Intermediate-risk Patients Research Articles

External validation of three prognostic scores for brain metastasis velocity in patients treated with intracranial stereotactic radiotherapy

Background and introductionBrain metastasis velocity (BMV) has been proposed as a prognostic factor for overall survival (OS) in patients with brain metastases (BMs). In this study, we conducted an external validation and comparative assessment of the performance of all three BMV scores. Materials and methodsPatients treated with intracranial stereotactic radiotherapy (SRT) for BM at a single center between 2014 and 2018 were identified. Where possible, all three BMV scores were calculated. Log-rank tests and linear, logistic and Cox regression analysis were used for validation and predictor identification of OS. ResultsFor 333 of 384 brain metastasis patients, at least one BMV score could be calculated. In a sub-group of 187 patients, “classic” BMV was validated as categorical (p < 0.0001) and continuous variable (HR 1.02; 95% CI 1.02–1.03; p < 0.0001). In a sub-group of 284 patients, “initial” BMV was validated as categorical variable (high-risk vs. low-risk; p < 0.01), but not as continuous variable (HR 1.02; 95% CI 0.99–1.04; p = 0.224). “Volume-based” BMV could not be validated in a sub-group of 104 patients. On multivariable Cox regression analysis, iBMV (HR 1.85; 95% CI 1.01–3.38; p < 0.05) and cBMV (HR 2.32; 95% CI 1.15 4.68; p < 0.05) were predictors for OS for intermediate-risk patients after first SRT and first DBFs, respectively. cBMV proved to be the dominant predictor for OS for high-risk patients (HR 2.99; 95% CI 1.30–6.91; p < 0.05). ConclusionThis study externally validated cBMV and iBMV as prognostic scores for OS in patients treated with SRT for BMs whereas validation of vBMV was not achieved.

Dynamic Risk Stratification Integrated with ATA Risk System for Predicting Long-Term Outcome in Papillary Thyroid Cancer.

In recent years, there has been a renewed interest in thyroid cancer management paradigms that use individualized risk assessments as the basis for treatment and follow-up recommendations. In this study, we assumed that the long-term follow-up of differentiated thyroid cancer patients might be better tailored by integrating the response to initial therapy with the America Thyroid Association (ATA) risk classes. This retrospective study included low- and intermediate-risk papillary thyroid cancer (PTC) patients followed up for a median time of 8 years and classified according to the response to initial therapy assessed 6-12 months after initial treatment. After a median follow-up of 8 years, in the initial excellent response subgroup of PTC patients (n = 522), the rate of recurrent disease was significantly higher in intermediate-risk patients than in low-risk PTC patients (6.9% versus 1.2%, p = 0.0005). Similarly, in the initial biochemical incomplete response subgroup (n = 82), the rate of excellent response was significantly higher in low-risk PTC patients (58.0%) than in intermediate-risk PTC patients (33.3%) (p = 0.007). Finally, in the initial structural incomplete response subgroup (n = 66), the rate of excellent response was higher in low-risk patients (80.0%) than in intermediate-risk patients (46.4%) (p = 0.08). Moreover, all patients with initial indeterminate response had an excellent response at the last follow-up visit. ATA risk classes were independently associated with long-term outcome in each subgroup of patients classified dynamically after initial therapy and the overall prognostic performance, defined via ROC curve analysis, of response to initial therapy integrated with the ATA risk system (AUC: 0.89; 95% CI: 0.86-0.92) was significantly higher compared to the ATA risk stratification (AUC 0.69; 95% CI: 0.65-0.74, p < 0.001) or the dynamic risk stratification (DRS) systems alone (AUC: 0.86 95% CI: 0.82-0.90, p = 0.007). This study of a large cohort of PTC patients showed that the initial ATA risk criteria may be useful for improving the risk-adapted management of PTC patients based on the response to initial therapy.

