SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study

Background: SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) from non-metastatic intracranial ependymoma in children aged 3 to 21 years, treated with a staged management strategy. Chemotherapy efficacy in ependymoma is debated and therefore the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide and cyclophosphamide (VEC) was an additional primary outcome. We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers. Methods: 74 participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation and 1q status were evaluated, alongside hTERT, ReLA, Tenascin-C, H3K27me3 and pAKT expression. Results: Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.003, HR=2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (p=0.005, HR=2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (p=0.003, HR=2.70, 95%CI 1.49-6.10 and p=0.014, HR=5.8, 95%CI 1.2-28 respectively) and H3K27me3 loss with worse OS (p=0.003, HR=4.6, 95%CI 1.5-13.2). DNA methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding a prespecified 45% RR. Conclusions: RR of STR to VEC exceeded the pre-specified criterion for efficacy. However, cases of inaccurate treatment stratification highlighted the need for rapid central review. Prognostic associations for 1q gain, H3K27me3 and hTERT were confirmed.

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EPEN-04. SIOP EPENDYMOMA I: FINAL RESULTS, LONG TERM FOLLOW-UP AND MOLECULAR ANALYSIS OF THE TRIAL COHORT: A BIOMECA CONSORTIUM STUDY

Neuro-Oncology ◽

10.1093/neuonc/noab090.054 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i14-i14

Author(s):

Timothy A. Ritzmann ◽

Rebecca J Chapman ◽

Donald Macarthur ◽

Conor Mallucci ◽

John-Paul Kilday ◽

...

Keyword(s):

Management Strategy ◽

Response Rate ◽

Htert Expression ◽

Intracranial Ependymoma ◽

Long Term Follow Up ◽

Post Hoc ◽

1Q Gain ◽

Final Cohort

Abstract Introduction Surgery and radiotherapy are established childhood ependymoma treatments. The efficacy of chemotherapy has been debated. We report final results of the SIOP Ependymoma I trial, with 12-year follow-up, in the context of a post-hoc analysis of more recently described biomarkers. Aims and Methods The trial assessed event free (EFS) and overall survival (OS) of patients aged three to 21 years with non-metastatic intracranial ependymoma, treated with a staged management strategy targeting maximum local control. The study also assessed: the response rate (RR) of subtotally resected (STR) disease to vincristine, etoposide and cyclophosphamide (VEC); and surgical operability. Children with gross total resection (GTR) received radiotherapy of 54 Gy in 30 daily fractions over six weeks, whilst those with STR received VEC before radiotherapy. We retrospectively assessed methylation and 1q status alongside hTERT, RELA, Tenascin C, H3K27me3 and pAKT expression. Results Between 1999 and 2007, 89 participants were enrolled, 15 were excluded with metastatic (n=4) or non-ependymoma tumours (n=11) leaving a final cohort of 74. Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. 1q gain was associated with poorer EFS (p=0.002, HR=3.00, 95%CI 1.49–6.10). hTERT expression was associated with worse five-year EFS (20.0% Vs 83.3%, p=0.014, HR=5.8). GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.006, HR=2.81, 95% confidence interval 1.35–5.84). There was an improvement in GTR rates in the latter half of the trial (1999-2002 32.4% versus 2003-2007 56.8%). Despite the protocol, 12 participants with STR did not receive chemotherapy. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7–82.1). Conclusions VEC exceeded the pre-specified RR of 45% in children over three years with STR intracranial ependymoma. However, cases of inaccurate stratification at treating centres highlights the need for rapid central review. We also confirmed associations between 1q gain, hTERT expression and outcome.

