Citations

Abstract The comprehensive evaluation of somatic variants in cancer requires consensus interpretation of their potential clinical significance (diagnosis, prognosis, and treatment response) and oncogenicity. To aid precision medicine through public interpretations, a multifaceted collaborative effort is required to bring together a community, structured guidance, and a public platform. The over 200 multi-disciplinary experts in the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) provide a community that develops data curation guidelines and standards and curates evidence to determine the clinical significance and oncogenicity of somatic alterations in cancer. The Somatic CDWG established the Pediatric Cancer, Hematological Cancer, and Solid Tumor Taskforces to facilitate membership growth and targeted curation projects. Within these Taskforces, Somatic Cancer Variant Curation Expert Panels (SC-VCEPs) are developed through a 4-step approval process adapted from ClinGen germline VCEP procedures. Five SC-VCEPs (NTRK-fusions, FGFR variants, FLT3 variants, Histone H3 variants, and BCR::ABL1-like B-ALL alterations) are working through the approval process and one (Established Significance) is in the planning stage. SC-VCEPs tailor AMP/ASCO/CAP [PMID:27993330] and ClinGen/CGC/VICC Oncogenicity [PMID:35101336] guidelines, or create new classification guidance to aid granular assessment of their genomic alterations of interest. The Clinical Interpretations of Variants in Cancer (CIViC) knowledgebase provides the public platform for the Taskforces and SC-VCEPs to display their high-quality somatic cancer variant interpretations. These groups curate evidence from published literature and create Assertions summarizing evidence collected. These Assertions are further disseminated through other resources like ClinVar and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. CIViC supports the application of AMP/ASCO/CAP tiering and levels for clinical significance Assertions. CIViC recently created Oncogenic Assertions, which supports the application of ClinGen/CGC/VICC codes. Three SC-VCEPs (FGFR, FLT3, and Histone H3) are tailoring the ClinGen/CGC/VICC Oncogenicity guidelines to their specific genes and CIViC will enable their ClinGen-approved, modified codes to be applied directly to their Oncogenic Assertions. Also, two SC-VCEPs (NTRK and BCR::ABL1-like) are developing fusion specific oncogenicity classification guidelines, which will be applied to their fusion specific CIViC Oncogenic Assertions. ClinGen Somatic groups have generated 695 CIViC Evidence Items and 33 Assertions from over 400 published papers. These numbers will continue to grow along with the development of more SC-VCEPs. ClinGen Somatic and CIViC foster collaboration, innovation, and most importantly the advancement of precision medicine. Citation Format: Jason Saliba, Arpad Danos, Kilannin Krysiak, Adam Coffman, Susanna Kiwala, Joshua McMichael, Cameron J. Grisdale, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Charles G. Mullighan, Yassmine Akkari, Gordana Raca, Angshumoy Roy, Alex H. Wagner, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic Clinical Domain Working Group. ClinGen Somatic and CIViC collaborate to comprehensively evaluate somatic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6569.

During the SARS-CoV2 pandemic vaccines were made available at a rapid pace in the United States (US) with support from the government. In Mississippi, vaccine hesitancy was marked. Across the country many areas of the US demonstrated reduced uptake regarding this specific vaccine due to a variety of reasons. Even with the efficacy of the vaccine indicative of a significant level of protection from mortality and serious morbidity, vaccine uptake and hesitancy were a significant concern. This study surveyed Mississippians on their willingness to take the vaccine or not, and in particular, investigated political ideology as a reason for vaccine hesitancy. Data was collected via an online survey and 589 adults (>18 years) responded. Those self-identifying as “Republican” were more than twice as likely to disagree that not getting the vaccine was a risk to their health and others (OR = 2.07, 95% CI 1.70, 2.54) as those who identified as “Democrat or independent” voters. Future health promotion efforts should specifically attempt to address this group in a more effective manner.