Prognostic value of axillary lymph node metastases in invasive lobular breast carcinoma

BackgroundAxillary lymph node involvement is a well-established prognostic factor for recurrence in breast cancer, specifically the number of nodes affected and the ratio of the number of affected nodes to the number of harvested nodes for non-specific invasive breast cancer (invasive ductal carcinoma). However, there is limited information on the impact of lymph node involvement in the case of invasive lobular carcinoma. Objectivesour study aimed to evaluate the prognostic impact of lymph node involvement on overall survival and distant metastatic-free survival according to the number of nodes affected and the ratio of positive nodes (LNR) for patients managed for invasive lobular carcinoma. MethodsThis is a monocentre, comparative, observational study of patients managed for invasive lobular carcinoma at the Gynaecology Department of the University Hospital Center of Tours between January 1, 2007 and December 31, 2018.The LNR cut-off values used were: low risk if LNR ≤ 0.2; intermediate risk if LNR > 0.2 and ≤ 0.65, and high risk for LNR >0.659. ResultsOur study demonstrated a significant difference in overall survival and distant metastasis free survival (p < 0.0001). The 5-years Overall survival was 94 % for N0 patients, 92.4 % for low-risk patients, 85.6 % for intermediate-risk patients and 58.5 % for high-risk patients. The 5-year distant metastasis-free survival was 98.2 % for N0 patients, 95.9 % for low-risk patients, 80.1 % for intermediate-risk patients, and 60.3 % for high-risk patients.Multivariate analysis identified age, invasive lobular histologic type, presence of clinical inflammation, and intermediate and high risk classes of LNR ratio as independent factors affecting overall survival. For metastatic-free survival, the presence of clinical inflammation, the presence of LVSI and the low, intermediate, or high-risk classes of LNR ratio were identified as independent factors. However, age and invasive lobular histologic type did not appear to be independent factors affecting metastatic-free survival. ConclusionOur study highlights the significant prognostic impact of lymph node involvement in patients with invasive lobular carcinoma. The LNR ratio can be used as a reliable predictor of overall survival and metastatic-free survival in these patients.

LDR-Brachytherapy monotherapy appears unsuited for NCCN unfavorable intermediate-risk prostate cancer patients

BackgroundTo validate the subdivision of intermediate-risk (IR) prostate cancer (PCa) into favorable intermediate-risk (FIR) and unfavorable intermediate-risk (UIR) PCa in a historical patient cohort and to compare 2 different radiotherapy regimens. MethodsPatients with intermediate-risk (IR) PCa, treated either by 125J-LDR-brachytherapy monotherapy (BT) or by combined-modality radiation therapy (CRT), were retrospectively subclassified into FIR and UIR and reanalyzed with regard to biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and prostate cancer-specific survival (CSS). Kaplan-Meier product-limit method and log-rank tests were applied to estimate survival probabilities and compare survival, respectively. Uni- and multivariable analyses were performed using Cox proportional hazard regression. ResultsOf 490 IR patients, 252 had received BT (86.5% FIR, 13.5% UIR), and 238 had received CRT (30% FIR, 70% UIR). Retrospective analysis revealed that BRFS at 10 years was 81% for BT, and 94% for CRT in FIR patients. For UIR patients, BRFS at 10 years was 37% for BT, and 89% for CRT. MFS at 10 years for FIR patients was 87% for BT, and 94% for CRT. For UIR patients MFS at 10 years was 78% for BT, and 95% for CRT. In multivariable analysis treatment (BT vs. CRT) was the single associated factor for biochemical recurrence, and for metastases in the UIR group (BFRS, P < 0.001, HR 16.07 (CI 4.23–61.10); MFS, P = 0.011, HR 8.43 (CI 1.62–43.9). ConclusionsSubclassification of IR prostate cancer into FIR and UIR subcategories appears mandatory. For FIR patients, outcomes after BT monotherapy were acceptable. However, clinical failure after 125J-LDR-BT in UIR patients was notably increased, suggesting that BT monotherapy was less successful in this risk group. In contrast, the outcome in UIR patients after CRT was excellent.

