657 Interleukin-6 receptor blockade for management of immune checkpoint inhibitor related adverse events in patients with melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A694-A694
Author(s):  
Chantal Saberian ◽  
Faisal Fa’ak ◽  
Jean Tayar ◽  
Maryam Buni ◽  
Sang Kim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Activity ◽  
Median Time ◽  
Interleukin 6 ◽  
Immune Checkpoint ◽  
Activity Index ◽  
Critical Role ◽  
Cancer Center ◽  
Interleukin 6 Receptor ◽  
Md Anderson

BackgroundManagement of certain immune mediated adverse events (irAEs) can be challenging and may require prolonged/chronic immune suppression with corticosteroids or other immunosuppressant which could compromise and even reverse the efficacy of immune checkpoint inhibitors (ICI). While the exact immunobiology of irAEs is not fully understood there is enough evidence that IL-6 induced Th-17 that may play critical role in the pathogenesis. Herein, we describe our clinical experience using interleukin-6 receptor (IL-6R) blockade in management of irAEs in melanoma patients.MethodsWe searched MD Anderson databases to identify cancer patients who had received ICIs between January 2004 and March 2020. Of 11,391 ICI-treated patients, 21 patients with melanoma who received IL-6R blockade after ICI infusion were identified and their medical records were reviewed.ResultsMedian age was 61 years (41–82), 52% were females, 90% received anti-programmed cell death-1 antibodies. Fourteen patients (67%) had de novo onset irAEs (11 had arthritis, and 1 each with polymyalgia rheumatica, oral mucositis, and CNS vasculitis), and 7 patients (33%) had flare of their pre-existing autoimmune diseases (5 had had rheumatoid arthritis, and 1 each with myasthenia gravis and Crohn’s disease). Median time from ICI initiation to irAEs was 91 days (range, 1–496) and to initiation of IL-6R blockade was 6.6 months (range, 0.6–24.3). Median number of IL-6R blockade was 12 (range, 1–35), and 16 patients (76%) were concomitantly receiving corticosteroids of median dose of 10 mg (range, 5–20 mg). Of the 21 patients, irAEs improved in 14 (67%) (95% CI: 46%-87%). Of 13 evaluable patients with arthritis, 11 (85%) achieved remission or minimal disease activity as defined by the clinical disease activity index. Median time from initiation of IL-6R blockade till improvement of irAEs was 2.9 months (range, 1.5–36.9). Nineteen patients tolerated well IL-6R blockade, while two patients stopped treatment due to abdominal pain and sinus tachycardia. The median CRP levels at irAEs was 84 mg/L (0.6–187) and decreased to 1.9 mg/L (0.56–12) at 10 weeks after initiation of IL-6R blockade (P=0.02). Of the 17 evaluable patients, the overall tumor response rate by RECIST-1.1 criteria was similar before and after IL-6R blockade initiation (41% vs. 53%).ConclusionsOur data demonstrated that IL-6R blockade could be an effective therapy for irAEs management without dampening the efficacy of ICIs. Prospective clinical trials with longitudinal blood, tumor, and inflamed tissue biopsies are planned to accurately validate these findings and better study the immunobiology of irAEs.Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition’s Ethics Board, approval number PA19-0089

Expansion of pharmacist clinical services to optimize the management of immune checkpoint inhibitor toxicities

2019 ◽  
Vol 25 (4) ◽  
pp. 954-960 ◽  
Author(s):  
Catherine E Renna ◽  
Elizabeth N Dow ◽  
Jason J Bergsbaken ◽  
Ticiana A Leal
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Management Program ◽  
Cancer Center ◽  
Caregiver Education

