Difference in Outcome of Adolescents with Acute Lymphoblastic Leukemia (ALL) Enrolled in Pediatric (AIEOP) and Adult (GIMEMA) Protocols.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1954-1954 ◽  
Author(s):  
Anna Maria Testi ◽  
Maria Grazia Valsecchi ◽  
Valentino Conter ◽  
Marco Vignetti ◽  
Francesca Paoloni ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Treatment Modalities ◽  
High Dose ◽  
Cranial Radiotherapy ◽  
Childhood All ◽  
High Risk Patients ◽  
Drug Induction ◽  
Risk Patients

Abstract Progress in the treatment of acute lymphoblastic leukaemia (ALL) has led to better survival rates; however, children have had a greater benefit from improved treatment modalities than adolescent who show an overall lower event-free survival (EFS) compared to younger patients. Some differences in the clinical and biologic characteristics of adolescents compared to childhood ALL may partly account for the different outcome, but adolescents treated on pediatric ALL trials seem to have a significantly better EFS than those treated on adult trials. We retrospectively compared the results obtained in a series of 245 patients ranging in age from 14 to 18 years diagnosed and enrolled in specific Italian children and adult ALL trials, between 4/1996 and 10/2003. One hundred and fifty patients, from 30 pediatric centers, underwent the childhood AIEOP ALL 95 and 2000 protocols; the other 95, from 28 adult centers, were enrolled in the GIMEMA ALL 0496 and 2000 protocols. The AIEOP 95 and 2000 trials are BFM-like protocols with a 7 drug induction followed by risk-modulated post-remission therapy that includes high-dose MTX and reinduction for low and intermediate groups, and intensive blocks (high-dose MTX and cytarabine) for high-risk patients. Standard maintenance therapy is administered up to a total of 2 years. Cranial radiotherapy is limited to high-risk patients. Stem cell transplantation is planned for very high-risk patients. The GIMEMA regimens are instead based on an induction with high-dose anthracyclines (cumulative dose 550 mg/m2), high-dose cytarabine as consolidation and do not include high-dose MTX and the reinduction phase. Standard maintenance with vincristine + daunorubicin/cyclophosphamide pulses is given for 2 years. Cranial radiotherapy is administered to all patients. The main patients characteristics at diagnosis, in the two groups under examination, were comparable except for age: median age was 15 and 16 years, respectively in the AIEOP and GIMEMA trials.Poor risk cytogenetic translocations and T-immunophenotype were equally dinstributed. Adolescents in the AIEOP protocols had a higher CR rate (94% vs 89%) and a lower relapse rate (17% vs 45%) compared to the adolescents enrolled in the GIMEMA trials. The 2-year overall survival rate was 80% in the AIEOP protocols and 71% in the GIMEMA trials. Detailed results according to the different clinical and biologic features of the adolescents analyzed will be presented. The results of our comparative study indicate that adolescents enrolled in pediatric trials have a more favourable clinical outcome.

Patterns of care in treating childhood neuroblastoma: Evidence from a population level study (SEER) in the United States.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22011-e22011
Author(s):  
Diarmuid Coughlan ◽  
Charles Lynch ◽  
Matthew Gianferante ◽  
Jennifer Stevens ◽  
Linda C Harlan
Keyword(s):  
United States ◽  
Clinical Trial ◽  
High Risk ◽  
Cancer Registries ◽  
The United States ◽  
Patterns Of Care ◽  
Treatment Modalities ◽  
High Dose ◽  
High Risk Patients ◽  
Risk Patients