Early computed tomography coronary angiography and preventative treatment in patients with suspected acute coronary syndrome: A secondary analysis of the RAPID-CTCA trial

Computed tomography coronary angiography (CTCA) offers detailed assessment of the presence of coronary atherosclerosis and helps guide patient management. We investigated influences of early CTCA on the subsequent use of preventative treatment in patients with suspected acute coronary syndrome. In this secondary analysis of a multicenter randomized controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, prescription of aspirin, P2Y12 receptor antagonist, statin, renin-angiotensin system blocker, and beta-blocker therapies from randomization to discharge were compared within then between those randomized to early CTCA or to standard of care only. Effects of CTCA findings on adjustment of these therapies were further examined. In 1,743 patients (874 randomized to early CTCA and 869 to standard of care only), prescription of P2Y12 receptor antagonist, dual antiplatelet, and statin therapies increased more in the early CTCA group (between-group difference: 4.6% [95% confidence interval, 0.3-8.9], 4.5% [95% confidence interval, 0.2-8.7], and 4.3% [95% confidence interval, 0.2-8.5], respectively), whereas prescription of other preventative therapies increased by similar extent in both study groups. Among patients randomized to early CTCA, there were additional increments of preventative treatment in those with obstructive coronary artery disease and higher rates of reductions in antiplatelet and beta-blocker therapies in those with normal coronary arteries. Prescription patterns of preventative treatment varied during index hospitalization in patients with suspected acute coronary syndrome. Early CTCA facilitated targeted individualization of these therapies based on the extent of coronary artery disease.

Impact of sarcopenia on long-term survival after cardiac surgery for end-stage renal disease patients.

The long-term mortality of end-stage renal disease (ESRD) patients is still unsatisfactory. Therefore, long-term risk assessments in ESRD patients undergoing cardiac surgery are needed. Recently, sarcopenia is major concern in cardiac surgery because of its association with poor long-term survival. However, the impact of sarcopenia on the long-term survival of ESRD patients undergoing cardiac surgery is not well understood. Eighty-two ESRD patients who underwent elective cardiac surgery were enrolled. Sarcopenia was identified based on noncontrast abdominal computed tomography. The impact of preoperative and intraoperative factors on long-term survival was investigated. Forty-three patients (52%) were diagnosed with sarcopenia. The in-hospital mortality rate was 4.9%. The 5-year overall survival rate was 48%. The multivariate analyses revealed that STS score ≥ 4 (odds ratio, 6.0; confidence interval, 2.5-14.7; p < 0.01) and presence of sarcopenia (odds ratio, 2.4; confidence interval, 1.3-4.5; p = 0.03) were independent risk factors for overall survival. The 5-year survival rates of low-risk (Society of Thoracic Surgeons score of < 4) patients without sarcopenia, low-risk with sarcopenia, more than intermediate-risk (Society of Thoracic Surgeons score of ≥ 4) without sarcopenia, and more than intermediate-risk with sarcopenia groups were 80%, 51%, 50%, and 26%, respectively. Among the ESRD patients, the low risk without sarcopenia group showed an excellent long-term survival, in contrast to more than intermediate-risk patients with sarcopenia, who can expect poor long-term survival. Preoperative assessment of sarcopenia in addition to the surgical risk score can be useful in developing a therapeutic strategy.

