ABCB1/P-glycoprotein (Pgp) expression as stratification factor for treatment of patients with non-metastaticextremity high-grade osteosarcoma: A merged analysis of an Italian (ISG) and a Spanish (GEIS) sarcoma groups' multicentric prospective trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11527-11527
Author(s):  
Emanuela Palmerini ◽  
Catalina Marquez ◽  
Cristina Meazza ◽  
Angela Tamburini ◽  
Gianni Bisogno ◽  
...  
Keyword(s):  
Poor Response ◽  
High Dose ◽  
High Grade ◽  
Histologic Response ◽  
P Glycoprotein ◽  
Metastatic Osteosarcoma ◽  
Diagnostic Biopsy ◽  
Prospective Trials ◽  
High Grade Osteosarcoma

11527 Background: Overexpression of ABCB1/P-glycoprotein (Pgp) predicts poor outcome in retrospective osteosarcoma series.Two prospective trials with Pgp expression and post-induction histologic response as stratification factors were activated in Italy (ISG/OS-2) and Spain (GEIS-33). Methods: Patients ≤ 40 years with extremity non-metastatic high-grade osteosarcoma were eligible. Analysisi of Pgp expression from diagnostic biopsy was centralized. Preoperatively, all patients received methotrexate, adriamycin, cisplatinum (MAP). Surgery was performed at week 8. All patients received a dose of adriamycin following surgery. In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months then weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor histologic response (necrosis < 90%) to MAP. Patients without overexpression of Pgp (Pgp-) received MAP postoperatively, regardless the pathological response. From March 2013, an amendment increased high dose methotrexate cumulative dose from 60 g/m2 (5 cycles) to 120 mg/m2 (10 cycles). The post-amendment regimen was adopted in the observational prospective study by GEIS. Here we present the merged analysis of ISG/OS-2 patients treated post-amendment and GEIS-33. Results: From March 2013 to April 2018, 274 patients were included. Median age was 14 years (range 4-38), male/female: 163/111; 90 were Pgp-, 164 were Pgp+, 20 not evaluable. With a median follow-up of 48 months (1.3-78.5 months), the 3-year EFS and OS were 71.9% (95%CI 66-76.9) and 88% (95%CI: 83.2-91.5) respectively, with no inferior survival for Pgp positive patients and improved survival for good responders (Table). Conclusions: In this prospective uncontrolled study with a risk-adapted strategy for non-metastatic osteosarcoma, survival is superior to that of all ISG/GEIS previous series. The 3-year EFS of 71.9% compares favorably with other reports. Pgp+ patients performed well in this study, in which mifamurtide and HDIFO were added after a poor response to MAP. Clinical trial information: NCT01459484; NCT04383288. [Table: see text]

Value of P-Glycoprotein and Clinicopathologic Factors as the Basis for New Treatment Strategies in High-Grade Osteosarcoma of the Extremities

2003 ◽  
Vol 21 (3) ◽  
pp. 536-542 ◽  
Author(s):  
Massimo Serra ◽  
Katia Scotlandi ◽  
Gemma Reverter-Branchat ◽  
Stefano Ferrari ◽  
Maria C. Manara ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Tumor Volume ◽  
Proportional Hazards ◽  
Treatment Strategies ◽  
High Dose ◽  
Postoperative Phase ◽  
High Grade ◽  
Treatment Protocols ◽  
P Glycoprotein ◽  
High Grade Osteosarcoma

Purpose: To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute. Patients and Methods: With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase. Results: P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols. Conclusion: Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.

scholarly journals High-Grade Osteosarcoma of the Foot: Presentation, Treatment, Prognostic Factors, and Outcome of 23 Cooperative Osteosarcoma Study Group COSS Patients

Sarcoma ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Anne J. Schuster ◽  
Leo Kager ◽  
Peter Reichardt ◽  
Daniel Baumhoer ◽  
Monika Csóka ◽  
...  
Keyword(s):  
Poor Response ◽  
Study Group ◽  
High Grade ◽  
Rare Presentation ◽  
Primary Tumors ◽  
Free Survival ◽  
Primary Surgery ◽  
Tumor Entity ◽  
High Grade Osteosarcoma

Osteosarcoma of the foot is a very rare presentation of a rare tumor entity. In a retrospective analysis, we investigated tumor- and treatment-related variables and outcome of patients registered in the Cooperative Osteosarcoma Study Group (COSS) database between January 1980 and April 2016 who suffered from primary high-grade osteosarcoma of the foot. Among the 23 eligible patients, median age was 32 years (range: 6–58 years), 10 were female, and 13 were male. The tarsus was the most commonly affected site (n=16). Three patients had primary metastases. All patients were operated: 5 underwent primary surgery and 18 received surgery following preoperative chemotherapy. In 21 of the 23 patients, complete surgical remission was achieved. In 4 of 17 patients, a poor response to neoadjuvant chemotherapy was observed in the resected primary tumors. Median follow-up was 4.2 years (range: 0.4–18.5). At the last follow-up, 15 of the 23 patients were alive and 8 had died. Five-year overall and event-free survival estimates were 64% (standard error (SE) 12%) and 54% (SE 13%), which is similar to that observed for osteosarcoma in general. Event-free and overall survival correlated with primary metastatic status and completeness of surgery. Our findings show that high-grade osteosarcoma in the foot has a similar outcome as osteosarcoma of other sites.