e22011 Background: Childhood neuroblastoma describes a heterogeneous group of extracranial solid tumors. This heterogeneity is reflected in the sequence and variety of treatment modalities administered. We describe the treatment pattern and survival of childhood neuroblastoma patients using population-based data in the United States. Methods: Using the National Cancer Institute’s (NCI) Patterns of Care data, we examined treatment provided to childhood neuroblastoma patients newly diagnosed in 2010 and 2011 and registered to one of 14 Surveillance, Epidemiology, and End Results (SEER) cancer registries. Data were re-abstracted from hospital records and treating physicians were contacted to verify the treatment given. Stratifying by the Children’s Oncology Group (COG)’s 3-level (low, intermediate and high) neuroblastoma risk classification system for therapeutic decision-making, gave a snapshot of community-based treatment patterns. Kaplan-Meier survival analyses were also performed. Results: The majority of 250 patients (76%) were enrolled on an open/active clinical trial. All low-risk patients received surgery with/without chemotherapy. The majority of intermediate-risk patients (77%) received chemotherapy regimen that included carboplatin, etoposide, cyclophosphamide and doxorubicin. High-risk patients received extensive, multimodal treatment consisting of chemotherapy, surgery, high dose chemotherapy with stem cell rescue (transplant), radiation, immunotherapy (dinutuximab), and isotretinoin therapy. Cyclophosphamide was the most utilized chemotherapy agent (94%) in high-risk patients. Survival with a maximum follow-up of 48 months, was lowest (68%) for patients diagnosed with high-risk disease. Conclusions: The majority of childhood neuroblastoma patients are registered on a risk-based open/active clinical trial. Variation in modality, systemic agents and sequence of treatment reflects the heterogeneity of therapy for childhood neuroblastoma patients.

Is high-dose nafamostat mesilate effective for the prevention of post-ERCP pancreatitis, especially in high-risk patients?

Pancreatology ◽  
2013 ◽  
Vol 13 (2) ◽  
pp. e42
Author(s):  
D.H. Kang ◽  
C.W. Choi ◽  
S.B. Park ◽  
H.W. Kim ◽  
J.H. Park ◽  
...  
Keyword(s):  
High Risk ◽  
High Dose ◽  
Nafamostat Mesilate ◽  
High Risk Patients ◽  
Risk Patients

Newly Diagnosed Myeloma Pateints Are at Risk of Venous Thrombotic Events - High Risk Patients Need To Be Identified and Recieve Thromboprophylaxis: The MRC Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2395-2395
Author(s):  
Faith E. Davies ◽  
J. Anthony Child ◽  
Kim Hawkins ◽  
Susan Bell ◽  
Julia Brown ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Autologous Transplantation ◽  
High Dose ◽  
Central Venous ◽  
Thrombotic Risk ◽  
Younger Patients ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

Abstract Standard treatment for younger patients with presenting myeloma is VAD followed by high-dose melphalan with stem cell support. However this regimen requires a central venous catheter with risks of recurrent line infections and central venous thrombus. A number of oral alternatives have been used including dexamethasone (Dex), thalidomide (Thal) or combinations (Thal/Dex), although to date no randomized control trial has compared an intravenous with oral induction therapy. In older patients melphalan/prednisolone (MP) remains the standard approach. Thal combinations (MPT, CTD, DVdT) improve response rates and providing side effects can be managed effectively may also be appropriate for an elderly population. Patients with myeloma have an increased risk of venous thrombotic events (VTEs), and presenting patients receiving Thal may be at increased risk due to bulk disease. Combination with anthracyclines may also exacerbate this risk. The MRC Myeloma IX trial has been designed to address some of these issues. Younger patients are randomized to receive intravenous CVAD or an oral Thal containing regimen, CTD prior to autologous transplantation; older patients are randomized to MP or the Thal containing regimen, CTDa. At trial initiation (May 2003) physicians were advised that patients should start low-dose Thal (100mg od in the intensive and 50mg od in the non-intensive arm) and slowly dose escalate to 200mg. Patients at high risk of VTE should be considered for full anticoagulation with either warfarin or LMWH. As of Aug 2004 420 patients (239 intensive, 181 non-intensive) have been randomized and a total of 30 VTEs in 28 patients have been reported (22 intensive, 6 non-intensive). In the intensive arm there were 8 DVT, 9 PE and 7 line-related thromboses. In the non-intensive arm there were 4 DVT and 2 PE. CVAD CTD CTDa MP DVT 4.2% 2.5% 4.4% 0% PE 1.7% 5.8% 2.2% 0% Line related 5.0% 0.8% NA NA Total 10.9% 9.1% 6.6% 0% The median time from randomization to DVT/PE was 54.5 days (range 15–113). 4 patients were identified who had additional risk factors (2 immobility, 1 recent operation, 1 renal failure). Only 1 patient was receiving prophylaxis having previously suffered a DVT. There was one PE-related death. Importantly 2 PE and 5 DVT occurred in patients not receiving Thal therapy. All central thrombosis occurred in relation to the central line. In the non-intensive arm the addition of Thal increased VTE risk compared to MP. In conclusion myeloma patients have an increased incidence of VTE (5.9%–8.3%) although in this study so far patients on MP appear to have no excess thrombotic risk. Patients receiving infusional regimes are also at increased risk of line-related events (additional 5.0%). Using the combination of a slowly increasing Thal dose and thromboprophylaxis based on identification of high risk patients the addition of Thal marginally increased DVT/PE risk over and above the risk seen in patients with infusional regimens, but even in a large study such as this the number of events are too small to make firm recommendations. Currently our advice remains unchanged and ALL high risk patients should receive thromboprophylaxis.