JS07.5.A PROGNOSTIC FACTORS ASSOCIATED WITH POOR OUTCOME IN ADULT PATIENTS WITH MEDULLOBLASTOMA

Abstract BACKGROUND Medulloblastoma (MB) is a rare tumor in adults. Current recommendations are based on scarce data available in adults, and mostly derived from pediatric series. Prognostic factors have not been uniformly defined in adults to date. MATERIAL AND METHODS We retrospectively collected all cases of adult patients diagnosed and treated between 1995 and 2019 in our institution for histopathological proven MB. We described patient´s characteristics, disease features, treatment modalities and studied the prognostic factors for survival outcomes using univariate and multivariate analysis. RESULTS We identified a total of 89 cases. Male gender (66%), lateral cerebellar location (48%), desmoplastic/nodular histology (43%), Sonic Hedgehog molecular group (76%) and Chang´s M0 (72%) were the most frequent patient´s and disease characteristics. Patients mostly achieved complete resection/near total resection (62%); surgery followed by chemotherapy/radiotherapy (CT/RT) was the most frequent initial strategy (76%), favoring carboplatin-based regimens (70%), posterior fossa RT ≥50 Gy (71%) and craniospinal RT ≥ 30 Gy (59%) as the most frequently regimen used. According to the Association of French Speaking Neuro-oncologists and the European Reference Network on Rare Adult Cancers risk scales (ANOCEF and EURACAN), we found 44 and 48% of intermediate-risk patients and 49 and 45% of high-risk patients, respectively. Both cerebral and spinal presentation at diagnosis was documented in 16 (18%) patients. Complete response was achieved in 71(80%) patients. Nine was the maximal number of progressions documented, 35(39%) patients relapsed, CT was the preferred strategy at relapses, privileging carboplatin-based regimens at first relapse. The median overall survival (mOS) was 124.42 months (95%CI 68.53 - 180.11) and the median progression free survival (mPFS) was 30.48 months (95%CI 13.46 - 47.51), the 5-year OS was 53% and the 5-year PFS was 51%. In multivariate analysis, Chang´s ≥ M2 metastatic classification (p=0.001), no CT in association to RT (p=0.005), and lower doses on craniospinal RT &amp;lt;30 Gy (p=0.015) were associated with poor prognosis for OS; Chang´s ≥ M2 (p=0.009) was also a prognostic factor for poor PFS. CONCLUSION This study dedicated specifically to adult MB patients suggests relevant prognostic factors for adult MB patients. We identify Chang´s ≥ M2 as poor prognostic factor of OS and PFS, and we confirm that the use of CT/RT at diagnosis and RT doses ≥ 30 Gy are associated with better survival in adults MB.

MDS-Comorbidity Index using register data has prognostic impact in Swedish MDS patients

Comorbidities influence the mortality in patients with myelodysplastic syndromes, and a growing body of evidence suggest that comorbidity history should be used in addition to established prognostic indices. A comorbidity index specific for MDS, the MDS-CI, was introduced a decade ago. In this study we aim to construct an MDS-CI version based on diagnoses from register data only, to expand its use beyond the clinical setting to retrospective and register based studies. We further test this version on a Swedish population-based MDS cohort of 2947 patients, and compare its prognostic accuracy to that of Charlson Comorbidity Index. Our register based MDS-CI divided patients into three risk groups of similar proportions as have been published for the original MDS-CI. Compared to low risk patients, intermediate and high risk patients had 50 % and 70 % higher mortality, respectively. The prognostic value of MDS-CI was equal to that of Charlson comorbidity index. Adding MDS-CI to the established prognostic factors IPSS-R and age increased the prognostic accuracy. In summary, we demonstrate that MDS-CI can be adequately estimated from diagnoses recorded in registers only, and that it is a useful tool in any future study on myelodysplastic syndromes with a need to adjust for comorbidities.

Comparing Active Surveillance and Watchful Waiting With Radical Treatment Using Machine Learning Models Among Patients With Prostate Cancer.

In 2021, 59.6% of low-risk patients with prostate cancer were under active surveillance (AS) as their first course of treatment. However, few studies have investigated AS and watchful waiting (WW) separately. The objectives of this study were to develop and validate a population-level machine learning model for distinguishing AS and WW in the conservative treatment group, and to investigate initial cancer management trends from 2004 to 2017 and the risk of chronic diseases among patients with prostate cancer with different treatment modalities. In a cohort of 18,134 patients with prostate adenocarcinoma diagnosed between 2004 and 2017, 1,926 patients with available AS/WW information were analyzed using machine learning algorithms with 10-fold cross-validation. Models were evaluated using performance metrics and Brier score. Cox proportional hazard models were used to estimate hazard ratios for chronic disease risk. Logistic regression models achieved a test area under the receiver operating curve of 0.73, F-score of 0.79, accuracy of 0.71, and Brier score of 0.29, demonstrating good calibration, precision, and recall values. We noted a sharp increase in AS use between 2004 and 2016 among patients with low-risk prostate cancer and a moderate increase among intermediate-risk patients between 2008 and 2017. Compared with the AS group, radical treatment was associated with a lower risk of prostate cancer-specific mortality but higher risks of Alzheimer disease, anemia, glaucoma, hyperlipidemia, and hypertension. A machine learning approach accurately distinguished AS and WW groups in conservative treatment in this decision analytical model study. Our results provide insight into the necessity to separate AS and WW in population-based studies.

