In vitro assay-assisted treatment selection for women with breast or ovarian cancer.

2002 ◽  
pp. 171-182 ◽  
Author(s):  
J P Fruehauf
Keyword(s):  
Drug Response ◽  
Selection Process ◽  
Stage Iv ◽  
Phase Iii ◽  
In Vitro Tests ◽  
Patient Response ◽  
Vitro Assay ◽  
Significant Prolongation ◽  
Stage Iv Disease

The selection of chemotherapy for women with breast or ovarian carcinoma has been traditionally based on results from phase III comparative trials that define the most active drugs and drug combinations. This approach has led to a significant prolongation of the lives of these patients. Unfortunately, few patients with advanced stage IV disease are cured using the currently available regimens. In order to improve the selection process for individual patients, various types of in vitro tests that assess the activity of standard drugs on a patient's tumor have been developed over the past five decades. As with bacterial culture and sensitivity tests, significant predictive correlations between in vitro drug-response assays and cancer patient response and survival have been demonstrated. Medicare currently covers in vitro drug-resistance assays. This review discusses the historical development of in vitro drug-response assays and the clinical validation of various technologies currently available to assist the clinician in selecting the optimal therapy for each patient.

scholarly journals Correlation of two in vitro tests with clinical response to immunosuppressive therapy in 54 patients with severe aplastic anemia

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 349-355 ◽  
Author(s):  
B Torok-Storb ◽  
K Doney ◽  
SL Brown ◽  
RL Prentice
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Antithymocyte Globulin ◽  
Mononuclear Cells ◽  
Response To Therapy ◽  
In Vitro Tests ◽  
Peripheral Blood Mononuclear ◽  
Patient Response ◽  
Blood Mononuclear Cells

Two in vitro tests were applied to 54 consecutive patients with severe aplastic anemia who were treated in Seattle with antithymocyte globulin. In the first test, peripheral blood mononuclear cells were collected from each patient before antithymocyte globulin therapy and then treated with a panel of monoclonal antibodies and complement. The treated peripheral blood mononuclear cells were assayed for erythroid burst-forming units (BFU-E). This test was designed to determine whether removing various subpopulations of peripheral blood mononuclear cells would increase the number of detectable BFU-E. In the second test, peripheral blood was collected within 48 hr after completion of antithymocyte globulin therapy, and cells were immediately assayed for BFU-E without any further treatment. Data from both tests were analyzed to determine whether the in vitro results correlated with patient response to therapy. Binary logistic regression analyses indicate that a modest correlation (p = 0.04) exists between test 1 in vitro results and patient response to therapy. However, the strength of this association appears to decrease as the interval between diagnosis and treatment increases. In contrast, test 2 had a very significant correlation (p = 0.001) with response to therapy among patients diagnosed more than 1 mo prior to treatment, whereas such an association was not apparent among patients treated within 1 mo of diagnosis.

EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma.

1993 ◽  
Vol 11 (8) ◽  
pp. 1573-1582 ◽  
Author(s):  
W H Wilson ◽  
G Bryant ◽  
S Bates ◽  
A Fojo ◽  
R E Wittes ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Prolonged Exposure ◽  
Oral Prednisone ◽  
Stage Iv ◽  
Dose Intensity ◽  
Primary Treatment ◽  
Treatment Regimens ◽  
Aggressive Lymphomas ◽  
Stage Iv Disease

PURPOSE Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. PATIENTS AND METHODS This is a phase II study of etoposide, vincristine, and doxorubicin, administered as a 96-hour continuous infusion, with intravenous (IV) bolus cyclophosphamide and oral prednisone (EPOCH) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule. Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. RESULTS Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. CONCLUSION EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.

High complete response (CR) rate in patients (pts) with esophageal carcinoma (EC) undergoing neoadjuvant combination of docetaxel and cisplatin (DC) ± cetuximab(DCE) chemoradiation therapy—a retrospective analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15093-15093
Author(s):  
T. J. Fillos ◽  
P. Hentschel ◽  
K. Watkins ◽  
M. S. Karpeh ◽  
A. Meek ◽  
...  
Keyword(s):  
Objective Response ◽  
Pathologic Complete Response ◽  
Stage Iv ◽  
Complete Response ◽  
Neoadjuvant Chemoradiation ◽  
High Rate ◽  
Phase Iii ◽  
Weekly Docetaxel ◽  
Stage Iv Disease ◽  
Grade 3

