Citations

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.

Introduction: Oncologic proximal femoral resection and reconstruction in skeletally immature children remains a formidable task due to the risk of developing hip instability with patient growth or interval leg lengthening through the prosthesis. Shelf pelvic osteotomy increases femoral head coverage and containment, and favorable long-term results have been reported in the setting of developmental dysplasia of the hip and Perthes disease. We present a technique of combining shelf osteotomy with expandable proximal femoral endoprosthesis reconstruction in pediatric limb-sparing surgery. Materials and Methods: Four surgeons at 2 centers from 2012 to 2020 performed proximal femoral reconstruction with shelf osteotomy. Data were collected retrospectively on operative technique, radiographic measurements, and complications including dislocation, subluxation, implant loosening, pain, function, and radiographic outcomes. Results: Five patients were included in the study. The mean follow-up was 49 months (range: 17 to 104 mo). The mean lateral center edge angle status postproximal femoral resection and reconstruction shelf osteotomy was 56.1 degrees (±30.5). There were no reported incidences of subluxations, dislocations, periprosthetic fractures, or soft tissue complications. The 3 patients with the longest follow-up at 3, 5, and 8 years tolerated serial lengthening of the endoprosthesis totaling 1 cm, 7.25 cm, and 9 cm, respectively, and demonstrated earlier triradiate cartilage closure in the operative side compared with the nonoperative side. All patients have returned to independent ambulation. Discussion: Combining proximal femoral reconstruction with shelf osteotomy in limb salvage pediatric orthopedic oncology may help to improve hip stability with serial lengthening and patient growth.

Abstract Purpose Accurately predicting the clinical breast cancer subtypes could be extremely helpful for radiologists, pathologists, surgeons, and clinicians and inform future treatment prediction algorithms. Therefore, we evaluate and compare the accuracy of radiomic features extracted from contrast enhanced mammography (CEM) and magnetic resonance imaging (MRI) scans to make predictions to subtypes of breast cancer. Methods This HIPAA-compliant prospective single institution study was approved by the local institutional review board with written informed consent. Women with breast tumors 2 cm or larger underwent dynamic contrast-enhanced MRI and/or CEM for surgical staging. Semi-manual regions of interest were drawn by radiologist using Cancer Imaging Phenomics Toolkit (CaPTk). Radiomic features were obtained using PyRadiomics and MR- and CEM- based classification models were built on a low-dimensional representation of the features obtained via kernel principal component analysis. We subscribed to an ensemble tree-based learning approach called extremely randomized trees (ERT) to predict cancer subtypes captured via immunohistochemistry markers. Results For MRI analysis, 124 women with newly diagnosed breast cancer were included in the analysis comprising 49 HR+HER2-, 37 HR+HER2+, 11 HR-HER2+, and 27 HR-HER2- cases. For CEM analysis, models were built using data from 170 female patients including 74 HR+HER2-, 41 HR+HER2+, 14 HR-HER2+, and 43 HR-HER2-. CEM based model resulted in accuracies of 55%, 72%, 88%, and 71% respectively for HR+HER2-, HR+HER2+, HR-HER2+, and HR-HER2- whereas MRI based model alone led to accuracies of 54%, 62%, 89%, and 76% respectively for HR+HER2-, HR+HER2+, HR-HER2+, and HR-HER2-. Conclusions Radiomic features extracted from CEM and MR were strong predictors of breast cancer subtypes with CEM-based radiomic features performing slightly better, though not statistically significantly better (p = 0.82), than its MRI counterpart.

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

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1. Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.

AbstractBackgroundFertility preservation (FP) may be underused after cancer diagnosis because of uncertainty around delays to cancer treatment and subsequent reproductive success.MethodsWomen aged 15 to 39 years diagnosed with cancer between 2004 and 2015 were identified from the North Carolina Central Cancer Registry. Use of assisted reproductive technology (ART) after cancer diagnosis between 2004 and 2018 (including FP) was assessed through linkage to the Society for Assisted Reproductive Technology. Linear regression was used to examine time to cancer treatment among women who did (n = 95) or did not (n = 469) use FP. Modified Poisson regression was used to estimate risk ratios (RRs) and 95% CIs for pregnancy and birth based on timing of ART initiation relative to cancer treatment (n = 18 initiated before treatment for FP vs n = 26 initiated after treatment without FP).ResultsThe median time to cancer treatment was 9 to 33 days longer among women who used FP compared with women who did not, matched on clinical factors. Women who initiated ART before cancer treatment may be more likely to have a live birth given pregnancy compared with women who initiated ART after cancer treatment (age‐adjusted RR, 1.47; 95% CI, 0.98‐2.23), though this may be affected by the more frequent use of gestational carriers in the former group (47% vs 20% of transfer cycles, respectively).ConclusionsFP delayed gonadotoxic cancer treatment by up to 4.5 weeks, a delay that would not be expected to alter prognosis for many women. Further study of the use of gestational carriers in cancer populations is warranted to better understand its effect on reproductive outcomes.

Abstract1q gain (+1q) is the most common high‐risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097–1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk‐scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re‐stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression‐free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high‐risk patients, therefore underlining the necessity for their re‐stratification. The proposed simple risk‐scoring model can estimate the outcomes of patients with +1q, which may help guide risk‐adapted treatment for such patients.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited survival. Janus kinases (JAKs), tyrosine kinases that transduce cytokine-mediated signals, are known to be involved, but their specific roles in lung fibrosis are not well defined. In this study, the interactions between JAK1/signal transducers and activators of transcription (STAT)3 signaling and transforming growth factor-beta (TGF-β)-induced fibroblast responses were investigated using both pharmacological and siRNA approaches in human normal and IPF-derived lung fibroblasts. We found that JAK1 directly interacts with the TGF-β receptor I subunit (TβRI), and silencing JAK1 promotes myofibroblast transdifferentiation. However, the suppression of JAK1 signaling in vitro and in vivo using an inhibitor (upadacitinib) did not alter lung fibroblast activation or fibrosis development. STAT3 was constitutively active in cultured primary lung fibroblasts; this STAT3 activation required JAK1 and repressed myofibroblast transdifferentiation. Loss of phosphorylated STAT3 following transcriptional JAK1 silencing promoted myofibroblast transdifferentiation. In contrast, transcriptional silencing of unphosphorylated STAT3 suppressed TGF-β signaling, decreased SMAD3 activation, and reduced myofibroblast transdifferentiation and ECM production. Taken together, these observations support a role for JAK1/STAT3 as a direct regulator of TGF-β signaling in lung fibroblasts. Modulation of JAK1/STAT3 signaling in lung fibroblasts represents a noncanonical approach to regulating TGF-β-induced fibrosis and suggests the potential for a novel approach to treat pulmonary fibrosis.