Intensified Conditioning for Children Undergoing BMT for First Bone Marrow Relapse of Acute Lymphoblastic Leukaemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5169-5169
Author(s):  
John Moppett ◽  
Jerry Hancock ◽  
Christopher J.C. Knechtli ◽  
Anthony Oakhill ◽  
Nicholas J. Goulden
Keyword(s):  
High Risk ◽  
Treatment Failure ◽  
Risk Group ◽  
Control Group ◽  
Childhood All ◽  
High Risk Patients ◽  
Significant Difference ◽  
Risk Patients ◽  
High Level ◽  
Risk Of Treatment

Abstract BMT remains the treatment of choice for early BM relapse of childhood ALL. We reasoned that further intensification of cytoreductive therapy pre-BMT may further improve survival amongst those with the highest risk of treatment failure, early BM relapse (BFM groups S3/4) and high level MRD pre-BMT. A cohort of 32 patients transplanted at a single institution (1996–1999) provided an historical control. 8 high risk patients transplanted 1999–2000 received additional fludarabine cytoreduction therapy at the time of transplant (FLA group). MRD analysis and time to relapse were used in a subsequent cohort of 22 patients (BMT 2000–2002) to allocate those at highest risk of treatment failure to receive a further cytoreductive block, FLX, pre-BMT. Method. All patients were conditioned with cyclophosphamide (60mg/m2 x2) and TBI (14.4 Gy). UD and haplo-BMT were T-cell depleted with Campth-1M in vitro and Campath-1G day -9 to -5 (Control and FLA group), and by Miltenyi CD34+ cell depletion (FLX group). GvHD prophylaxis - CSA + MTX for matched related, CSA for Campath treated grafts and none for Miltenyi grafts. The FLA group received fludarabine 25mg/m2 from d −12 to d −10. Patients with on treatment relapse (S4) or high level MRD pre-BMT (MRD++) in the FLX group received DaunoXome 100mg/m2, fludarabine 30mg/m2 x 5d and cytosine 2g/m2 x 5d 3 weeks prior to BMT. Patients and donors. Control group: 28 precursor-B ALL 4 T-ALL; donors - 7 matched related, 13 matched unrelated (MUD) and 12 mismatched unrelated (MMUD); 14 S2, 18 S3/4. FLA group: 5 presursor-B ALL and 3 T-ALL; donors - 2 SIB, 4 MUD, 1 MMUD and 2 haplo; all S4. FLX group: 21 precursor-B and 1 T-ALL; donors - 6 SIB, 7 MUD, 5 MMUD and 4 haplo;13 S2, 9 S4. 7 patients received FLX intensified conditioning (6 S4, 5 high level MRD ++). 3 high risk patients violated protocol and did not receive FLX (1 age <1yr on treatment relapse, 2 S2 MRD ++). Results. Considering those in the high-risk S3/4 group, there was no significant difference in OS between the 3 groups. Survival by study and risk group Study S2 S3/4 Overall Control 10/14 (71%) 3/18 (17%) 13/32 (41%) FLA 2/8 (25%) 2/8 (25%) FLX 11/13 (85%) 3/9 (33%) 14/22 (64%) No excess cardiac events were seen. The TRM is higher in the FLX group than in the control. Outcome data Study TRM Relapse Alive Total Control 3 16 13 32 S2 2 2 10 14 S3/4 1 14 3 18 FLA 3 3 6 12 S2 - - - - S3/4 3 3 3 9 FLX 6 2 14 22 S2 2 0 11 13 S3/4 4 2 3 9 Total 12 21 33 66 2 of 7 patients treated with FLX are in CCR, 2 relapsed and 3 died of TRM. The 3 high risk patients in the FLX study, but who did not receive FLX, are also in CCR. Survival in those in the S2 group (late BM relapse) has been good throughout the study period. Conclusion. In this study the addition of intensive pre-BMT conditioning has not improved survival amongst high risk (S3/4 or MRD ++ pre-BMT) relapses. The number of post-BMT relapses has fallen but this is not clearly related to the use of FLX. The use of more haploidentical donors, more immunosupressive BMT regimes and additional cytoreductive chemotherapy may have contributed to the increased TRM seen. Time and site of relapse remain the clearest predictor of outcome. Further novel strategies are required to improve survival for the S4 risk group. The good OS for children receiving BMT in the S2 group should be noted.

