Citations

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and < 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.

Expanding use of immune‐checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune‐related adverse events (irAE‐N). We evaluate the real‐world frequency, phenotypes, co‐occurring immune‐related adverse events (irAEs), and long‐term outcomes of severe, grade III to V irAE‐N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE‐N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE‐N reporting are outlined. ANN NEUROL 2020;87:659–669

Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.

AbstractBackground and ObjectivesStandard treatment for extremity sarcoma is limb‐sparing surgery often with radiation, but complications occur frequently. We sought to determine factors predictive of wound complications after thigh sarcoma resection and reconstruction while analyzing trends over time.MethodsWe reviewed all thigh defects requiring plastic surgeon reconstruction following sarcoma resection at our institution from 1997 to 2014. Patient demographics, comorbidities, operative characteristics, multi‐modality therapies, and complications were analyzed. Wound complications were: infection, dehiscence, seroma, hematoma, or partial/total flap loss.ResultsThere were 159 thigh reconstructions followed for 30 months on average. Eighty‐seven percent of patients underwent radiation and 42% had chemotherapy. Almost half (49.1%) had a complication. The most common wound complication was surgical site infection (23.3%) followed by dehiscence (19.5%), and seroma (10.7%). Less common were partial (2.5%) or total flap loss (0.6%). Reoperation was required in 21 patients (13.2%). Tobacco use, older patient age, cardiac disease, and higher body mass index were independently associated with wound complications. Complications trended towards decreasing over time, but this was not statistically significant.ConclusionsTobacco use, cardiac disease, and higher body mass index, but not the timing of reconstruction, appear to increase the risk of wound complications after thigh soft tissue sarcomas resection and plastic surgery reconstruction.

Abstract Objective The study sought to determine the dependence of the Electronic Medical Records and Genomics (eMERGE) rheumatoid arthritis (RA) algorithm on both RA and electronic health record (EHR) duration. Materials and Methods Using a population-based cohort from the Mayo Clinic Biobank, we identified 497 patients with at least 1 RA diagnosis code. RA case status was manually determined using validated criteria for RA. RA duration was defined as time from first RA code to the index date of biobank enrollment. To simulate EHR duration, various years of EHR lookback were applied, starting at the index date and going backward. Model performance was determined by sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC). Results The eMERGE algorithm performed well in this cohort, with overall sensitivity 53%, specificity 99%, positive predictive value 97%, negative predictive value 74%, and AUC 76%. Among patients with RA duration &lt;2 years, sensitivity and AUC were only 9% and 54%, respectively, but increased to 71% and 85% among patients with RA duration &gt;10 years. Longer EHR lookback also improved model performance up to a threshold of 10 years, in which sensitivity reached 52% and AUC 75%. However, optimal EHR lookback varied by RA duration; an EHR lookback of 3 years was best able to identify recently diagnosed RA cases. Conclusions eMERGE algorithm performance improves with longer RA duration as well as EHR duration up to 10 years, though shorter EHR lookback can improve identification of recently diagnosed RA cases.

Cirrhosis is a complex disease that is associated with disturbances in different organs besides the liver, including kidneys, heart, arterial circulation, lungs, gut, and brain. As a consequence, patients develop a number of complications that result in frequent hospital admissions and high morbidity and mortality. Patients with cirrhosis require constant and rigorous monitoring both in and outside the hospital. In this context, the role of nurses in the care of patients with cirrhosis has not been sufficiently emphasized and there is very limited information about nursing care of patients with cirrhosis compared with other chronic diseases. The current article provides a review of nursing care for the different complications of patients with cirrhosis. Nurses with specific knowledge on liver diseases should be incorporated into multidisciplinary teams managing patients with cirrhosis, both inpatient and outpatient. Conclusion: Nurses play an important role in the management and prevention of complications of the disease and improvement in patients’ quality of life and bridge the gap between clinicians and families, between primary care and hospital care, and provide medical education to patients and caregivers.

Abstract Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. Patients and Methods: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti–PD-1 response. Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). Conclusions: We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti–PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.

OBJECTIVE The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.