Apatinib for patients with unresectable high-grade osteosarcoma progressing after standard chemotherapy: A multi-center retrospective study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11031-11031 ◽  
Author(s):  
Wenxi Yu ◽  
Xiuchun Yu ◽  
Sujia Wu ◽  
Lina Tang ◽  
Shui'er Zheng ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Kinase Inhibitor ◽  
Multidisciplinary Treatment ◽  
Objective Response ◽  
Progression Free Survival ◽  
High Dose ◽  
High Grade ◽  
Second Line ◽  
Metastatic Osteosarcoma ◽  
High Grade Osteosarcoma

11031 Background: Prognosis for patients with relapsed/metastatic osteosarcoma is dismal and the optimal treatment strategy remains to be refined. Sorafenib and sorafenib plus everolimus are the only two second-line targeted therapies recommend by FDA. The median progression-free survival (PFS) was 4–5 months. In this study, the efficacy and safety of apatinib, another oral tyrosine kinase inhibitor targeting VEGFR-2, were evaluated in patients (pts) with inoperable high-grade osteosarcoma progressing after standard multidisciplinary treatment. Methods: This retrospective study reviewed the medical records of 26 pts with metastatic osteosarcoma who received apatinib at a dose of 500 mg qd or 250 mg bid after failure of standard treatment including doxorubicin, cisplatin, ifosfamide and high-dose methotrexate from Jul 2015 to Nov 2016. Results: Among all pts, 25 (96.2%) had pulmonary metastases and 4 (15.4%) had metastases in the bone (Table). Eleven pts achieved partial response, 10 stable disease and 5 progressive disease, yielding an objective response rate of 42.3% and a clinical benefit rate of 80.8%. Followed up to Dec 31 2016, the median PFS was 8 months (95%CI, 3.2–12.8 months), and the median overall survival (OS) was not reached. The 12-month PFS and OS rates were 22.5% (95%CI, 1.6%–58.1%) and 68.7% (95%CI, 37.5%–86.5%), respectively. Noteworthy, the 12-month PFS rate for patients treated with apatinib in the second-line setting was 51.3% (95%CI, 9.1%–83.1%). The most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (HFSR) (84.6%), hypertension (46.2%), and diarrhea (23.1%). Severe AEs included grade 3 HFSR (7.7%) and hypertension (3.8%). No unexpected AE was found. Conclusions: Apatinib was well tolerated and demonstrated activity as a second- or later-line treatment in patients with metastatic osteosarcoma, which deserves further investigations. [Table: see text]

MAP plus maintenance pegylated interferon α-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 “good response” randomization.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA10504-LBA10504 ◽  
Author(s):  
Stefan S. Bielack ◽  
Sigbjorn Smeland ◽  
Jeremy Whelan ◽  
Neyssa Marina ◽  
Jane Hook ◽  
...  
Keyword(s):  
Cox Model ◽  
Controlled Trial ◽  
Final Analysis ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
High Grade ◽  
Treatment Optimization ◽  
Histologic Response ◽  
High Grade Osteosarcoma