15093 Background: EC is a highly lethal disease with 5 year survival less than 15%. Surgery offers a chance for cure in early disease. Still, fewer than 20% of pts treated with surgery alone are alive at 5 years. Neoadjuvant chemoradiation offers the theoretical advantage of increasing R0 resections and reducing early local and distal metastases which may translate into improved survival. Several clinical trials have resulted in pathologic complete response (pCR) rates of 20–30%. Methods: Newly diagnosed pts with EC Stage 2A (T3) to 4 received weekly Docetaxel (D)25–30mg/m2 and Cisplatin (C)25–30mg/m2.for 6–8 weeks concurrently with radiation, 5040 cGy in 28 fractions. Cetuximab (E) 200mg/m2 was added after it became accepted treatment in head and neck cancers. Pts were scheduled 4 - 6 weeks later for surgery followed by the same chemotherapy for total of 16 weeks of treatment. Pts were assessed for time to progression, overall survival and toxicities. Results: Fifteen pts treated in 2005–6 underwent IRB approved evaluation; 11 male and 4 female, median age of 62(range 44–78) . Four had squamous cell (SCC) and 11 adenocarcinomas. Nine pts had Stage II, 4 pts stage III and 2 pts stage IV disease. Seven pts underwent surgery, all R0 resections. Four of them had pCR, one pPR (downstaged from T3 to T1) and two pts had stable disease. An additional 3 pts had radiological and endoscopic proven CR (medically not surgical candidates) for an objective response (CR+PR) in 8 out of 15 pts (3 SCC and 5 adenoca). Five out of 9 receiving DC had an objective response while 3 of 6 receiving DCE responded. Five pts progressed prior to surgery. Grade 3/4 neutropenia occurred in 2, nausea in 3, and 1 pt experienced Grade 3 dehydration. Four patients required dose reductions by 20%. Six patients had one cycle and 2 had 3 cycles delayed by one week each. Conclusions: Neoadjuvant chemoradiation treatment with weekly Docetaxel and Cisplatin ± Cetuximab is tolerable with high rate of CRs. There was no observed difference in response with the addition of cetuximab. A Phase III study is suggested. No significant financial relationships to disclose.

Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Asian subgroup analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7549-7549
Author(s):  
Yukito Ichinose ◽  
Kaoru Kubota ◽  
Giorgio Scagliotti ◽  
David R. Spigel ◽  
Joo-Hang Kim ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Objective Response ◽  
Stage Iv ◽  
Phase Iii ◽  
Stage Iv Disease ◽  
Phase Iii Study ◽  
Prior Systemic Therapy ◽  
Mortality Table ◽  
Nonsquamous Nsclc

7549 Background: MONET1 evaluated overall survival (OS) in patients (pts) with nonsquamous NSCLC receiving motesanib (an oral VEGFR 1, 2 and 3, PDGFR and Kit inhibitor) plus C/P compared with pts receiving placebo plus C/P. Analysis of the total population (N=1090) showed that motesanib + C/P did not significantly improve OS vs C/P alone (primary endpoint). Here we present results of a subgroup analysis of Asian pts. Methods: Asian pts (Japan, S. Korea, Philippines, Hong Kong, Taiwan, Singapore) with stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC were analysed. Pts were randomized to up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. Results: 227 Asian pts (incl. 106 Japanese pts) with nonsquamous NSCLC were randomized (Arm A/B, n=110/117); 198 had adenocarcinoma (n=97/101). Median age was 60 y (range 30–78); 80% had stage IV disease. At the time of analysis, 139 pts had died (118 pts with adenocarcinoma). Pts received a median of 164 days of motesanib vs 125 days of placebo (vs 106 and 126 days in non-Asian pts). Median follow-up was 63 wks. Efficacy results are shown in the table. Motesanib/placebo-related AEs were seen in 94/74% of pts respectively; Gr ≥3 related AEs in 48/22%. Most common emergent AEs were (Arm A/B) alopecia (78/76%), diarrhea (63/33%), and nausea (55/43%); gallbladder disorders (Gr 1–2) were seen in 9/2% of pts. Gr ≥3 AEs more frequent in Arm A vs B included neutropenia (36/22%) and hypertension (13/3%). Emergent Gr 5 events were seen in (Arm A/B) 5/4% vs 16/11% in non-Asian pts. Conclusions: In contrast to non-Asian pts, in the subgroup of Asian pts with advanced nonsquamous NSCLC, motesanib plus C/P treatment was associated with increased OS, PFS, and objective response rates (ORR) compared with C/P alone, with no excess of treatment-related mortality. [Table: see text]