Introduction The development of immune checkpoint inhibitors has revolutionized cancer treatment and is now a part of the treatment paradigm for several malignancies. Although immune checkpoint inhibitors are generally well tolerated, treatment is associated with immune-related adverse events, some serious and potentially life threatening. Early identification and prompt appropriate management of immune-related adverse events are crucial to prevent morbidity and mortality. The complexity and severity of immune-related adverse events require interdisciplinary collaboration to optimize care. Patient and caregiver education and continued communication between patients and members of the oncology care team are vital for timely recognition and successful management of immune-related adverse events. The objective of this program is to provide a proof of concept; a pharmacist-led immune checkpoint inhibitor management program will increase early recognition and management of immune-related adverse events through patient and caregiver education and proactively assessing patients for toxicities. Methods At the University of Wisconsin Carbone Cancer Center, we developed and implemented a pharmacist-driven program, referred to as the immune checkpoint inhibitor program, which aimed to ensure patient and caregiver education and continuous monitoring of immune-related adverse events. This program utilized pharmacist–patient encounters to improve patient and caregiver education and follow-up monitoring. The design and implementation are detailed. Pharmacist interventions and patient outcomes were evaluated. Results At interim analysis, 47 patients were enrolled in the program and pharmacists completed 34 interventions on 26 patients. Pharmacists are well positioned to educate patients and caregivers on immune checkpoint inhibitor therapy and provide proactive monitoring to detect immune-related adverse events. We hypothesize that the interventions made by pharmacist may lead to earlier recognition and treatment of immune-related adverse events.

scholarly journals Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000144 ◽  
Author(s):  
Sarah Abou Alaiwi ◽  
Wanling Xie ◽  
Amin H Nassar ◽  
Shaan Dudani ◽  
Dylan Martini ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Median Time ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety And Efficacy ◽  
Clinically Significant

BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.

Oligometastasiertes nicht kleinzelliges Lungenkarzinom: Vorteile einer lokalen Konsolidierungstherapie nutzen

2019 ◽  
Vol 7 (6) ◽  
pp. 312-313
Author(s):  
Wolfgang Schütte ◽  
Miriam Möller
Keyword(s):  
Adverse Events ◽  
Maintenance Therapy ◽  
Systemic Therapy ◽  
Maintenance Treatment ◽  
Therapy Group ◽  
Progression Free Survival ◽  
Cancer Center ◽  
First Line ◽  
Free Survival ◽  
Md Anderson

Background: Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival. Methods: In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation. First-line therapy was four or more cycles of platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK rearrangements, respectively. Patients were randomly assigned (1:1) to either local consolidative therapy ([chemo]radiotherapy or resection of all lesions) with or without subsequent maintenance treatment or to maintenance treatment alone, which could be observation only. Maintenance treatment was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic treatment. Randomisation was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, CNS metastases, intrathoracic nodal status, and EGFR and ALK status. The primary endpoint was progression-free survival analysed in all patients who were treated and had at least one post-baseline imaging assessment. The study is ongoing but not recruiting participants. This study is registered with ClinicalTrials.gov, number NCT01725165. Findings: Between Nov 28, 2012, and Jan 19, 2016, 74 patients were enrolled either during or at the completion of first-line systemic therapy. The study was terminated early after randomisation of 49 patients (25 in the local consolidative therapy group and 24 in the maintenance treatment group) as part of the annual analyses done by the Data Safety Monitoring Committee of all randomised trials at MD Anderson Cancer Center, and before a planned interim analysis of 44 events. At a median follow-up time for all randomised patients of 12·39 months (IQR 5·52-20·30), the median progression-free survival in the local consolidative therapy group was 11·9 months (90% CI 5·7-20·9) versus 3·9 months (2·3-6·6) in the maintenance treatment group (hazard ratio 0·35 [90% CI 0·18-0·66], log-rank p=0·0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Grade 3 adverse events in the maintenance therapy group were fatigue (n=1) and anaemia (n=1) and in the local consolidative therapy group were oesophagitis (n=2), anaemia (n=1), pneumothorax (n=1), and abdominal pain (n=1, unlikely related). Interpretation: Local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone. These findings suggest that aggressive local therapy should be further explored in phase 3 trials as a standard treatment option in this clinical scenario. Funding: MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core), National Cancer Institute, National Institutes of Health.

Treatment of patients with metastatic renal cell carcinoma (RCC) and end-stage renal disease (ESRD) with targeted therapy (TT): A case series.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 453-453 ◽  
Author(s):  
Amber Flaherty ◽  
Marc Ryan Matrana ◽  
Bradley J. Atkinson ◽  
Nizar M. Tannir
Keyword(s):  
Adverse Events ◽  
Clear Cell ◽  
Case Series ◽  
Median Number ◽  
Cancer Center ◽  
Limited Data ◽  
Inclusion Criteria ◽  
Md Anderson ◽  
Stage Renal Disease ◽  
End Stage