Accurate Documentation Contributes to Guideline-concordant Surveillance of Nonmuscle Invasive Bladder Cancer: A Multisite Department of Veterans Affairs Study

To determine if accurate documentation of bladder cancer risk was associated with a clinician surveillance recommendation that is concordant with AUA guidelines among patients with nonmuscle invasive bladder cancer (NMIBC). We prospectively collected data from cystoscopy encounter notes from four Department of Veterans Affairs (VA) sites to ascertain whether they included accurate documentation of bladder cancer risk and a recommendation for a guideline-concordant surveillance interval. Accurate documentation was a clinician-recorded risk classification matching a gold standard assigned by the research team. Clinician recommendations were guideline-concordant if the clinician recorded a surveillance interval that was in line with the AUA guideline. Among 296 encounters, 75 were for low-, 98 for intermediate-, and 123 for high-risk NMIBC. 52% of encounters had accurate documentation of NMIBC risk. Accurate documentation of risk was less common among encounters for low-risk bladder cancer (36% vs 52% for intermediate- and 62% for high-risk, P<.05). Guideline-concordant surveillance recommendations were also less common in patients with low-risk bladder cancer (67% vs 89% for intermediate- and 94% for high-risk, P<.05). Accurate documentation was associated with a 29% and 15% increase in guideline-concordant surveillance recommendations for low- and intermediate-risk disease, respectively (P<.05). Accurate risk documentation was associated with more guideline-concordant surveillance recommendations among low- and intermediate-risk patients. Implementation strategies facilitating assessment and documentation of risk may be useful to reduce overuse of surveillance in this group and to prevent unnecessary cost, anxiety, and procedural harms.

Patterns of multispecialty care for low- and intermediate-risk prostate cancer in the use of active surveillance.

Multidisciplinary models of care have been advocated for prostate cancer (PC) to promote shared decision-making and facilitate quality care. Yet, how this model applies to low-risk disease where the preferred management is expectant remains unclear. Accordingly, we examined recent practice patterns in specialty visits for low/intermediate-risk PC and resultant use of active surveillance (AS). Using SEER-Medicare, we ascertained whether patients saw urology and radiation oncology (i.e., multispecialty care) versus urology alone, based on self-designated specialty codes, for newly diagnosed PC from 2010 to 2017. We also examined the association with AS, defined as the absence of treatment within 12 months of diagnosis. Time trends were analyzed using Cochran-Armitage test. Chi-squared and logistic regression analyses were applied to compare sociodemographic and clinicopathologic characteristics between these models of care. The proportion of patients seeing both specialists was 35.5% and 46.5% for low- and intermediate-risk patients respectively. Trend analysis showed a decline in multispecialty care in low-risk patients (44.1% to 25.3% years 2010-2017; P < 0.001). Between 2010 and 2017, the use of AS increased 40.9% to 68.6% (P < 0.001) and 13.1% to 24.6% (P < 0.001) for patients seeing urology and those seeing both specialists respectively. Age, urban residence, higher education, SEER region, co-morbidities, frailty, Gleason score, predicted receipt of multispecialty care (all P < 0.02). Uptake of AS among men with low-risk PC has occurred primarily under the purview of urologists. While selection is certainly at play, these data suggest that multispecialty care may not be required to promote the utilization of AS for men with low-risk PC.

Prostate Cancer–specific and All-cause Mortality After Robot-assisted Radical Prostatectomy: 20 Years’ Report from the European Association of Urology Robotic Urology Section Scientific Working Group

