Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia

Background Glucocorticoid (GC)-exacerbated hyperglycemia is prevalent in hospitalized patients with diabetes mellitus (DM) but evidence-based insulin guidelines in inpatient settings are lacking. Methods and findings Retrospective cohort study with capillary blood glucose (CBG) readings and insulin use, dosed with 50% basal (glargine)-50% bolus (lispro) insulin, analyzed in hospitalized patients with insulin-treated DM given GC and matched controls without GC (n = 131 pairs). GC group (median daily prednisone-equivalent dose: 53.36 mg (IQR 30.00, 80.04)) had greatest CBG differences compared to controls at dinner (254±69 vs. 184±63 mg/dL, P<0.001) and bedtime (260±72 vs. 182±55 mg/dL, P<0.001). In GC group, dinner CBG was 30% higher than lunch (254±69 vs. 199±77 mg/dL, P<0.001) when similar lispro to controls given at lunch. Bedtime CBG not different from dinner when 20% more lispro given at dinner (0.12 units/kg (IQR 0.08, 0.17) vs. 0.10 units/kg (0.06, 0.14), P<0.01). Despite receiving more lispro, bedtime hypoglycemic events were lower in GC group (0.0% vs. 5.9%, P = 0.03). Conclusions Since equal bolus doses inadequately treat large dinner and bedtime GC-exacerbated glycemic excursions, initiating higher bolus insulin at lunch and dinner with additional enhanced GC-specific insulin supplemental scale may be needed as initial insulin doses in setting of high-dose GC.

Virus-Negative Necrotizing Coronary Vasculitis with Aneurysm Formation in Human SARS-CoV-2 Infection

We report a case of myopericarditis associated to SARS-CoV-2 infection with necrotizing coronary vasculitis of intramural vessels, giving rise to biventricular apical microaneurysms and to electrical instability. Negativity of myocardial polymerase chain reaction for the most common cardiotropic viruses and for SARS-CoV-2 suggested an immune-mediated myocardial and pericardial inflammatory disease. High dose (1 mg/Kg daily) prednisone and anti-viral (Remdesivir, IDA Business, Carrigtohill, County Cork, T45 DP77, Ireland) therapy led to resolution of cardiac inflammation and ventricular arrhythmias. Morpho-molecular characterization of endomyocardial tissue may improve the outcome in subjects with SARS-CoV-2-associated myopericarditis and coronary vasculitis.

Prostate cancer intensive, non-cross reactive therapy (PRINT) for CRPC: Interim analysis of efficacy endpoints.

e17027 Background: The standard mCRPC treatment paradigm, with sequential single agents administered until resistance, may be limited due to heterogenous tumors comprised of clones differentially sensitive to available therapies. An alternative approach involves rapid cycling of non-cross resistant therapies in an attempt to efficiently eradicate sensitive clones, mitigate resistance, and minimize toxicity. Methods: Patients with mCRPC received 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month study regimen, patients continued ADT alone. The primary endpoint is time to progression (TTP). A sample size of 33 patients will provide 90% power for a one-sided test at the 5% level to detect increase in TTP compared with historical control. Secondary endpoints include PSA response (>90%, >50%) with each module, and changes to alkaline phosphatase levels. Results: From 3/2017 to 11/2020, 40 mCRPC patients were enrolled. As of the data cut-off of 1/03/2021, 31 patients have completed the 9-month study regimen and are evaluable for TTP analysis. With a median follow up of 20.7 months, the median time to PSA progression is 3.8 months (95%CI; 2.1-6.3 mo). PSA declines >90% from baseline was achieved in 35.5% after module 1, 41.9% after module 2, 58.1% after module 3. Of the patients with bone metastasis and elevated alkaline phosphatase levels at baseline (9/31), 78% had normalization of alkaline phosphatase upon completion of study regimen. Five of 31 patients (16%) were able to be maintained on ADT alone for over a year during the post-study surveillance period: three patients were subsequently restarted on a mCRPC agent at time of disease progression (14.4 mo, 17.0 mo, 24.8 mo), two patients demonstrate sustained disease control and remain on ADT alone (16.3+ mo, 21.5+ mo). Shared baseline clinical features of the 5 patients with prolonged control include PSA of <10 ng/mL and normal alkaline phosphatase levels (< 126 IU/L); Gleason score and presence of bone and nodal metastases varied. Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross resistant regimen is feasible and a subset of patients achieve prolonged disease control on ADT alone after completion of study treatment. Rapid cycling of available CRPC therapies may eliminate castration-resistant clones in a subset of patients, a concept warranting further preclinical and clinical evaluation. Clinical trial information: NCT02903160. [Table: see text]

