specific motor aberrations and disorder specificity among 7-year-old children with a familial risk of schizophrenia or bipolar disorder by comparing children in familial risk groups with each other and with children not in these risk groups. In the Danish High Risk and Resilience Study, we established a cohort of 7-year-old children with no, one, or two parents with schizophrenia or bipolar disorder in Denmark between Jan 1, 2013, and Jan 31, 2016. We matched children of parents diagnosed with schizophrenia to children of parents without schizophrenia on the basis of their home address, age, and sex. Even though we did not match children of parents with bipolar disorder directly to controls because of resource constraints, we only recruited children into the three groups who did not differ in terms of age, sex, and urbanicity. We investigated motor function in children using the Movement Assessment Battery for Children-Second Edition. Motor function raters were masked to participants' clinical risk status during assessments. We assessed the effects of familial risk group in a mixed-model analysis with repeated measures with an unstructured variance component matrix. We studied 514 children (198 [39%] children of parents with schizophrenia, 119 [23%] of parents with bipolar disorder, and 197 [38%] of parents without schizophrenia or bipolar disorder). Children of parents with schizophrenia showed impaired motor performance compared with those of parents without in the subdomains of manual dexterity (mean difference -1·42 [95% CI -2·08 to -0·77]; p<0·0001) and balance (-1·38 [-2·03 to -0·72]; p<0·0001), but not of aiming and catching (-0·39 [-0·97 to 0·19]; p=0·18). Children of parents with bipolar disorder did not show any significant difference in motor performance to children of parents without in the subdomains of manual dexterity (-0·69 [-1·44 to 0·07]; p=0·08), balance (-0·68 [-1·44 to 0·08]; p=0·08), and aiming and catching (-0·36 [-1·03 to 0·31]; p=0·29). Comparison of familial risk groups of mental disorders revealed no significant differences in the subdomains of manual dexterity (-0·74 [-1·49 to 0·02]; p=0·06), balance (-0·70 [-1·46 to 0·06]; p=0·07), or aiming and catching (-0·03 [-0·70 to 0·63]; p=0·92). Motor abnormalities in children with a familial risk of schizophrenia are specific at 7 years of age with respect to fine motor function and balance, but non-specific with respect to familial risk of bipolar disorder. Clinicians should be aware of motor symptoms and refer children with definite motor problems (below the fifth percentile) to a child physiotherapist. Mental Health Services of the Capital Region of Denmark, Aarhus University, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research.

Quantifying the impact of known clinical risk factors and deprivation on preterm births: a retrospective cohort study

ObjectiveTo explore preterm birth (PTB) rates according to the clinical risk status with a particular focus on low risk pregnancies and their socioeconomic status.DesignRetrospective cohort study.Population51 426 live births from...