Citations

Background. Comorbid chronic pain and post-traumatic stress disorder (PTSD) complicate the treatment of both conditions. Previous research has identified pain catastrophizing as a potentially important variable contributing to the relationship between chronic pain and PTSD. However, little is known regarding how the different dimensions of pain catastrophizing—rumination, magnification, and helplessness—uniquely contribute to the relationship between PTSD symptomatology and measures of pain outcome. Methods. 491 treatment seeking participants were admitted to a three-week interdisciplinary pain rehabilitation program between July 2016 and March 2020. The patients completed measures of pain severity, pain interference, pain catastrophizing, depressive symptoms, quality of life (QOL), and PTSD symptoms at pretreatment. Results. Parallel mediation analyses were conducted to evaluate the mediating effect of the Pain Catastrophizing Scale subscales on the relationship between PTSD symptomatology and pain-relevant variables. The helplessness subscale accounted for significant unique variance in the relationship between PTSD symptomatology and pain severity (b = 0.010, SE = 0.002, 95% CI: 0.006, 0.014), pain interference (b = 0.004, SE = 0.002, 95% CI: 0.001, 0.008), and mental health QOL (b = −0.117, SE = 0.031, 95% CI: −0.179, −0.059), while the rumination and magnification subscales had no significant influence. Conclusions. Pain catastrophizing is a multifaceted construct. These results suggest that the helplessness dimension of pain catastrophizing may be the primary target when treating patients with comorbid chronic pain and PTSD symptoms. This study represents the first to evaluate the influence of the individual dimensions of pain catastrophizing on the relationship between PTSD symptomatology and chronic pain outcome.

Peripheral Artery Disease (PAD) is a vascular disease that affects over 8 million Americans. PAD patients commonly have difficulty walking due to pain in the legs during physical exertion. Supervised walking therapy has been recommended to improve walking performance and attenuate disease progression; however, this therapy remains underutilized in PAD patients. Recently, there has been evidence to suggest that stretching accomplished via an ankle dorsiflexion splint may improve vascular health and walking performance in PAD; however, it is currently unknown how this protocol affects tissue oxygenation (StO 2 ). The purpose of this study was to determine the impact of 4 wks of ankle dorsiflexion stretching on measures of tissue oxygenation in patients with PAD. Thirteen PAD patients (67.7 ± 7.9 years) were randomized to a stretch (n = 9) or a non-stretch control (n = 4) group. Patients in the stretch were instructed to wear the splint for 30 min/day, 5 days/wk for 4 wks. A 5-min vascular occlusion test was administered before and after the intervention. Measures of StO 2 recovery were calculated following the vascular occlusion test and while completing a 6-minute walk test (6MWT). All measures of StO 2 were derived via Near-Infrared Spectroscopy. Repeated measures ANOVA was used to analyze data. There was a significant improvement in StO 2 recovery in the stretch group compared to the control (Stretch: 0.35 ± 0.25 %/sec vs 0.53 ± 0.29 %/sec; Control: 0.57 ± 0.43 %/sec vs 0.32 ± 0.19 %/sec; p = 0.002). During the 6MWT, patients completing the stretching protocol significantly improved oxygen extraction in the first minute of the test (-0.63 ± 0.05 StO 2 vs -0.73 ± 0.09 StO 2 ); however, this improvement was not significantly different compared to changes in the control group. These results indicate an improvement in microvascular reactivity and oxygen extraction following 4 wks of splint-based stretching. This stretching intervention holds potential therapeutic value for PAD patients and warrants further investigation.

Abstract Background: Uptake of genetic testing for cancer susceptibility in family members of cancer patients is suboptimal. The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated two strategies of remote genetic education and testing in relatives of pancreatic ductal adenocarcinoma (PDAC) patients. Methods: Eligible participants had: a first-degree relative with PDAC or had a known pathogenic germline variant (PGV) in one of thirteen PDAC predisposition genes (APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53) and a first- or second-degree relative with PDAC. Participants were cluster-randomized by family into one of two arms. Arm 1 included an interactive telemedicine session with a genetic counselor, followed by genetic testing at a commercial laboratory. Arm 2 involved remote online genetic education and testing at the commercial laboratory without the interactive session. The primary outcome was uptake of genetic testing across study arms, which was compared by permutation tests and mixed-effects logistic regression models. Results: Between 5/8/2019 and 6/1/2021, 424 families were randomized, including 601 participants (n=296 Arm 1; n=305 Arm 2). The uptake of genetic testing was 87% (257/296) in Arm 1 and 93% (284/305) in Arm 2 (p=0.014). Participants in Arm 1 were significantly less likely to obtain genetic testing compared to Arm 2 (Adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). BRCA2, ATM, CDKN2A and PALB2 were the most common PDAC susceptibility genes in which PGVs were identified. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional germline susceptibility testing. Citation Format: Nicolette J. Rodriguez, C. Sloane Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Ileana Fortes, Alyson Caruso, Alison N. Schwartz, Jill E. Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H. Nelson, Sydney Okumura, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Miki Horiguchi, Allyson J. Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. A randomized study of two Strategies of remote Genetic Education, Risk Assessment, and Testing (GENERATE) for family members of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A029.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Background A gap remains in the role of neoadjuvant therapy for patients with ILC. Method Single-institution retrospective review of patients with ILC who received neoadjuvant therapy between 2008 and 2019. Results 141 patients met inclusion criteria: 71 neoadjuvant chemotherapy (NACT) and 70 neoadjuvant endocrine therapy (NET). 7/71 (9.9%) patients had a pCR following NACT compared to 1/70 (1.4%) with NET ( P = .063). pCR was observed in 5/18 (27.8%) patients with Her2Neu-positive disease following NACT, compared to 2/53 (3.8%) with Her2Neu-negative disease ( P = .01). For luminal B tumors, median Ki-67 decrease was similar following NACT and NET (18.3 vs 16.3, P = .26). T category decreased in 59 (42.1%) patients following neoadjuvant therapy, increased in 9 (6.4%), and was unchanged in 72 (51.4%). More patients had an increase (28.6%) than decrease (12.1%) in their N category, including 13/60 (21.7%) who were clinically node-negative at diagnosis and identified to have node-positive disease following neoadjuvant therapy, at definitive surgery. Conclusion In Her2Neu-negative ILC, the potential of a pCR with NACT or NET is low. Most patients’ nodal status and tumor size remain unchanged. There is a potential for pathologic stage to be higher at surgery compared to the clinical stage prior to neoadjuvant therapy.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

AbstractGermline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer‐ and polyposis‐focused panels, as well as on broader pan‐cancer panels. With up to 1%–2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross‐sectional self‐report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase ( IDH) –mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.