Entecavir-associated thrombocytopenia

Entecavir (ETV) is widely used in the treatment of hepatitis B, but there are only a few reports about entecavir-associated thrombocytopenia, and it is considered as an immediate response and inappropriate to continue the treatment with other nucleoside analogues. Now, we report the third case, and this case was delayed response and we switched to treatment with tenofovir (TDF). There was a 66-year-old female who was infected with hepatitis B virus (HBV). Her platelet count decreased from 111*109/L to 3*109/L and was prone to gum bleeding and skin ecchymosis after she received ETV treatment for 88 days. As a treatment option, ETV was replaced by TDF immediately, frequent platelets transfusions and thrombopoietin were applied for several days, daily prednisone of 50 mg was concomitantly taken, and then platelet count improved after 10 days. She was diagnosed with entecavir-associated thrombocytopenia after analysis of the temporal relationship and exclusion of other causes of thrombocytopenia by blood and bone marrow examinations. Our case suggested that the platelet count should be monitored regularly in patients during ETV treatment, and it may be a feasible option to choose TDF to maintain antiviral treatment when entecavir-associated thrombocytopenia occurs.

Statin Associated Autoimmune Myonecrosis: Case Report With Delayed Onset and Treatment Challenges

Purpose: A case of delayed statin associated autoimmune myopathy (SAAM) is presented along with review of clinical findings and treatment strategies. Summary: A 54 year old male presented with proximal extremity weakness, difficulty ambulating, and dysphagia. Symptoms began when restarting atorvastatin 40 mg daily for a recent NSTEMI, following 10 years of statin use, interrupted after diagnosis of NASH. Relevant labs included CK of 13,618 IU/L, ALT/ AST of 568/407 IU/L, while additional liver, renal, and toxicology tests were normal. Following treatment response to prednisone 40 mg daily for 3 days, outpatient testing for anti-HMGCR antibodies was ordered. Twelve days from discharge, the patient was readmitted for myalgia and dysphagia, CK = 6042 IU/L, ALT/AST = 360/112 IU/L, and positive anti-HMGCR antibodies. Newly diagnosed with SAAM, symptoms improved with methylprednisolone and intravenous immunoglobulin (IVIG), continuing outpatient as daily prednisone and monthly IVIG. Four days later, the patient relapsed with worsened weakness and dysphagia, CK = 5812 IU/L, and ALT/AST = 647/337 IU/L. After response to methylprednisolone and rituximab, the patient was discharged on a corticosteroid taper, biweekly rituximab, and monthly IVIG. Two weeks later, a final admission involved a syncopal episode and fall, with a CK = 1461 IU/L. Treatment included IVIG, rituximab, and corticosteroid taper, which lead to remission for greater than 6 months. Conclusion: Statin associated autoimmune myopathy occurred when restarting atorvastatin, following 10 years of statin use. Clinical findings and positive anti-HMGCR antibodies confirmed the diagnosis. Recurrent relapses required triple combination therapy including addition of rituximab to achieve remission.

CARD: Overall survival (OS) analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel versus abiraterone or enzalutamide.