BackgroundEvidence on long-term oncological efficacy is available only for open radical prostatectomy but remains scarce for robot-assisted radical prostatectomy (RARP). ObjectiveTo validate the long-term survival rates after RARP and provide stratified outcomes based on contemporary prostate cancer (PCa) risk-stratification tools. Design, setting, and participantsA retrospective analysis of the European Association of Urology (EAU) Robotic Urology Section Scientific Working Group international multicenter database for RARP was performed. Patients who underwent RARP at seven pioneer robotic urology programs in Europe and the USA between 2002 and 2012 were included. Outcome measurements and statistical analysisThe primary outcomes were PCa-specific mortality and all-cause mortality. The probability of cancer-specific survival (CSS) was estimated with the competing risks method, and the probability of overall survival (OS) was estimated with the Kaplan-Meier method. Results and limitationsA total of 9876 patients who underwent RARP between 2002 and 2012 were included. Within follow-up, 1071 deaths occurred and 159 were due to PCa. At 15 yr of follow-up, CSS and OS were 97.6% (97.2%, 98.0%) and 85.5% (84.6%, 86.4%), respectively. Stratified analyses based on EAU risk groups at diagnosis and pT stage showed favorable survival rates, with low-risk (n = 4601, 46.6%), intermediate-risk (n = 4056, 41.1%), and high-risk (n = 1219, 12.3%) patients demonstrating CSS rates of 99%, 98%, and 90% at 15 yr, respectively. Notably, patients with pT3a disease had similar survival outcomes to those with pT2 disease, with worse CSS in patients with pT3b PCa (98.9% vs 97.4% vs 86.5%). Multivariable analyses identified age, prostate-specific antigen, biopsy Gleason grade group, clinical T stage, and treatment year as independent predictors of worse oncological outcomes. ConclusionsOur multicenter study with long-term follow-up confirms favorable survival outcomes after RARP for localized PCa. Patients with low- and intermediate-risk disease face a higher risk of mortality from causes other than PCa. On the contrary, high-risk patients have a significantly higher risk of PCa-specific mortality. Patient summaryIn the present study, we reported the outcomes of patients with prostate cancer (PCa) who underwent robot-assisted radical prostatectomy between 10 and 20 yr ago, and we found a very low probability of dying from PCa in patients with low- and intermediate-risk PCa.

Hybridizing machine learning in survival analysis of cardiac PET/CT imaging

BackgroundMachine Learning (ML) allows integration of the numerous variables delivered by cardiac PET/CT, while traditional survival analysis can provide explainable prognostic estimates from a restricted number of input variables. We implemented a hybrid ML-and-survival analysis of multimodal PET/CT data to identify patients who developed myocardial infarction (MI) or death in long-term follow up.MethodsData from 739 intermediate risk patients who underwent coronary CT and selectively stress 15O-water-PET perfusion were analyzed for the occurrence of MI and all-cause mortality. Images were evaluated segmentally for atherosclerosis and absolute myocardial perfusion through 75 variables that were integrated through ML into an ML-CCTA and an ML-PET score. These scores were then modeled along with clinical variables through Cox regression. This hybridized model was compared against an expert interpretation-based and a calcium score-based model.ResultsCompared with expert- and calcium score-based models, the hybridized ML-survival model showed the highest performance (CI .81 vs .71 and .64). The strongest predictor for outcomes was the ML-CCTA score.ConclusionPrognostic modeling of PET/CT data for the long-term occurrence of adverse events may be improved through ML imaging score integration and subsequent traditional survival analysis with clinical variables. This hybridization of methods offers an alternative to traditional survival modeling of conventional expert image scoring and interpretation.

The oncologic and safety outcomes of low-dose-rate brachytherapy for the treatment of prostate cancer.

Around 40years have passed since a modern low-dose-rate (LDR) brachytherapy for prostate cancer was introduced. LDR brachytherapy has become one of the definitive treatment options besides radical prostatectomy (RP) and external beam radiation therapy (EBRT). LDR brachytherapy has several advantages over EBRT such as a higher prescribed dose to the prostate gland while avoiding unnecessary irradiation of organs at risk, a precipitous dose gradient, a brief treatment time, and a short hospital stay. Previous reports revealed that the long-term oncologic outcomes of LDR brachytherapy are superior to those of EBRT. The oncologic outcomes of low- to intermediate-risk patients are equivalent to those of RP using the recurrence definition of surgery of prostate specific antigen (PSA) >0.2ng/mL, while the oncologic outcomes of LDR brachytherapy as tri-modality (combined EBRT and androgen deprivation therapy) for high-risk patients is superior to that of RP using the recurrence definition of surgery. In respect of toxicity, urinary disorders such as urgency and frequency are often observed after the acute phase of treatment, but these events usually resolve, while the quality of life of urinary continence is well preserved for a long time. Erectile function decreases yearly, but is relatively preserved compared to RP. In conclusion, the most noteworthy strength of LDR brachytherapy for low- to intermediate-risk patients is the "brief treatment time" that provides long recurrence-free survival, while that for high-risk patients who received LDR brachytherapy (tri-modality) is "excellent disease control."