Effect of MM-141 on gemcitabine and nab-paclitaxel potentiation in preclinical models of pancreatic cancer through induction of IGF-1R and ErbB3 degradation.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 289-289 ◽  
Author(s):  
Emily Pace ◽  
Sharlene Adams ◽  
Adam Camblin ◽  
Michael Curley ◽  
Victoria Rimkunas ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Cell Lines ◽  
Stage Iv ◽  
Akt Signaling ◽  
Preclinical Models ◽  
Patient Response ◽  
Receptor Complexes

289 Background: Gemcitabine, the first-line treatment for pancreatic cancer, has been improved by addition of nab-paclitaxel. However, patient response to this regimen is limited. Oncogenic insulin-like growth factor 1 (IGF-1) and heregulin (HRG) signaling are associated with increased cancer risk and decreased response to anti-metabolites and taxanes. Therefore, we explored MM-141, a novel bispecific antibody that blocks ErbB3 and IGF-1 receptor (IGF-1R) signaling, in combination with nab-paclitaxel and gemcitabine in preclinical models of pancreatic cancer. Methods: Combinations with MM-141, gemcitabine, and nab-paclitaxel were investigated in pancreatic cancer cell lines, in vitro and in vivo. The effects of MM-141, gemcitabine, and nab-paclitaxel on tumor growth and signaling were measured by 3D spheroid growth, ELISA, Western, and mouse xenograft experiments. Results: In vitro studies show that IGF-1 and HRG are potent activators of AKT signaling, leading to increased pancreatic tumor cell proliferation and decreased sensitivity to gemcitabine and nab-paclitaxel. MM-141 inhibits ligand-induced AKT activation, induces IGF-1R and ErbB3 degradation better than a mixture of IGF-1R and ErbB3 antibodies, and sensitizes cells to gemcitabine and nab-paclitaxel, in vitro. In vivo, MM-141 combines favorably with a nab-paclitaxel/gemcitabine regimen, leading to curative outcomes in a subset of treated mice. Conclusions: ErbB3 and IGF-1R co-inhibition is required to inhibit AKT signaling in pancreatic adenocarcinoma cell lines. These receptors are associated with chemoresistance to gemcitabine and nab-paclitaxel, which is abrogated by co-administration with MM-141. MM-141-induced degradation of oncogenic receptor complexes is likely essential to reverse chemoresistance and enhance effects of the nab-paclitaxel/gemcitabine regimen. These data, taken together with wide-spread expression of IGF-1R and ErbB3 in Stage IV pancreatic adenocarcinoma tissue, support clinical exploration of a MM-141/nab-paclitaxel/gemcitabine regimen in frontline metastatic pancreatic cancer. Preparations for a randomized Phase 2 study are underway.

Activity of an oral hyroxysterol.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20587-e20587
Author(s):  
Nabil Habib ◽  
Hamid Elia Daaboul ◽  
George Hage ◽  
Abdo Jabbour ◽  
Hind Zeitouni ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cancer Cell ◽  
Symptom Control ◽  
Stage Iv ◽  
Cell Types ◽  
Experimental Models ◽  
Stage Iv Disease ◽  
Key Enzyme ◽  
Breast And Prostate Cancer

e20587 Background: Hydroxysterols are oxygenated derivatives of cholesterol. They have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells. They control the transcription and the turnover of the key enzyme in cholesterol synthesis. Hydroxysterols interfere with PI3K/AKT, MAPK/ERK, hedgehog and Wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, hydroxysterols invariably both slow down proliferation and provoke cell death. Many of these compounds show antitumor activity in experimental models and most of them are very toxic. (24-ethyl-cholestane- 3β,5α,6α-triol) is the first oxysterol being tested in the clinic. It is also one of the safest in this class of compounds. Methods: We have treated with this new drug 18 patients suffering from Non-small cell lung cancer (NSCLC); sixteen males and two females. Thirteen had adenocarcinomas and five had squamous-cell carcinoma. The median age was 65. Sixteen patients had a stage IV disease and two had a stage III disease. Seven had a PS: 1, seven had a PS: 2 and four had a PS:3. Seventy-five percent were symptomatic and fifty percent were taking pain killers. Six patients only did not receive previous chemotherapy and five received radiotherapy. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided in 3 equal doses, until disease progression. Results: Twelve patients had a partial response (PR), three patients had a stable disease (NC) and three patients had a disease progression (PD). The median duration of response was 8 months but 2 patients are still under treatment. No toxicity was observed so ever. Seventy-five percent of symptomatic patients had a remarkable symptom control. Conclusions: These encouraging results make this new and safe drug a good candidate for further clinical trials either alone or in association with other drugs for the treatment of NSCLC.