5569 Background: The CARD trial (NCT02485691) compared cabazitaxel vs. an androgen receptor targeted agent (ART; abiraterone/enzalutamide) in mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), in any order. These post hoc analyses assessed OS from various time points and the impact of prognostic factors. Methods: Patients with mCRPC previously treated with docetaxel and progressing ≤ 12 months on prior abiraterone/enzalutamide were randomized 1:1 to cabazitaxel (25 mg/m2 IV Q3W + daily prednisone + prophylactic G-CSF) vs. abiraterone (1000 mg PO + daily prednisone) or enzalutamide (160 mg PO). OS was calculated from date of diagnosis of metastatic disease, date of mCRPC, and start of 1st, 2nd or 3rd life-extending therapy (LET). A stratified multivariate Cox regression analysis assessed the impact of 14 prognostic factors on OS using a stepwise model selection approach with a significance level of 0.10 for entry into the model and 0.05 for removal. Results: In the CARD study (N = 255), median OS was longer with cabazitaxel vs. abiraterone/enzalutamide (13.6 vs 11.0 months; HR 0.64, 95% CI 0.46–0.89; p = 0.008). OS was numerically improved for cabazitaxel vs. abiraterone/enzalutamide when assessed from the time of diagnosis of metastatic disease or mCRPC, or from start of 1st or 2nd LET (Table). In the multivariate analysis, low hemoglobin, high baseline neutrophil to lymphocyte ratio, and high PSA values at baseline were associated with worse OS. In presence of these factors, the OS benefit observed with cabazitaxel versus abiraterone/enzalutamide remained significant (HR 0.63, 95% CI 0.42–0.94, p = 0.022). Conclusions: Cabazitaxel numerically improved OS vs. abiraterone/enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), whatever the time point considered. The robustness of this OS benefit was confirmed by stratified multivariate analysis. Sanofi funded. Clinical trial information: NCT02485691 . [Table: see text]

PRINT: Prostate cancer intensive, non-cross reactive therapy for CRPC—Early observations of efficacy.

e17575 Background: Optimal sequencing of therapeutic agents in mCRPC remains debated, but the standard approach is to treat with one agent until resistance is met before switching. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat intrinsic heterogeneity, delay or prevent drug resistance, and minimize treatment toxicity. Methods: Patients received treatment with 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 50 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month regimen, patients are followed on ADT alone. Primary endpoint for the study is PSA or radiographic time to progression (TTP). Results: From 3/2017 to 1/2020, 38 of 40 planned men with mCRPC were enrolled, 28 patients have completed the 9-month study regimen and evaluable for TTP analysis. With median follow up of 54+ weeks, median time to PSA progression after therapy completion is 14.7+ weeks (95%CI; 5.5-23.9+ weeks). PSA response rates showed successive improvements with each sequential treatment module (Table). Eight patients (21.1%) continue on post-study surveillance with ADT alone, two of which have remained off any mCRPC agents for over a year (82+ weeks, 79+ weeks). In patients needing to restart therapy, experience with efficacy and tolerability of each agent while on the study, has helped inform subsequent mCRPC drug selection. The study regimen is well-tolerated, with few grade 3/4 AE’s: hyperglycemia (15.8%), diarrhea (5.3%), anemia (2.6%), fatigue (2.6%), neutropenia (2.6%), and thrombocytopenia (2.6%). Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen demonstrates significant antitumor benefits, with potential for long-term suppression of disease. Further longitudinal follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160 . [Table: see text]

PRINT: Prostate cancer intensive, non-cross reactive therapy for CRP—Early observations of efficacy.