LBA10504 Background: EURAMOS-1 (NCT00134030) is an international randomized controlled trial investigating treatment optimization in osteosarcoma on the basis of histologic response to preoperative chemotherapy (CT). In patients (pts) with “good response” (GR; <10% viable tumor at surgery) to induction CT, efficacy of maintenance therapy with pegylated interferon α-2b (Ifn) was investigated. Methods: Pts ≤40yrs with resectable localized or primary metastatic high-grade extremity or axial osteosarcoma were eligible for registration at diagnosis. Eligibility for randomization included: [a] receipt of two cycles pre-op methotrexate, doxorubicin, cisplatin (MAP); [b] complete macroscopic resection of primary tumor; and [c] no disease progression. GR pts were randomized (1:1) after surgery to four cycles MAP +/-Ifn. Ifn (0.5-1.0 μg/kg/wk) was given after CT until 2yr post registration. Primary endpoint: event free survival (EFS); secondary: overall survival, toxicity. The trial design sought improved 3yr EFS from 70% to 80% (80% power, 2-sided alpha 5%). The final analysis was planned after 147 EFS events. Results: 2,260 pts were registered (Apr 05 to Jun 11) from 17 countries (326 sites) making it the largest trial in this rare cancer. GR was reported in 1,034 pts and 715 consented to randomization (358 MAP, 357 MAPIfn) with baseline characteristics balanced by arm: median age 14yr, 59% male, 79% localized disease. 271/357 (76%) pts started Ifn; main reason for not starting was treatment refusal, 66/86. By Feb 13 234/271 had stopped Ifn. Median duration of Ifn if started was 455 days; grade 3+ toxicity during Ifn reported by 81pts (30%). Median follow-up is 3.1yr with 174 EFS events reported: 93 MAP, 81 MAPIfn. Hazard ratio for EFS from adjusted Cox model was 0.82 (95% CI 0.61-1.11; p=0.201) in favor of MAPIfn. Conclusions: With current follow-up, EFS for MAPIfn is not statistically superior to MAP alone in pts with high-grade osteosarcoma and good response to pre-op MAP. One-quarter of pts did not start Ifn, which may have influenced this finding. Further follow-up for events and survival continues. Clinical trial information: NCT00134030.

scholarly journals Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial

2015 ◽  
Vol 33 (20) ◽  
pp. 2279-2287 ◽  
Author(s):  
Stefan S. Bielack ◽  
Sigbjørn Smeland ◽  
Jeremy S. Whelan ◽  
Neyssa Marina ◽  
Gordana Jovic ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Pegylated Interferon ◽  
Interferon Alfa ◽  
High Grade ◽  
Random Assignment ◽  
Histologic Response ◽  
Randomized Controlled ◽  
Pegylated Interferon Alfa ◽  
High Grade Osteosarcoma

Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

KAI-1 Expression in Pediatric High-Grade Osteosarcoma

2006 ◽  
Vol 9 (3) ◽  
pp. 219-224 ◽  
Author(s):  
Patrick J. Leavey ◽  
Charles Timmons ◽  
William Frawley ◽  
Donald Lombardi ◽  
Raheela Ashfaq
Keyword(s):  
Prognostic Markers ◽  
Clinical Phenotype ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Surface Proteins ◽  
High Grade ◽  
Free Survival ◽  
Treatment Groups ◽  
High Grade Osteosarcoma

Recent evidence implicates cell surface proteins of the tetraspanin superfamily in the process of metastasis whereas the downregulation of KAI-1, a member of the tetraspanin family, is associated with an aggressive clinical phenotype in several types of human cancers. To determine if expression of KAI-1-1 is associated with any known prognostic marker or clinical outcome in high-grade osteosarcoma, we examined 91 nondecalcified archival samples from 47 patients for the expression of KAI-1. Archival, paraffin-embedded, and decalcified pathologic samples were examined by immunohistochemistry and results were correlated to clinical outcomes and known prognostic markers. There were 46 samples from diagnostic biopsies (1 diagnostic sample was not available), 32 tumor resection samples, and 13 metastasis samples. Thirty-three percent (n = 30) of the samples expressed KAI-1 (16 biopsies, 9 resections, and 5 metastasis). KAI-1 expression was not significantly related to known prognostic markers or to either tumor necrosis after neoadjuvant therapy or the incidence of metastasis at diagnosis. KAI-1 expression was not significantly different between paired diagnostic tumor samples and either resection or metastasis tumor samples. Twenty-five patients remain alive at a median follow-up of 95 months. The overall and progression-free survival percentages at 5 years were 62% and 47% for KAI-1-positive patients and 49% and 38% for KAI-1-negative patients, respectively. This difference was not statistically significant. We conclude that KAI-1 is expressed in a proportion of high-grade osteosarcoma but is not of clinical significance and cannot be used to stratify treatment groups for these patients.

scholarly journals Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

2018 ◽  
pp. 1-10 ◽  
Author(s):  
Jyoti Bajpai ◽  
Arun Chandrasekharan ◽  
Vijai Simha ◽  
Vikas Talreja ◽  
Ashay Karpe ◽  
...  
Keyword(s):  
International Standards ◽  
High Dose ◽  
The Novel ◽  
High Dose Methotrexate ◽  
Histologic Response ◽  
Term Survival ◽  
Dose Methotrexate ◽  
Metastatic Osteosarcoma ◽  
Treatment Naïve ◽  
Dose Dense