The Evaluation of Pesticide Ingredients and Formulations In Vitro and Correlations with In Vivo Data

1995 ◽  
Vol 23 (5) ◽  
pp. 667-675
Author(s):  
Richard H. Clothier ◽  
Joanne Morris ◽  
William T. Lankford
Keyword(s):  
Exposure Period ◽  
Cellular Protein ◽  
In Vitro Assay ◽  
In Vitro Tests ◽  
Technical Grade ◽  
Vitro Assay ◽  
Pesticide Formulations ◽  
High Concentrations

Pesticides are often insoluble directly in aqueous solvents, but can be dissolved/suspended in surfactant-uased formulations. Both surfactants and pesticides can induce irritation. Since a single in vitro assay has proved inadequate for evaluating the toxicity of a chemical and its ability to cause an irritant response, a combination of assays was employed to examine the potential toxicities of two pesticide formulations. The surfactant-based vehicles had toxicities that reflected their surfactant concentration. The formulation containing 5% permethrin required a more concentrated vehicle than was needed to dissolve 0.1% cypermethrin. In vitro, the ID50 dose (i.e. the dose which inhibited the increase in total cellular protein by 50%) was 576μg/ml for the permethrin formulation and 1080μg/ml for the cypermethrin formulation. This corresponded closely to the ID50 values for the vehicles alone (464μg/ml and 1230μg/ml, respectively). When tested at high concentrations on confluent cells over a 1-minute exposure period to mimic potential exposure of the eye, the more concentrated vehicle, Lanosol 50 ME, was 4–6 times more toxic than Siege II. Technical grade permethrin and cypermethrin had low toxicities in each of the in vitro tests employed. Taken together, these results reflected the in vivo profiles available.

Prospective randomized phase III trial of triplet chemotherapy with paclitaxel + gemcitabine + cisplatin compared to standard doublet chemotherapy with vinorelbine + cisplatin in advanced non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8034-8034
Author(s):  
J. Sorensen ◽  
O. Hansen ◽  
A. Vilmar ◽  
H. Frank
Keyword(s):  
Median Survival ◽  
Performance Status ◽  
Stage Iv ◽  
Phase Iii ◽  
Survival Times ◽  
Median Response ◽  
Histologic Subtype ◽  
Type 1 Error ◽  
Stage Iv Disease ◽  
One Year

8034 Background: Paclitaxel + gemcitabine + cisplatin showed promising results in phase II with 59% response rate and 48 weeks median survival. Hence, it was compared to a standard doublet regimen to examine for superiority. Methods: Histologically verified inoperable NSCLC patients (pts) aged 18–75 years, performance status 0–2 and normal organ function were randomized to regimen A (paclitaxel 180 mg/m2 and cisplatin 100 mg/m2 day 1 with gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks) or regimen B (cisplatin 100 mg/m2 day 1 and weekly i.v. vinorelbine every 4 weeks) for maximum 6 cycles. Totally 428 pts were needed to detect a 30% median survival increase with 80% power and two-sided type 1-error of 5%. Results: 221 pts.received reg. A and 222 reg. B. Overall, median age was 62 years (range 38–75 yrs), 58% were males, 11% had performance status 2, 62% stage IV disease, 46% adenocarcinoma, and 28% squamous cell carcinoma (SCC), equally distributed between the regimens. Median no. of treatment courses were 4 in both regimens. Frequencies of CTC grade 4 leucocytopenia, thrombocytopenia, or grade 3+4 nausea, neurotoxicity, or nephrotoxicity were 15%, 17%, 19%, 8%, and 8% in reg. A, and 18%, 5% (p=0.001), 17%, 11%(p=0.014), and 7% in reg. B, respectively. Febrile leucopenia episodes were 14% and 10% in reg. A and B, while thrombocytopenic bleedings occurred in 12% and 4% of pts (p=0.008), respectively, with two toxic deaths due to bleeding in reg. A and none in reg. B. Response rates were 52% and 49% in reg. A and reg. B, median response durations were 263 and 217 days (not significant), median times to progressions (TTP) 6.7 and 5.8 months (p=0.453), and median survival times 11.4 and 10.8 months (p=0.415), respectively. In SCC subtype, TTP was higher in reg. A than reg. B (medians 7.0 mths vs. 4.1 mths, p=0.001) and survival was increased (medians 13.5 mths vs 9.7 mths, p=0.020). Conclusions: The triplet regimen A had significantly higher activity in SCC, both with respect to TTP and to survival with median survival in excess of one year and may be preferred in this histologic subtype. [Table: see text]