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Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/13524585211000280 ◽

2021 ◽

pp. 135245852110002

Author(s):

Bruce AC Cree ◽

Jeffrey A Cohen ◽

Anthony T Reder ◽

Davorka Tomic ◽

Diego Silva ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Trials ◽

Therapeutic Benefit ◽

Disease Modifying Therapies ◽

Long Term Follow Up ◽

Post Hoc ◽

Switch Group ◽

Relevant Outcome

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

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Hemiarthroplasty versus internal fixation for displaced intracapsular hip fractures: A long-term follow-up of a randomised trial

Yearbook of Orthopedics ◽

10.1016/s0276-1092(10)79792-3 ◽

2010 ◽

Vol 2010 ◽

pp. 40-42

Author(s):

M.F. Swiontkowski

Keyword(s):

Internal Fixation ◽

Hip Fractures ◽

Randomised Trial ◽

Long Term Follow Up

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Poor Associations Between Radiographic Tibiofemoral Osteoarthritis and Patient-Reported Outcomes at 16 Years After Anterior Cruciate Ligament Reconstruction

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967120951174 ◽

2020 ◽

Vol 8 (9) ◽

pp. 232596712095117

Author(s):

Fredrik Identeg ◽

Eric Hamrin Senorski ◽

Eleonor Svantesson ◽

Kristian Samuelsson ◽

Ninni Sernert ◽

...

Keyword(s):

Acl Reconstruction ◽

Patient Reported Outcomes ◽

Cruciate Ligament ◽

Patient Reported ◽

Long Term Follow Up ◽

Ikdc Score ◽

Anterior Cruciate ◽

Grade 3

Background: Radiographic tibiofemoral (TF) osteoarthritis (OA) is common in patients after anterior cruciate ligament (ACL) reconstruction at long-term follow-up. The association between radiographic OA and patient-reported outcomes has not been thoroughly investigated. Purpose: To determine the association between radiographic TF OA and patient-reported outcome measure (PROM) scores at 16 years after ACL reconstruction. Study Design: Case-control study; Level of evidence, 3. Methods: This study was based on 2 randomized controlled studies comprising 193 patients who underwent unilateral ACL reconstruction. A long-term follow-up was carried out at 16.4 ± 1.7 years after surgery and included a radiographic examination of the knee and recording of PROM scores. Correlation analyses were performed between radiographic OA (Kellgren-Lawrence [K-L], Ahlbäck, and cumulative Fairbank grades) and the PROMs of the International Knee Documentation Committee (IKDC) subjective knee form, Lysholm score, and Tegner activity scale. A linear univariable regression model was used to assess how the IKDC score differed with each grade of radiographic OA. Results: Of 193 patients at baseline, 147 attended the long-term follow-up. At long-term follow-up, 44.2% of the patients had a K-L grade of ≥2 in the injured leg, compared with 6.8% in the uninjured leg. The mean IKDC score at follow-up was 71.2 ± 19.9. Higher grades of radiographic OA were significantly correlated with lower IKDC and Lysholm scores ( r = –0.36 to –0.22). Patients with a K-L grade of 3 to 4 had significantly lower IKDC scores compared with patients without radiographic OA (K-L grade 0-1). Adjusted beta values were –15.7 (95% CI, –27.5 to –4.0; P = .0093; R 2 = 0.09) for K-L grade 3 and –25.2 (95% CI, –41.7 to –8.6; P = .0033; R 2 = 0.09) for K-L grade 4. Conclusion: There was a poor but significant correlation between radiographic TF OA and more knee-related limitations, as measured by the IKDC form and the Lysholm score. Patients with high grades of radiographic TF OA (K-L grade 3-4) had a statistically significant decrease in IKDC scores compared with patients without radiographic TF OA at 16 years after ACL reconstruction. No associations were found between radiographic TF OA and the Tegner activity level.

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The transvenous retrograde pressure cooker technique for the curative embolization of high-grade brain arteriovenous malformations

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2020-016566 ◽

2020 ◽

pp. neurintsurg-2020-016566

Author(s):

Masaomi Koyanagi ◽

Pascal John Mosimann ◽

Hannes Nordmeyer ◽

Markus Heddier ◽

Juergen Krause ◽

...