A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aβ immunotherapies for Alzheimer’s disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aβ-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aβ-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aβ42/Aβ40 testing, whereas step 1 alone determined Aβ-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aβ-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.

Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy

Lymphocytes play an important role in antitumor immunity; however, they are also especially vulnerable to depletion during chemoradiation therapy (CRT). The purpose of this study was to compare the incidence of grade 4 lymphopenia (G4L) between proton beam therapy (PBT) and intensity modulated photon radiation therapy (IMRT) in patients with esophageal cancer treated with CRT in a completed randomized trial and to ascertain patient heterogeneity to G4L risk based on treatment and established prognostic factors. Between April 2012 and March 2019, a single-institution, open-label, nonblinded, phase 2 randomized trial (NCT01512589) was conducted at the University of Texas MD Anderson Cancer Center. Patients were randomly assigned to IMRT or PBT, either definitively or preoperatively. This secondary analysis of the randomized trial was G4L during concurrent CRT according to Common Terminology Criteria for Adverse Events version 5.0. Among 105 patients evaluable for analysis, 44 patients (42%) experienced G4L at a median of 28 days after the start date of concurrent CRT. Induction chemotherapy (P=.003), baseline absolute lymphocyte count (P < .001), radiation therapy modality (P=.002), and planning treatment volume (P=.033) were found to be significantly associated with G4L. Multivariate classification analysis partitioned patients into 5 subgroups for whom the incidence of G4L was observed in 0%, 14%, 35%, 70%, and 100% of patients. The benefit of PBT over IMRT was most pronounced in patients with an intermediate baseline absolute lymphocyte count and large planning treatment volume (P=.011). This is the first prospective evidence that limiting dose scatter by PBT significantly reduced the incidence of G4L, especially in the intermediate-risk patients. The implication of this immune-sparing effect of PBT, especially in the context of standard adjuvant immunotherapy, needs further examination in the current phase 3 randomized trials.

High-dose aciclovir in CMV infection prophylaxis after allogeneic HSCT: a single-center long-term experience

There is only limited data on cytomegalovirus (CMV) prophylaxis with high-dose (HD) aciclovir after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a retrospective analysis on a total of 179 patients who underwent their allo-HSCT with HD-aciclovir prophylaxis at our center. A clinically significant CMV infection (cs-CMVi) was observed in 56 (31%) cases with a median time of 49 (range 25–147) days after HSCT. A significantly higher CMV infection rate was observed in seropositive recipients with a seronegative donor (74%) compared to seropositive recipients with a seropositive donor, and seronegative recipients with seropositive and seronegative donors (24%, 18%, 7% respectively; p < 0.001). The CMV serostatus was the only significant risk factor for CMV infection in our analysis. CMV disease developed in three patients with CMV-related death in two cases. During HD-aciclovir prophylaxis, we did not observe any medical condition attributable to HD-aciclovir’s adverse effects. Compared to published results, we observed a low incidence of cs-CMVi with HD-aciclovir prophylaxis in several patient subgroups, especially in seropositive recipients with a seropositive donor. With respect to the determined threshold, HD-aciclovir prophylaxis seems to have good efficacy in an intermediate cs-CMVi risk patients, but prospective randomized trials would be needed for definite conclusions.

Quantitative Late Gadolinium Enhancement Cardiac Magnetic Resonance and Sudden Death in Hypertrophic Cardiomyopathy: A Meta-Analysis

