Citations

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

AbstractWe conducted the first large genome‐wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first‐line oxaliplatin‐based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population‐based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression‐free survival. The analysis was performed for studies individually, and the results were combined using fixed‐effect meta‐analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene‐based analysis as well as in silico bioinformatics analysis for CRC‐relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin‐based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10−8). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10−7). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene‐based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10−6). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first‐line treatment and improve clinical outcomes.

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

This review emphasizes the importance of cardiopulmonary exercise testing (CPET) in patients diagnosed with hypertrophic cardiomyopathy (HCM). In contrast to standard exercise testing and stress echoes, which are limited due to the ECG changes and wall motion abnormalities that characterize this condition, CPET allows for the assessment of the complex pathophysiology and severity of the disease, its mechanisms of functional limitation, and its risk stratification. It is useful tool to evaluate the risk for sudden cardiac death and select patients for cardiac resynchronization therapy (CRT), cardiac transplantation, or mechanical circulatory support, especially when symptomatology and functional status are uncertain. It may help in differentiating HCM from other forms of cardiac hypertrophy, such as athletes’ heart. Finally, it is used to guide and monitor therapy as well as for exercise prescription. It may be considered every 2 years in clinically stable patients or every year in patients with worsening symptoms. Although performed only in specialized centers, CPET combined with echocardiography (i.e., CPET imaging) and invasive CPET are more informative and provide a better assessment of cardiac functional status, left ventricular outflow tract obstruction, and diastolic dysfunction during exercise in patients with HCM.

Purpose of review The purpose of the review is to critically evaluate the evidence from the literature to establish the current perspective on fluid resuscitation (FR) in acute pancreatitis (AP). We will review the rationale, type of fluid, rate of administration, total volume, duration, monitoring, ideal outcomes to be studied in clinical trials and recommendations for future studies. Recent findings FR remains the key component of supportive therapy in AP. The paradigm has shifted from administration of aggressive fluid resuscitation towards more moderate FR strategies. Lactated Ringer's remains the preferred fluid for resuscitation. There remain critical gaps in knowledge regarding the end point(s) to indicate adequate resuscitation, and accurate assessments of fluid sequestration and intravascular volume deficit in AP. Summary There is insufficient evidence to state that goal-directed therapy, using any of the parameters to guide fluid administration, reduces the risk of persistent organ failure, infected pancreatic necrosis, or mortality in AP, as well as the most appropriate method for the same.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Abstract Chimeric antigen receptor T-cell (CAR-T) therapy represents a major advance in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide was shown to reduce endothelial cell activation in vitro and is approved in the United States for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT), and in the European Union for severe VOD/SOS after HCT in patients aged &gt;1 month. Defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T–associated neurotoxicity. This phase 2 study evaluated the safety and efficacy of defibrotide for prevention of CAR-T–associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. Part 1 established the recommended phase 2 dose (RP2D; 6.25 mg/kg); 20 patients (from parts 1 and 2) receiving the RP2D were evaluable for efficacy. Rate of CAR-T–associated neurotoxicity by day 30 (primary end point) was ∼50%, lower than reported in the ZUMA-1 trial (64%). Median event duration of grade ≥3 neurotoxicity was 7 days. No unexpected defibrotide-related safety findings and defibrotide-related treatment-emergent adverse events or deaths were reported. Results showed modest reduction in rate of CAR-T–associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, reduction was unlikely to meet the primary end point, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T–associated neurotoxicity. This trial was registered at www.clinicaltrials.gov as #NCT03954106.

SIGNIFICANCE This pilot randomized trial, the first to evaluate a specific base‐in relieving prism treatment strategy for childhood intermittent exotropia, did not support proceeding to a full‐scale clinical trial. Defining and measuring prism adaptation in children with intermittent exotropia are challenging and need further study. PURPOSE This study aimed to determine whether to proceed to a full‐scale trial of relieving base‐in prism spectacles versus refractive correction alone for children with intermittent exotropia. METHODS Children 3 years old to those younger than 13 years with distance intermittent exotropia control score of ≥2 points on the Intermittent Exotropia Office Control Scale (Strabismus 2006;14:147–150; 0 [phoria] to 5 [constant]), ≥1 episode of spontaneous exotropia, and 16 to 35∆ by prism‐and‐alternate‐cover test, who did not fully prism adapt on a 30‐minute in‐office prism‐adaptation test were randomized to base‐in relieving prism (40% of the larger of distance and near exodeviations) or nonprism spectacles for 8 weeks. A priori criteria to conduct a full‐scale trial were defined for the adjusted treatment group difference in mean distance control: “proceed” (≥0.75 points favoring prism), “uncertain” (>0 to <0.75 points favoring prism), or “do not proceed” (≥0 points favoring nonprism). RESULTS Fifty‐seven children (mean age, 6.6 ± 2.2 years; mean baseline distance control, 3.5 points) received prism (n = 28) or nonprism (n = 29) spectacles. At 8 weeks, mean control values were 3.6 and 3.3 points in prism (n = 25) and nonprism (n = 25) groups, respectively, with an adjusted difference of 0.3 points (95% confidence interval, −0.5 to 1.1 points) favoring nonprism (meeting our a priori “do not proceed” criterion). CONCLUSIONS Base‐in prism spectacles, equal to 40% of the larger of the exodeviations at distance or near, worn for 8 weeks by 3‐ to 12‐year‐old children with intermittent exotropia did not yield better distance control than refractive correction alone, with the confidence interval indicating that a favorable effect of 0.75 points or larger is unlikely. There was insufficient evidence to warrant a full‐scale randomized trial.

AbstractBackgroundPrimary cutaneous B‐cell lymphoma (PCBCL) is a group of B‐cell lymphomas of the skin containing primary cutaneous follicle centre lymphoma (PCFCL) and marginal zone B‐cell lymphoma/lymphoproliferative disorder (PCMZL), which are indolent, and diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), which is aggressive.ObjectivesTo evaluate treatment outcomes between PCBCL subtypes after treatment with rituximab and to compare the efficacy of intralesional against systemic rituximab in indolent subtypes.MethodsA search for patients diagnosed with PCBCL and treated with rituximab (systemic or intralesional) across all Mayo Clinic sites was performed, yielding 39 patients.ResultsEight patients had PCFCL (six treated intralesionally and two systemically), 11 had PCMZL (four intralesional, eight systemic with one dual‐treated) and 20 had PCDLBCL‐LT (all systemic). The average age at diagnosis was 62.1 years (SD = 15.1), with average follow‐up of 1852.6 days (SD = 1473.2). 69.2% of all patients treated with any form of rituximab experienced a complete response (100% PCFCL, 81.8% PCMZL and 50% PCDLBCL‐LT). When comparing all three subtypes, a significant difference was seen in overall treatment response (p = 0.022), and progressive disease rates (p = 0.015), but not in retreatment with rituximab (p = 0.440), time to retreatment (p = 0.757), recurrence (p = 0.907) or survival (p = 0.093). In the indolent subtypes, no difference in overall treatment response (p = 1.000), progressive disease rates (p = 1.000), recurrence (p = 0.650), rituximab retreatment (p = 0.650) or time to retreatment (p = 0.724) was observed.ConclusionsThis study suggests that rituximab, as systemic therapy and intralesional therapy, is effective in the management of PCBCL, and that intralesional therapy should be considered before more aggressive therapy in indolent disease.