Keyword(s):

Arteriovenous Malformations ◽

High Grade ◽

Transvenous Embolization ◽

Cure Rate ◽

Brain Arteriovenous Malformations ◽

Long Term Follow Up ◽

Occlusion Rate ◽

Grade 3

BackgroundTransvenous embolization of brain arteriovenous malformations (AVMs) can be curative. We aimed to evaluate the cure rate and safety of the transvenous retrograde pressure cooker technique (RPCT) using coils and n-butyl-2-cyanoacrylate as a venous plug.MethodsAll AVM patients treated via transvenous embolization between December 2004 and February 2017 in a single center were extracted from our database. Inclusion criteria were: inability to achieve transarterial cure alone; AVM < 3 cm; and single main draining vein. Outcome measures were immediate and 90 days' angiographic AVM occlusion rate, and morbidity and mortality at 30 days and 12 months, according to the modified Rankin Scale (mRS) score.ResultsFifty-one patients (20 women; median age 47 years) were included. A majority (71%) were high grade (3 to 5 in the Spetzler–Martin classification). AVMs were deeply seated in 30 (59%) and cortical in 21 patients (41%). Thirty-three patients were previously embolized transarterially (65%). All patients but one were cured within a single session with the RPCT (96%). Cure was confirmed on follow-up digital subtraction angiography at 3 months in 82% of patients. Three patients experienced intracranial hemorrhage (6%), one requiring surgical evacuation. There were no deaths. One treatment-related major permanent deficit was observed (2.0%). Mean mRS before treatment, at 30 days, and 12 months after RPCT was 1.5, 1.5, and 1.3, respectively.ConclusionsThe retrograde pressure cooker technique can be curative in carefully selected high-grade AVMs. Long-term follow-up and prospective studies are needed to confirm our results.

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Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial

Molecular Oncology ◽

10.1002/1878-0261.12803 ◽

2020 ◽

Vol 14 (11) ◽

pp. 2713-2726

Author(s):

Martin Sjöström ◽

Cynthia Veenstra ◽

Erik Holmberg ◽

Per Karlsson ◽

Fredrika Killander ◽

...

Keyword(s):

Randomised Trial ◽

Breast Conserving Surgery ◽

Long Term Follow Up

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Long-term follow-up results of a phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma (NKTCL): JCOG0211.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8050 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8050-8050

Author(s):

Motoko Yamaguchi ◽

Kensei Tobinai ◽

Masahiko Oguchi ◽

Naoki Ishizuka ◽

Yukio Kobayashi ◽

...

Keyword(s):

Phase I ◽

Concurrent Chemoradiotherapy ◽

Elevated Serum ◽

Progression Free Survival ◽

Disease Recurrence ◽

Newly Diagnosed ◽

Long Term Follow Up ◽

Grade 3

8050 Background: Concurrent chemoradiotherapy has been regarded as one of the standard management for localized nasal NKTCL. However, its long-term efficacy and toxicity is not known. Methods: The JCOG0211 trial is a phase I/II study of concurrent chemoradiotherapy consisting of radiotherapy (RT) of 50 Gy and 3 cycles of DeVIC (carboplatin, etoposide, ifosfamide, dexamethasone) for newly diagnosed, localized nasal NKTCL (JCO 2009). Patients (Pts) with newly diagnosed, localized diseases (IE & contiguous IIE with cervical node involvement) who were 20-69 yrs of age with PS 0-2 were eligible. 3-D conformal RT planning with a wide margin (+ 2 cm to the gross tumor, the entire nasal cavity and the nasopharynx) and a 2-step cone down were required. 33 pts were enrolled in the study, 27 of whom were treated with RT and a 2/3-dose of DeVIC, which was selected as the recommended phase II dose in the preceding phase I portion of the trial. All pts completed RT without any protocol violations. Long-term follow-up results on overall survival (OS), progression-free survival (PFS) and toxicity were evaluated. Results: The median follow-up was 69 months (range, 62-96). The pt (N=33) characteristics were as follows: median age 54 yrs (range, 21-68); stage IIE 33%; B symptom (+) 36%; elevated serum LDH 21%. %5-yr OS and PFS were 73% (95%CI, 54-85%) and 67% (95%CI, 48-80%), respectively. 11 pts (33%) experienced disease recurrence. Two achieved a 2nd CR by salvage chemotherapies followed by allogeneic stem cell transplantation, and the remaining 9 pts died of disease. There was no observed death and disease progression after 34 and 31 months, respectively. One pt experienced Grade 3 irregular menstruation for 3 years. No other Grade 3 or 4 late non-RT-associated adverse events (AEs) were observed. One pt received plastic surgery due to Grade 4 RT dermatitis. No other Grade 3 or greater RT-associated late AEs were encountered. Conclusions: Both survival benefit and disease control from concurrent chemoradiotherapy with RT and DeVIC are maintained during a 5-yr follow-up, indicating the excellent efficacy of this approach as a first-line therapy for localized nasal NKTCL. Long-term toxicity is acceptable.