BackgroundQuantitative late gadolinium enhancement (LGE) cardiac magnetic resonance provides important prognostic information for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, it has not been fully integrated into clinical practice. ObjectivesThe purpose of this study was to assess the prognostic value of LGE extent in predicting SCD in adults with HCM across different methods of quantification, thresholds, and patients’ clinical profile. MethodsThe authors searched PubMed, Web of Science, and Cochrane Library for studies investigating the prognostic value of LGE% in predicting SCD in HCM. Pooled ORs were calculated with 95% CIs. The optimal threshold was determined using a multiple cutoffs model. ResultsEleven studies were included in the meta-analysis with a total of 5,550 patients and a median follow-up time of 5.2 years. Two studies quantified LGE manually, 7 studies used the 6 SD technique, 1 study used the 4 SD technique, and 1 study the 2 SD technique. There was no statistically significant difference in predicting SCD between these 4 methods (P = 0.443). Optimal cutoff could be determined only for the 6 SD technique. LGE 10% was the optimal threshold of the 6 SD technique with sensitivity 0.73 and specificity 0.67. ConclusionsThe different LGE quantification techniques have comparable accuracy in predicting SCD. When the more extensively studied 6 SD technique is used, LGE 10% is the optimal cutoff and can effectively restratify intermediate-risk patients. LGE extent can improve HCM risk stratification, but it is unlikely to become a standalone tool.

Surgical Treatment of Hepatocellular Carcinoma: Multicenter Competing-risk Analysis of Tumor-related Death Following Liver Resection and Transplantation Under an Intention-to-treat Perspective.

Early-stage hepatocellular carcinoma could benefit from upfront liver resection (LR) or liver transplantation (LT), but the optimal strategy in terms of tumor-related outcomes is still debated. We compared the oncological outcomes of LR and LT for hepatocellular carcinoma, stratifying the study population into a low-, intermediate-, and high-risk class according to the risk of death at 5-y predicted by a previously developed prognostic model. The impact of tumor pathology on oncological outcomes of low- and intermediate-risk patients undergoing LR was investigated as a secondary outcome. We performed a retrospective multicentric cohort study involving 2640 patients consecutively treated by LR or LT from 4 tertiary hepatobiliary and transplant centers between 2005 and 2015, focusing on patients amenable to both treatments upfront. Tumor-related survival and overall survival were compared under an intention-to-treat perspective. We identified 468 LR and 579 LT candidates: 512 LT candidates underwent LT, whereas 68 (11.7%) dropped-out for tumor progression. Ninety-nine high-risk patients were selected from each treatment cohort after propensity score matching. Three and 5-y cumulative incidence of tumor-related death were 29.7% and 39.5% versus 17.2% and 18.3% for LR and LT group ( P = 0.039), respectively. Low-risk and intermediate-risk patients treated by LR and presenting satellite nodules and microvascular invasion had a significantly higher 5-y incidence of tumor-related death (29.2% versus 12.5%; P < 0.001). High-risk patients showed significantly better intention-to-treat tumor-related survival after upfront LT rather than LR. Cancer-specific survival of low- and intermediate-risk LR patients was significantly impaired by unfavorable pathology, suggesting the application of ab-initio salvage LT in such scenarios.

Surveillance for Nonmuscle Invasive Bladder Cancer: Identifying the Point of Diminishing Returns

To characterize first and second recurrence patterns using 26years of cohort-level follow-up and microsimulation modeling. Patients diagnosed with nonmuscle-invasive bladder cancer in Stockholm County between 1995 and 1996 were included. Clinical, pathological, and longitudinal follow-up data were gathered. Logistic regressions, Kaplan Meier curves, and Cox proportional hazards models were run to generate assumptions for a microsimulation model, simulating first and second recurrence and progression for 10,000 patients. Three hundred eighty-six patients were included: 67.4% were male; >50% were TaLG; and 37.5% were American Urological Association high-risk. Median time to recurrence was 300days. Three patients had missing data. Cohort follow-up has been carried out for 26years. For simulated first-recurrences, low-risk patients recurred at 56.6% over 15years of follow-up, with 2.2% muscle-invasive (MI) progression; intermediate-risk patients recurred at 62.8%, with 4.3% MI progression; high-risk patients recurred at 48.7% over 15years, with MI progression at 14.3%. For second recurrences, 70.7%, 75.7%, and 84.7% of low, medium, and high-risk patients recurred. No patients were seen to have first recurrences after 9years, with low, but notable, rates beyond 5years. These data suggest that low-, intermediate-, and high-risk patients without recurrence at 5years may be potentially transitioned to less invasive monitoring.