89 Background: Optimal sequencing of therapeutic agents in mCRPC remains debated, but the standard approach is to treat with one agent until resistance is met before switching. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat intrinsic heterogeneity, delay/prevent drug resistance, and minimize toxicity. Methods: Enrolled patients all received 3 consecutive treatment modules, each 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month regimen, patients are followed on ADT alone. Primary endpoint for the study is PSA or radiographic time to progression (TTP). Results: From 3/2017 to 10/2019, 35 of 40 planned men with mCRPC were enrolled, 25 patients have completed the 9-month study regimen and evaluable for TTP analysis. With median follow up of 52 weeks, median time to PSA progression after therapy completion is 15.5 weeks (95%CI; 5-26.1+ weeks). PSA response rates show successive improvements with each sequential treatment module (Table). Six (24%) patients continue on post-study surveillance with ADT alone, two of which have remained off any mCRPC agents for over a year (64+ weeks, 54+ weeks). In patients needing to restart therapy, experience with efficacy and tolerability of each agent while on the study, has helped inform subsequent mCRPC drug selection. The study regimen is well-tolerated, with few grade 3/4 AE’s: hyperglycemia (14.3%), diarrhea (5.7%), anemia (2.9%), fatigue (2.9%), neutropenia (2.9%), and thrombocytopenia (2.9%). Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen demonstrates significant antitumor benefits, with potential for long-term suppression of disease. Further longitudinal follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160. [Table: see text]

A233 VEDOLIZUMAB FOR STEROID & INFLIXIMAB-REFRACTORY ICI-COLITIS

Background Immune checkpoint inhibitors (ICI), such as anti-PD1, improve survival in melanoma, renal carcinoma and prostate cancer. However, by disinhibiting the immune system, these treatments cause significant immune-related adverse events (irAE), including colitis. For ICI-colitis, guidelines suggest escalating from observation to steroids to infliximab, without strong evidence for additional options should these fail. Vedolizumab has been used in a small number of cases for steroid-refractory or dependent ICI-colitis; only 9 cases have been reported in patients who failed infliximab therapy with a response rate of 67%. Aims To discuss a case of ICI-colitis that failed multiple steroid courses and infliximab infusions, but achieved remission with vedolizumab. Methods A 65-year-old male with malignant melanoma was randomized to adjuvant nivolumab +/- ipilimumab and developed non-bloody diarrhea. Despite loperamide, diarrhea worsened to 4–5 bowel movements daily. Stool cultures and C. diff were negative and 85mg of daily prednisone was started, while the ICI was held for 8 weeks. After a 2nd steroid taper, diarrhea recurred and the patient received 2 infliximab infusions 18 days apart. Despite initial improvement, biopsies demonstrated colitis and he underwent a 3rd infusion with little response. Clinical and biopsy-confirmed remission was only achieved once 2 vedolizumab infusions were given. Results Colitis is the most common ICI irAE, ranging in severity from mild to perforation and death. The incidence of grade 3 and 4 colitis, which require ICI discontinuation, is 1.3% for anti-PD1 and 13.6% in combination therapy. The severity of irAE is positively correlated with malignancy response and stopping ICI risks recurrence. Those that fail irAE medical management may require surgery. Thus, there is an impetus to continue the ICI and provide effective medical management for irAE. ICI-colitis guidelines are based on the CTCAE diarrhea classification and suggest supportive management and ICI continuation for grade 1. For grade 2, the ICI is held and steroids are started; infliximab is added for grades 3 and 4. However, 33–66% of patients are steroid-refractory or dependent; and patients may be infliximab non-responders, or unable to tolerate systemic side effects. Vedolizumab, an anti-α4β7-integrin, acts locally to inhibit T cells in the bowel wall, reducing inflammation in IBD. Recent reports, including ours, suggest usefulness in steroid and infliximab-refractory ICI colitis after only 2–4 infusions. When the inflammatory burden is high, the response rate is &gt;80% and given its gut-specificity, side effects are minimal compared to infliximab. Although further evaluation is required, using vedolizumab as second-line therapy is reasonable. Conclusions Given vedolizumab’s safety and gut-specificity, it should readily be considered in the treatment of ICI irAE. Funding Agencies None