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Long-term follow-up of previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) treated with ofatumumab (OFA) and chlorambucil (CHL): Final analysis of the phase 3 COMPLEMENT 1 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7528 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7528-7528

Author(s):

Fritz Offner ◽

Tadeusz Robak ◽

Ann Janssens ◽

Govind Babu Kanakasetty ◽

Janusz Kloczko ◽

...

Keyword(s):

Progression Free Survival ◽

Final Analysis ◽

Lymphocytic Leukemia ◽

Primary Analysis ◽

Free Survival ◽

Anti Cancer ◽

Long Term Follow Up ◽

Grade 3

7528 Background: Previously in the COMPLEMENT 1 study, treatment with OFA and CHL in pts with untreated CLL had shown a significant improvement in the progression-free survival (PFS) compared with CHL alone, and was well tolerated. Here, we report the final overall survival (OS) analysis of the 5-year (y) follow-up, updated investigator-assessed PFS and safety from the study. Methods: Untreated pts, not fit for fludarabine-based therapy (due to advanced age or co-morbidities) were randomized 1:1 to OFA+CHL or CHL alone. Pts in OFA+CHL arm received OFA (Cycle 1: 300 mg day (d) 1, 1000 mg d8; subsequent cycles: 1000 mg d1) in addition to CHL (10 mg/m2, d1-7) for 3 to 12 cycles of 28 d each. Pts in CHL arm received CHL only. Results: Overall, 447 pts were randomized to OFA+CHL (n = 221) or CHL (n = 226); 168 (76%) and 164 (73%) pts completed the scheduled treatments, respectively. Baseline characteristics were similar in both arms. The investigator-assessed median PFS was 23.4 months (mos) in the OFA+CHL arm and 14.7 mos in the CHL arm (HR: 0.61 [95% CI 0.49, 0.76], p < 0.001). Median OS could not be estimated for the OFA+CHL arm and was 84.7 mos for the CHL arm (HR: 0.88 [95% CI 0.65, 1.17], p = 0.363). Estimated OS rate (95% CI) at 5 y was 68.5% (61.5%, 74.5%) in the OFA+CHL arm, and 65.7% (58.6%, 71.9%) in the CHL arm. Post-treatment anti-cancer therapy after discontinuation was received by a greater proportion of pts in the CHL (66%) vs. OFA+CHL (56%), and started earlier in the CHL arm (486 d) vs. OFA+CHL (743 d) arm. Overall, 84 (39%) pts in the OFA+CHL, and 99 (44%) pts in the CHL arms died during the study with 5 on-treatment deaths in each group. Grade ≥3 adverse events were seen in 64% and 48% of pts in the OFA+CHL vs. CHL arms, respectively, most common being (≥5% in either arm) neutropenia (26% vs. 15%), thrombocytopenia (5% vs. 10%), pneumonia (9% vs. 5%), and anemia (5% vs. 5%). Conclusions: This 5-y survival follow-up analysis supported the results from primary analysis with an estimated 12% (not significant) and 39% risk reduction in OS and PFS, respectively, in the OFA+CHL arm compared with the CHL arm. No new safety concerns were observed in the OFA+CHL arm. Clinical trial information: NCT00748189.

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