scholarly journals Correlation of two in vitro tests with clinical response to immunosuppressive therapy in 54 patients with severe aplastic anemia

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 349-355 ◽  
Author(s):  
B Torok-Storb ◽  
K Doney ◽  
SL Brown ◽  
RL Prentice
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Antithymocyte Globulin ◽  
Mononuclear Cells ◽  
Response To Therapy ◽  
In Vitro Tests ◽  
Peripheral Blood Mononuclear ◽  
Patient Response ◽  
Blood Mononuclear Cells

Abstract Two in vitro tests were applied to 54 consecutive patients with severe aplastic anemia who were treated in Seattle with antithymocyte globulin. In the first test, peripheral blood mononuclear cells were collected from each patient before antithymocyte globulin therapy and then treated with a panel of monoclonal antibodies and complement. The treated peripheral blood mononuclear cells were assayed for erythroid burst-forming units (BFU-E). This test was designed to determine whether removing various subpopulations of peripheral blood mononuclear cells would increase the number of detectable BFU-E. In the second test, peripheral blood was collected within 48 hr after completion of antithymocyte globulin therapy, and cells were immediately assayed for BFU-E without any further treatment. Data from both tests were analyzed to determine whether the in vitro results correlated with patient response to therapy. Binary logistic regression analyses indicate that a modest correlation (p = 0.04) exists between test 1 in vitro results and patient response to therapy. However, the strength of this association appears to decrease as the interval between diagnosis and treatment increases. In contrast, test 2 had a very significant correlation (p = 0.001) with response to therapy among patients diagnosed more than 1 mo prior to treatment, whereas such an association was not apparent among patients treated within 1 mo of diagnosis.

scholarly journals Evaluation of selected categories of pet treats using in vitro assay and texture analysis

2020 ◽  
Vol 4 (2) ◽  
pp. 1023-1030
Author(s):  
Fei He ◽  
Grace Holben ◽  
Maria R C de Godoy
Keyword(s):  
Selection Process ◽  
Meat Product ◽  
Meat Products ◽  
Principal Component ◽  
Enzymatic Digestion ◽  
Vitro Assay ◽  
Intestinal Phase ◽  
Pet Owners

Abstract Treats are important contributors to the economics of the U.S. pet product industry. Not only do pet owners use them to build an emotional bond or interact with their pets, but treats also can deliver functional or health benefits. The objective of this study was to evaluate the digestion and safety of selected commercial treats by measuring their in vitro dry matter disappearance (DMD) using the modified in vitro method of Boisen and Eggum, which was developed to simulate in vivo digestibility of nonruminant animals. Twenty-five commercial treats were classified into six categories based on their appearance, size, and functionality. These categories included biscuit, chew, dental, meat product, rawhide, and cat treat. Each commercial product was analyzed in triplicate and in vitro DMD was calculated after enzymatic digestion and incubation. A wide variation in DMD was observed among and within different treat categories in both gastric and gastric + small intestinal phases of digestion. For the gastric phase, DMD ranged from 8.40% to 92.20%, whereas intestinal phase digestion had a DMD range of 35.10–100% (P < 0.05). In general, treats from meat products, dental, chew, biscuit, and cat treat categories had a high DMD (>85%) after the intestinal phase, whereas DMD of rawhide treats varied from 35.10% to 95.70%. Principal component analysis, in addition, has visually shown that rawhide treats displayed the largest portion of variation from the other treats. A low DMD at gastric phase is a concern because it may pose a risk for gastrointestinal blockage and intolerance, particularly for treats of large size that remained intact during this phase. In vitro DMD results can be used as a potential predictor of in vivo digestibility, facilitate recommendations about pet treat safety for professionals and manufacturers in the pet industry, and assist pet owners in the treat selection process and with treat purchasing decisions.

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