A GITIL Prospective Randomized Multicenter Phase III Study of High Dose Sequential Chemotherapy with Rituximab (R-HDS) and Autologous Transplantation (ASCT) of Peripheral Blood Stem Cells Versus CHOP and Rituximab Delivered Every 14 Days (R-CHOP-14) in High-Risk Patients with Diffuse Large B-Cell Lymphomas (DLBCL): Interim Analysis on Feasibility and Toxicity (Protocol R-HDS 0305).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1898-1898
Author(s):  
Sergio Cortelazzo ◽  
Atto Billio ◽  
Alessandro Rambaldi ◽  
Corrado Tarella ◽  
Ingnazio Majolino ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Iii ◽  
Control Group ◽  
High Dose ◽  
Advanced Stage ◽  
Bulky Disease ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients ◽  
Ecog Ps

Abstract R-HDS 0305 (Clinical Trials. gov. number NCT00355199) is a multi-centre, unblinded, randomized controlled phase III trial involving 240 patients in 3 years from 16 Italian Cancer Centres, with DLBCL without CNS involvement, advanced stage (stage ≥IIB, bulk), age from 18 to 60 years with ECOG-PS=0–3 and aaIPI=2–3 or age from 61 to 65 years with ECOG-PS=0–2 and IPI 3–5. The control group received R-CHOP-14, which comprised 8 courses of chemotherapy every 14 days, supported by GCSF (day 7–11)±IFRT, if they achieved at least a PR after 4 cycles. Cases refractory to R-CHOP-14 were given R-HDS as salvage therapy. Experimental arm consisted in a R-HDS program, including a debulking phase of 3 courses of doxorubicin-containing chemotherapy (APO), followed by high-dose (HD)-cyclophosphamide (CTX) 7g/sqm, HD-Ara-C (2 g/sqm every 12 hours for 6 days), HD-etoposide 2g/sqm+Cisplatin 100 mg/sqm. After HDS chemotherapy, HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) or a BEAM (BCNU 300 mg/sqm, etoposide 200 mg/sqm, Ara-C 4000 mg/sqm, L-PAM 140 mg/sqm) conditioning regimen with ASCT±IFRT was planned. Rituximab (375 mg/sqm) is given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest, and twice after ASCT. The primary outcomes of the study are complete remission and disease-free survival, overall survival, event-free survival and toxicity. From July 2005 to July 2007, 89 patients were enrolled in the study (R-CHOP-14=43; R-HDS=46). The median age was 51 (range 19–65 years), 11 (12%) had ≥60 years and the M/F was 1.3. Patients presented with adverse features such as advanced stage (88%), BM infiltration (28%), bulky disease (71%), elevated LDH (84%), poor ECOG-PS (55%) and >1 extranodal sites (59%). Until now only 3 patients (3.4%) were refractory to planned treatment: 1/43 (2%) patients belonging to R-CHOP-14 arm shifted to R-HDS salvage treatment and other 2 patients died from lymphoma progression. The main G 3–4 WHO toxicity was haematological: anemia, granulocytopenia and thrombocytopenia occurred in 8%, 18% and 13% of patients, respectively. Grade 2–3 gastrointestinal toxicity and infectious episodes were recorded in 6% and 9% of patients, respectively. Two patients recovered from acute respiratory distress and 2 died of treatment-related toxicity (2.2%). In conclusion, if the R-HDS trial confirms earlier results, preliminary data show that intensive programs such as dose-dense chemo-immunotherapy and R-HDS with ASCT are feasible until 65 years with an acceptable toxic profile, also on the multi-centre basis. At completion of the trial we will assess the role of R-HDS and ASCT on the outcome of high-risk patients with DLBCL.