AbstractThis study defined and compared the course of native, impaired and growth factor‐stimulated bone regeneration in a rat femoral defect model. A mid‐diaphyseal defect with rigid internal fixation was surgically created in the right femur of male Fischer rats and serially analyzed over 36 weeks. Native bone regeneration was modeled using a sub‐critical, 1 mm size defect, which healed uneventfully. Critical size defects of 5 mm were used to analyze impaired bone regeneration. In a third group, the 5 mm defects were filled with 11 µg of recombinant human bone morphogenetic protein 2 (rhBMP2) impregnated onto an absorbable collagen sponge, modeling its clinical use. Native bone regeneration was characterized by endochondral ossification with progressive remodeling to ultimately resemble intact femora. An endochondral response was also observed under conditions of impaired bone regeneration, but by week 8 medullary capping occurred with fibrofatty consolidation of the tissue within the defect, resembling an atrophic non‐union. rhBMP2 treatment was associated with prolonged inflammatory cytokine expression and rapid intramembranous bone formation occurring with reduced expression of cartilage‐associated collagens. Between weeks 4 and 36, rhBMP2‐treated bones demonstrated decreased trabecular number and increased trabecular separation, which resulted in inferior mechanical properties compared with bones that healed naturally. Clinical Significance: Recombinant human bone morphogenetic protein 2 (rhBMP2) is used clinically to promote healing of long bones. Our data suggest that it drives intramembraneous ossification producing an inferior regenerate that deteriorates with time. Clinical outcomes would be improved by technologies favoring endochondral regenerative ossification.

Abstract 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. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of 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. 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)]. In 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. (Main MS: 3201 words)