453 Background: Studies have shown that RCC is more prevalent in patients with ESRD, and RCC outcomes in patients with ESRD differ from those of the general RCC population. There is limited data regarding the use of TT in patients with metastatic RCC (mRCC) who are maintained on dialysis for ESRD. Methods: We retrospectively reviewed records of patients with mRCC who were seen at UT MD Anderson Cancer Center and received TT (sunitinib, sorafenib, pazopanib, temsirolimus, everolimus, erlotinib, or bevacizumab) over the last eight years (2003-2011) and who also had ESRD and underwent hemodialysis (HD) or peritoneal dialysis (PD). Overall survival (OS) was determined from initiation of TT to death. Results: Eleven patients (6 males; 8 with clear cell, 3 with papillary) were identified who met the above inclusion criteria. Median age was 57.4 years. Comorbidities included hypertension in 10, diabetes in 4, and hyperlipidemia in 6. Median number of TT was 4 (range, 1-6). Median time on treatment (TOT) was 769 days (range, 73-1792), Seven patients have died. Seven patients were on both HD and TT for over 1 year. Median OS was 1075 days (95% CI, 722-1428). TT related adverse events (AEs) included hypertension (HTN), hand-foot skin reaction (HFS), fatigue, diarrhea, rash and pneumonitis [Table]. There were no treatment related deaths. Conclusions: In this small retrospective series of patients with mRCC and ESRD who were treated with TT, adverse events were acceptable, and relatively prolonged disease courses were noted. [Table: see text]

scholarly journals Tocilizumab Was Effective in Repairing the Large Geode in a Patient with Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Takuya Izumiyama ◽  
Yu Mori ◽  
Eiji Itoi
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Treatment Effect ◽  
Interleukin 6 ◽  
Present Report ◽  
Joint Destruction ◽  
Chronic Arthritis ◽  
Biologic Agents ◽  
Lateral Epicondyle ◽  
Interleukin 6 Receptor

Rheumatoid arthritis is characterized by multiple chronic arthritis subsequently inducing joint destruction. Although subchondral geode is a well-known feature of high-disease activity, a large geode is rare. Moreover, the treatment effect of biologic agents in the repair of large geode has not been reported. The present report shows the significant effect of interleukin-6 receptor blocker, tocilizumab, in repairing the large geode in the left humeral lateral epicondyle. This case implies that tocilizumab might be an effective treatment in patients with rheumatoid arthritis even with large geode.

scholarly journals Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis

2019 ◽  
Vol 20 (18) ◽  
pp. 4633 ◽  
Author(s):  
Elinoar Hoffman ◽  
Michal A. Rahat ◽  
Joy Feld ◽  
Muna Elias ◽  
Itzhak Rosner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Lipid Profile ◽  
Interleukin 6 ◽  
Density Lipoprotein ◽  
High Sensitivity ◽  
Mechanistic Explanation ◽  
Receptor Antibody ◽  
Increased Risk ◽  
Interleukin 6 Receptor

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon.

scholarly journals Three Cases of Previous Smokers with Rheumatoid Arthritis Who Did Not Respond to Tumor Necrosis Factor Inhibitors Were Treated Successfully with an Anti-Interleukin-6 Receptor Antibody

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Yasuo Iwata
Keyword(s):  
Disease Activity ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
High Disease Activity ◽  
Knee Joints ◽  
Receptor Antibody ◽  
Interleukin 6 Receptor ◽  
Smoking Index ◽  
Necrosis Factor ◽  
Over Time

We report three cases of previous smokers who did not respond to TNF inhibitors but who responded successfully to an anti-interleukin-6 receptor antibody (tocilizumab (TCZ)). Case 1 is a 63-year-old woman whose smoking index was 200 and had been complaining of polyarthralgia since 1996. She started treatment with etanercept due to high disease activity, but her DAS28-CRP was 4.2. She was therefore switched to TCZ, which dramatically improved her symptoms; her DAS28-CRP had decreased to 2.1. Case 2 is a 64-year-old man whose smoking index was 1600 and had been complaining of polyarthralgia since 2006. Because his DAS28-CRP score increased over time to 5.9, etanercept and adalimumab were added sequentially, but he showed no response over the course of two years. The patient was therefore switched to TCZ, which dramatically improved his symptoms: his DAS28-CRP decreased to 2.7. Case 3 is a 48-year-old woman whose smoking index was 560 and had been complaining of pain in both knee joints since 2001. She was treated with adalimumab due to high disease activity but showed no response over the course of 1.5 years. The patient was therefore switched to TCZ, and her DAS28-CRP decreased to 1.8. An IL-6 blockade might be suitable for treating these 3 cases of previous smokers.

Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21712-e21712 ◽  
Author(s):  
Chipman Robert Geoffrey Stroud ◽  
Cynthia R. Cherry ◽  
Abdul Rafeh Naqash ◽  
Nitika Sharma ◽  
Sulochana Devi Cherukuri ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Improvement ◽  
Median Time ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Immune Checkpoint Blockade ◽  
Inpatient Setting ◽  
Immune Mediated ◽  
Steroid Refractory

e21712 Background: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events (irAEs) is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid-refractory irAEs. Methods:The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over 1 hour. C-reactive protein was drawn at first nivolumab infusion and at q 2 weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital d/c within 7 days. Results:Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All pts were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, cytokine release syndrome/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). Median CRP at initial tocilizumab dose was 100.5 mg/L (2.0 -350.4). Clinical improvement was noted in 27/34 pts (79.4%). 52.9% of pts required a single dose, while 35.3% required two, 8.8% required three and 1 pt required 4 doses. Twenty seven doses were given in the inpatient setting (49.1%). Median time to discharge was 4 days (range 1-27). Seventy four percent of pts were discharged home. For the 55 doses of tocilizumab that were delivered there was a cost savings of $147,174.94 (WAC) during the 18 month period versus infliximab 5 mg/kg IV dose. Conclusions: Tocilizumab is a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.

Correlation of pathogenic POLE mutations with clinical benefit to immune checkpoint inhibitor therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
Benjamin Garmezy ◽  
Jinesh S. Gheeya ◽  
Kyaw Zin Thein ◽  
Patrick Glen Pilie ◽  
Wanlin Wang ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cancer Center ◽  
Chi Square ◽  
Dna Polymerase Epsilon ◽  
Number Variation ◽  
Md Anderson ◽  
Chi Square Analysis

3008 Background: Mutations in DNA polymerase epsilon ( POLE) may induce DNA replication errors, increasing neoantigen load and potentially enhancing clinical benefit to immune checkpoint inhibitors (ICI). We present a clinicopathologic analysis of patients (pts) with advanced cancers harboring POLE mutations and their response to ICI therapy at MD Anderson Cancer Center. Methods: We used targeted exome sequencing via CLIA-certified next generation sequencing assays to identify pts with POLE-aberrant tumors and their co-occurring mutations. The pathogenicity of each POLE mutation was annotated utilizing InterVar and ClinVar databases. Chi-square analysis was performed. Results: Tumors from 12,947 pts were analyzed and 448 (3.5%) pts had a mutation or copy number variation in POLE (3.5%), comparable to the TCGA PanCancer Atlas (4.0%). Clinical data were available for 293 pts; the most common cancers were colorectal (14.7%), non-small cell lung (13.7%), cholangiocarcinoma (13.3%) and melanoma (10.2%). There were 267 unique co-mutations, including KRAS (23.0%), ARID1A (21.5%), BRCA2 (18.7%), ATM (18.4%), CDKN2A (17.5%), BRAF (15.3%), EGFR (15.3%), ATRX (12.6%), CREBBP (11.7%), APC (11.3%), ATR (11.0%), BRCA1 (11.0%) and CDK12 (10.4%). POLE variants were annotated in all pts: pathogenic/likely pathogenic (n = 34, 11.6%), benign/likely benign (61, 20.8%), and variant of unknown significance (198, 67.6%). 104 (35.8%) of 293 pts with POLE mutations received PD-1/L1 inhibitors as monotherapy or in combination. 93 (88.4%) of 104 pts were evaluable for response: Radiological CR 4.3% (n = 4), PR 26.9% (n = 25), SD 22.6% (n = 21), PD 46.2% (n = 43), for a clinical benefit rate (CR + PR + SD) of 53.8%. Pathogenic status of POLE mutation was associated with clinical benefit to PD-1/L1 inhibitors (p = 0.04). TMB (p = 0.44), PD-L1 (p = 0.11), and MSI (p = 0.66) status were not associated with pathogenic status. MSI-H status was not over-represented in pts with ICI clinical benefit (p = 0.36). Conclusions: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutations as a predictive biomarker. Multiple co-occurring DNA damage response mutations were found, which may contribute to ICI clinical benefit.

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