Outcome of Patients with T-Cell Lymphoblastic Leukemia or Lymphoma: The GRAALL Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2818-2818
Author(s):  
Stéphane Leprètre ◽  
Martine Escoffre-Barbe ◽  
Patrice Chevallier ◽  
Thibaut Leguay ◽  
Laurence Legros ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Cell Phenotype ◽  
High Dose ◽  
Cns Involvement ◽  
Childhood All ◽  
High Risk Disease ◽  
Mediastinal Disease

Abstract In 2003, the GRAALL intergroup initiated two twin protocols for adult patients with acute lymphoblastic leukemia (ALL; ≥ 20% marrow blasts) or lymphoblastic lymphoma (LL; < 20% marrow blasts), namely the GRAALL-2003 and LL-2003 trials. Treatment strategy was inspired by childhood ALL trials, including corticosteroid prephase, 5-drug induction, high dose-intensity consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and 2-year maintenance. An original induction reinforcement with sequential cyclophosphamide (HyperC) was offered to ALL patients with poor early response (cortico- and/or chemo-resistance) and to all LL patients. A total of 108 patients with T-cell phenotype have been treated (76 ALL and 32 LL; median age, 30 years; M/F sex ratio, 86/22; CNS+, 9; median follow-up, 2 years). Baseline characteristics were not different among ALL and LL subgroups, except for marrow blast percentage and mediastinal enlargement (47% vs 78% for ALL vs LL; P=.005), which correlated negatively, as well as for blood counts (WBC, 27 vs 8.7 × 109/L; platelets, 60 vs 328 × 109/L; Hb, 116 vs 134 g/L for ALL vs LL; P<.001). Bulky mediastinal disease was present in 57% LL vs 22% ALL patients (P=.002). Two patients (1 ALL, 1 LL) died early while the 106 remaining (98%) reached CR. With respect to mediastinal involvement, need for a salvage course with idarubicine and high-dose cytarabine to reach CR was more frequent in LL than in ALL patients (10 LL vs 2 ALL, P<.001). Allogeneic stem cell transplantation (SCT) was offered to patients with high-risk disease, defined here as CNS involvement, poor early response, or need for salvage. Among the 55 CR patients with high-risk disease (41 ALL, 14 LL), 26 received allogeneic SCT in first CR (20 ALL, 6 LL). Overall, 23/106 CR patients relapsed (18 ALL, 5 LL) while 8 died in first CR (7 ALL, 1 LL; 4 after SCT). At 2 years, estimated DFS and overall survival were 66% (64% vs 75% for ALL vs LL, P=.59) and 75% (74% vs 78% for ALL vs LL, P=.75), respectively. The only factors which influenced outcome in this risk-adapted strategy were need for salvage (higher relapse incidence) and CNS involvement (shorter survival). As compared to historical experiences, we report here a notable gain in outcome when treating patients with T-cell lymphoblastic disease, including lymphoma, with a pediatric-inspired ALL strategy. The efficacy of this approach leads to comparable outcome for both diseases. The systematic use of HyperC induction in LL patients was well tolerated, but the need for salvage therapy was more frequent in these patients possibly due to difficulty in early mediastinal response evaluation. The presence of CNS disease at diagnosis remains an unfavorable feature. The role of HyperC during induction and the place of allogeneic SCT in first CR deserve further evaluation in this new context.