Importance Little is known about the burden and outcomes of respiratory syncytial virus (RSV)–positive acute respiratory infection (ARI) in community-dwelling older adults. Objective To assess the incidence of RSV-positive ARI before and during the COVID-19 pandemic, and to assess outcomes for RSV-positive ARI in older adults. Design, Setting, and Participants This was a community-based cohort study of adults residing in southeast Minnesota that followed up with 2325 adults aged 50 years or older for 2 RSV seasons (2019-2021) to assess the incidence of RSV-positive ARI. The study assessed outcomes at 2 to 4 weeks, 6 to 7 months, and 12 to 13 months after RSV-positive ARI. Exposure RSV-positive and -negative ARI. Main Outcomes and Measures RSV status was the main study outcome. Incidence and attack rates of RSV-positive ARI were calculated during each RSV season, including before (October 2019 to April 2020) and during (October 2020 to April 2021) COVID-19 pandemic, and further calculated during non-RSV season (May to September 2021) for assessing impact of COVID-19. The self-reported quality of life (QOL) by Short-Form Health Survey-36 (SF-36) and physical functional measures (eg, 6-minute walk and spirometry) at each time point was assessed. Results In this study of 2325 participants, the median (range) age of study participants was 67 (50-98) years, 1380 (59%) were female, and 2240 (96%) were non-Hispanic White individuals. The prepandemic incidence rate of RSV-positive ARI was 48.6 (95% CI, 36.9-62.9) per 1000 person-years with a 2.50% (95% CI, 1.90%-3.21%) attack rate. No RSV-positive ARI case was identified during the COVID-19 pandemic RSV season. Incidence of 10.2 (95% CI, 4.1-21.1) per 1000 person-years and attack rate of 0.42%; (95% CI, 0.17%-0.86%) were observed during the summer of 2021. Based on prepandemic RSV season results, participants with RSV-positive ARI (vs matched RSV-negative ARI) reported significantly lower QOL adjusted mean difference (limitations due to physical health, −16.7 [95% CI, −31.8 to −1.8]; fatigue, −8.4 [95% CI, −14.3 to −2.4]; and difficulty in social functioning, −11.9 [95% CI, −19.8 to −4.0] within 2 to 4 weeks after RSV-positive ARI [ie, short-term outcome]). Compared with participants with RSV-negative ARI, those with RSV-positive ARI also had lower QOL (fatigue: −4.0 [95% CI, −8.5 to −1.3]; difficulty in social functioning, −5.8 [95% CI, −10.3 to −1.3]; and limitation due to emotional problem, −7.0 [95% CI, −12.7 to −1.3] at 6 to 7 months after RSV-positive ARI [intermediate-term outcome]; fatigue, −4.4 [95% CI, −7.3 to −1.5]; difficulty in social functioning, −5.2 [95% CI, −8.7 to −1.7] and limitation due to emotional problem, −5.7 [95% CI, −10.7 to −0.6] at 12-13 months after RSV-positive ARI [ie, long-term outcomes]) independent of age, sex, race and/or ethnicity, socioeconomic status, and high-risk comorbidities. Conclusions and Relevance In this cohort study, the burden of RSV-positive ARI in older adults during the pre-COVID-19 period was substantial. After a reduction of RSV-positive ARI incidence from October 2020 to April 2021, RSV-positive ARI re-emerged during the summer of 2021. RSV-positive ARI was associated with significant long-term lower QOL beyond the short-term lower QOL in older adults.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Abstract Background Hepatitis B virus (HBV) vaccine seroprotection rates with conventional aluminum adjuvanted recombinant HBV vaccines (HepB-alum) among people with HIV (PWH) are varied. HepB-CpG, a novel adjuvanted recombinant HBV vaccine, has shown higher seroprotection rates in immunocompetent patients but is not well studied in PWH. There are no published studies comparing seroprotection rates between HepB-alum and HepB-CpG in PWH. The purpose of this study was to evaluate and compare the seroprotection incidence of HepB-CpG versus HepB-alum in adults at least 18 years of age with HIV. Methods This retrospective, observational, cohort study screened for inclusion adults diagnosed with HIV who received a 3-dose series of HepB-alum or a 2-dose series of HepB-CpG between January 1, 2015 through December 31, 2021 at a community health center in Phoenix, Arizona. Patients who had a confirmed diagnosis of HIV and a hepatitis B surface antibody < 10 IU/L at the time of the first vaccine dose were included until an adequate sample size was achieved. The primary outcome was to compare seroconversion incidence of HepB-CpG and HepB-alum in PWH. Secondary outcomes included identifying factors associated with an increased likelihood of response to HBV vaccination. Seroconversion incidence data was analyzed using Fisher’s exact test using BlueSky Statistics. Results A total of 121 patients were included in this study, 59 in the HepB-alum cohort and 61 in the HepB-CpG cohort. In the HepB-alum cohort, 57.6% (34/59) achieved seroconversion, compared to 93.4% (57/61) in the HepB-CpG group (p < 0.001). Univariate comparisons of comorbidities among the vaccine cohorts found no significant differences in sex, body mass index, diabetic status, kidney/liver disease, CD4 count, HIV viral load, or active/prior history of substance use. Conclusion Among PWH at a single community health center, HepB-CpG provided a statistically higher incidence of seroprotection against HBV compared to HepB-alum. The higher seroprotection rate for HepB-CpG versus HepB-alum patients is not due to differences in group demographics or reported comorbidities. Disclosures Carlos Hartmann, MD, Viiv Pharmaceuticals: Speaker.

Purpose of review To assess the present status of gene therapy for osteoarthritis (OA). Recent findings An expanding list of cDNAs show therapeutic activity when introduced into the joints of animals with experimental models of OA. In vivo delivery with adenovirus or adeno-associated virus is most commonly used for this purpose. The list of encoded products includes cytokines, cytokine antagonists, enzymes, enzyme inhibitors, growth factors and noncoding RNA. Elements of CRISPR-Cas have also been delivered to mouse knees to ablate key genes. Several human trials have been initiated, using transgenes encoding transforming growth factor-β 1 , interleukin-1 receptor antagonist, interferon-β, the NKX3.2 transcription factor or variant interleukin-10. The first of these, using ex vivo delivery with allogeneic chondrocytes, gained approval in Korea which was subsequently retracted. However, it is undergoing Phase III clinical trials in the United States. The other trials are in Phase I or II. No gene therapy for OA has current marketing approval in any jurisdiction. Summary Extensive preclinical data support the use of intra-articular gene therapy for treating OA. Translation is beginning to accelerate and six gene therapeutics are in clinical trials. Importantly, venture capital has begun to flow and at least seven companies are developing products. Significant progress in the future can be expected.