Purpose Metastatic osteosarcoma is largely treated with high-dose methotrexate (HDMTX)–based therapy, especially in the pediatric population. This mandates complex pharmacokinetic monitoring in a costly inpatient setting to mitigate unpredictable serious toxicities. Hence, a non-HDMTX–based regimen is worth exploring, especially in India and low- and middle-income countries. Materials and Methods All consecutive treatment-naïve patients with metastatic osteosarcoma were prospectively treated on the novel OGS-12 protocol consisting of sequential doublets of doxorubicin, cisplatin, and ifosfamide. Four cycles were administered as neoadjuvant therapy followed by planned curative intent surgery and metastasectomy when feasible, followed by four cycles of adjuvant chemotherapy. Baseline characteristics, histologic response, event-free survival (EFS), overall survival (OS), and toxicity data were prospectively collected. Results Three hundred seventeen patients were enrolled onto the OGS-12 protocol from 2011 to 2014, of whom 80 (25%) had metastatic disease; median age was 17 years. The majority of patients were nutritionally challenged with high-risk features. At presentation, 83% of patients (66 patients) had lung metastases. After neoadjuvant chemotherapy, 57% of patients were histologically good responders. Four-year EFS and OS rates were 24% and 27%, respectively, in the intent-to-treat population and 27% and 29%, respectively, in the per-protocol analysis. Significant grade 3 or 4 toxicities were febrile neutropenia (51%), thrombocytopenia (36%), and anemia (54%). Histologic response was an independent predictor for EFS and OS in patients who underwent surgery. Surgical intervention was found to be significant for survival in univariable analysis. Conclusion The novel, low-cost, non-HDMTX–based, dose-dense OGS-12 regimen has shown comparable outcomes to international standards in metastatic osteosarcomas and is worthy of wider clinical application. An aggressive multimodality approach may result in long-term survival in a select group of patients and, hence, is worth considering.

scholarly journals Treatment Outcomes for Adult Patients with Localized Osteosarcoma Treated with Chemotherapy without Methotrexate

2020 ◽  
Author(s):  
MRM Silva ◽  
RC Bonadio ◽  
GDR Matos ◽  
D Toloi ◽  
M Nardo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Strategies ◽  
Additional Treatment ◽  
Adult Patients ◽  
Cancer Center ◽  
High Dose ◽  
High Grade ◽  
Grade 3 ◽  
High Grade Osteosarcoma ◽  
Cure Rates

AbstractBackgroundStandard treatment for pediatric patients with localized osteosarcoma include high-dose methotrexate (HDMTX) and cure rates greater than 60% are observed. In adult patients, however, the toxicity profile limits the use of HDMTX and it is usually excluded from chemotherapy protocols for this group. We aimed to evaluate the outcomes of adult patients with localized osteosarcoma treated with chemotherapy without methotrexate.MethodsIn this retrospective cohort, we evaluated adult patients with high-grade osteosarcoma who received treatment with chemotherapy without methotrexate in a reference cancer center from 2007 to 2018. Outcomes analyzed were recurrence-free survival (RFS), overall survival (OS), and prognostic factors associated with overall survival.ResultsA total of 48 patients had localized disease and received treatment with chemotherapy without methotrexate. The majority of them received chemotherapy with a combination of cisplatin and doxorubicin (N=42, 87.5%). Median age was 27 years. (range 16.8 – 66.7) With a median follow-up of 29.2 months, median RFS was 29.9 months. Median OS was not reached. 5-year RFS and OS rates were 35.1% (95% CI 20.3 – 50.2%) and 71.6% (95% CI 52.3 – 84.2%), respectively. Patients who received cumulative doses of doxorubicin ≥ 375 mg/m2 had better OS than those who received lower doses (HR 0.26, 95% CI 0.07 – 0.94, P = 0.041). Similarly, patients who received ≥ 6 cycles of neoadjuvant/ adjuvant cisplatin tended to have better OS than those who received < 6 cycles (HR 0.30, 95% CI 0.08 – 1.09, P = 0.069).Nineteen patients received less than 6 cycles of cisplatin and doxorubicin mainly because of grade 3 or 4 toxicities (11), disease progression (6),patient refusal(1), physician choice(1).ConclusionIn our study, adult patients with localized high-grade osteosarcoma who were treated with chemotherapy without methotrexate had unfavorable outcomes. The cumulative doxorubicin dose and the number of cisplatin/doxorubicin cycles were associated with improved OS. The investigation of additional treatment strategies is of utmost importance to improve adult patients outcomes.

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

1991 ◽  
Vol 9 (10) ◽  
pp. 1766-1775 ◽  
Author(s):  
G Saeter ◽  
T A Alvegård ◽  
I Elomaa ◽  
A E Stenwig ◽  
T Holmström ◽  
...  
Keyword(s):  
Preoperative Chemotherapy ◽  
Single Agent ◽  
High Dose ◽  
Preoperative Treatment ◽  
High Dose Methotrexate ◽  
Histologic Response ◽  
Dose Methotrexate ◽  
High Grade Osteosarcoma ◽  
The Individual ◽  
Grade Iii

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

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