Outcome of Adult AML at First Relapse Following a Risk-Oriented Strategy: An Update of the Northern Italy Leukemia Group (NILG) Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4385-4385 ◽  
Author(s):  
Irene Cavattoni ◽  
Enrico Morello ◽  
Elena Oldani ◽  
Tamara Intermesoli ◽  
Ernesta Audisio ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Risk Category ◽  
High Dose ◽  
High Risk Patients ◽  
Risk Patients ◽  
First Relapse ◽  
Group 2 ◽  
Standard Risk ◽  
Group 1

Abstract INTRODUCTION The impact on post-relapse survival of selected prognostic factors and salvage therapy (finalized to perform an allo-SCT) was retrospectively analyzed in 172 patients (patients) with relapsed non-APL AML, who had been initially treated with standard induction and risk-adapatiented consolidation. The aim was to identify factors associated with a better outcome at first relapse. METHODS All 172 patients were at first recurrence following consolidation of CR1 with high-dose Ara-C (HiDAC) multicycle therapy supported by blood stem cells (standard risk, as defined by mixed clinical-cytogenetic criteria) or allo-SCT in case of high-risk prognostic profile. Median age at relapse was 55 y (range 21–70). CR1 duration was &lt;6 months in 50 patients (29%), ranging from 0.6 to 52,7 mo (median 9,1). High risk patients were 128/172 (74%) and 43/172 patients (25%) had an unfavourable cytogenetics (CG). One hundred-eleven patients (64%) received HiDAC and 24 (14%) an allo-SCT according to study design. RESULTS 140 patients (81%) received salvage treatment. The remaining 32 patients (19%) received palliation and all of them died. The median OS was 17.1 mo, with a 2yOS of 34%. Favorable prognostic factors identified by univariate analisys were: favourable or intermediate CG (p=0,007), standard risk category according to first line protocol (p=0.004), availibility of a HLA matched donor (p= 0.048), achievement of an early CR1(p=0,000), HiDAC as first line therapy(p=0,000), alloHSCT perfomed at relapse (p=0,000) and a DFS from CR1&gt;12 mo (p=0,000). In multivariate analysis favourable or intermediate CG and DFS &gt;12 mo were confirmed as independent prognostic factors (p=0,036 and p=0,001 respectively). Among the 140 patients, 50 received an allo-SCT following relapse (36%, group 1), and the remaining 90 (64%, group 2) received high dose chemotherapy alone (85), autologous SCT (2), or DLI (3, in case of previous alloSCT). Both groups were comparable regarding age &gt;55 y, prior allo-SCT and risk class at diagnosis. After salvage therapy, 44 patients(88%) in the group 1 achieved CR2, compared to 26 patients (29%) in the group 2. The median duration of CR2 was 9 mo (range 2–64) and 3 mo (range 1–34) in group 1 and 2 respectively. NRM was 17/140: 12 patients (24%) in the allo-SCT group and 5 (6%) in group 2. The 2yOS was 57% and 23% respectively (p=0,000). Moreover, among 50 alloSCT patients, survival was affected by risk category at diagnosis: 2yOS of 19 (38%) standard risk patients was 83% compared to 42% in 31 high risk patients (62%) (p=0.01). This risk stratification has no impact on OS in the group 2. CONCLUSIONS DFS &gt; 12 mo and standard risk category at diagnosis, according to NILG protocol, are the most important independent positive prognostic factors impacting OS of AML relapsed patients. The availibility of a HLA matched donor and a subsequent intensification with alloSCT may offer substantial salvage rates and its outcome is affected by the risk stratification at diagnosis. Nevertheless, high risk patients could benefit from alloSCT, reaching an 2yOS of 42%.

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