Longer Follow-up Data Research Articles

Abstract ES9-2: Special indications where local therapy should be considered

Abstract Clarity for the clinical issue of which patients with metastatic breast cancer should undergo local/regional therapy (LRT) was provided by the recent presentation of the prospective randomized ECOG-ACRIN 2108 trial data. This study, which randomized Stage IV breast cancer patients (initially treated with optimal systemic therapy for 4-8 months) to early local therapy or to continued systemic therapy alone, failed to demonstrate an improvement in overall survival for patients who had early local therapy compared to continued systemic therapy alone. However, there are some special indications that fall outside of this trial, and which remain areas of controversy. For instance, the subset of patients with inflammatory breast cancer (IBC) were not included in the ECOG trial, and therefore there are no prospective randomized clinical trial data available to determine if LRT improves survival in de novo stage IV IBC patients. To further confound the issue, several retrospective studies show clear survival benefit for Stage IV IBC patients who complete LRT, versus those who do not. While we all recognize that some differences could be attributed to selection bias, the differences in outcome are so striking that we believe that it warrants further discussion of the possible value of LRT in the IBC group. Furthermore, patients with IBC are more likely to be found to have Stage IV disease at presentation, complicating the discussion of whether complete trimodal therapy (neoadjuvant chemotherapy, mastectomy, and post-mastectomy radiation therapy) should still be considered at initial treatment planning, or whether LRT should be omitted altogether. Finally, due to the skin involvement and rapid progression inherent to IBC, these patients often require LRT for palliation of advanced disease (to control fungating tumors, brachial plexus involvement, etc.), so palliative surgery plays an important role in the management of the patient with IBC. During this presentation, we plan to discuss the available data regarding optimal LRT decisions for patients with de novo Stage IV IBC. Beyond the subset of IBC patients, several studies have identified non-IBC patients with Stage IV disease who might benefit from LRT. We will also discuss subsets of Stage IV breast cancer patients, including those with HR+ tumors, those with bone-only oligometastasis, and younger age patients, where LRT has shown survival benefit, based mainly on longer follow-up data from the randomized MF07-01 trial. Our objective is to improve knowledge of the local/regional treatment recommendations of select subgroups of Stage IV patients, where the use of LRT could translate to not only improved local control, but possibly to improved survival in carefully selected patients. Citation Format: A Lucci. Special indications where local therapy should be considered [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES9-2.

POS-054 PERSISTENT MARKERS OF RENAL INJURY IN CHILDREN WHO DEVELOPED ACUTE KIDNEY INJURY AFTER PEDIATRIC CARDIAC SURGERY: A PROSPECTIVE COHORT STUDY

Acute kidney injury (AKI) in the immediate postoperative period is common, occurring in 30-60% of children undergoing pediatric cardiac surgery for congenital heart disease (CHD). Longer-term outcomes and the incidence of chronic kidney disease (CKD) after AKI are not well known. This is an important issue, as CKD occurs in 30-50% of the growing ACHD population, being responsible for an excess burden in healthcare utilization. Currently, AKI guidelines in children offer no recommendations on structured renal follow-up. Therefore, this prospective cohort study investigated the long-term renal consequences of AKI after pediatric cardiac surgery, based on a formal assessment visit conducted at 5 years of follow-up and blood samples collected during the latest available visit at >10 years after the index AKI episode. All eligible children (<16 years) who had developed AKI following cardiac surgery at our tertiary referral hospital between December 2004 and December 2008 were prospectively invited for a formal renal assessment 5 years after AKI, including measurements of estimated glomerular filtration rate (eGFR), proteinuria, alpha-1-microglobulin, renal ultrasound, and blood pressure. Longer follow-up data on renal function (>10 years after AKI) were collected at latest available visit. Of 640 cardiac operations performed in 571 patients between December 2004-2008. AKI occurred in 113 patients (19.7%) following 122 procedures (19.1%). Fifteen of these patients (13.3%) died at a median of 31 days (interquartile range, IQR 9-57) after surgery. A total of 66 patients participated in the renal assessment at a median of 4.8 years (IQR 3.9-5.7) after the index AKI episode. Reduced renal function (eGFR <90mL/min/1.73m²; CKD stages 2-5) was present in 9 patients (13.6%), proteinuria in 27 (40.9%), alpha-1-microglobinuria in 5 (7.6%), hypertension in 13 (19.7%), abnormalities on renal ultrasound in 9 (13.6%), and CKD stages 1-5 (eGFR <90mL/min/1.73m² or eGFR 90-100mL/min/1.73m² with echocardiographic or laboratory abnormalities) in 18 (27.3%). No differences were observed between AKIN stages. Patients with CKD were more likely to have an associated syndrome (55.6% versus 20.8%, p=0.015) and had a lower lower height percentile (10, IQR 1.88-34.2 versus 50, IQR 10-53.2, p=0.005), despite similar weight percentile (17.5, IQR 3-35.2 versus 25, IQR 5.25-50, p=0.181), when compared to those without CKD. At 13.1 years (IQR 11.2-14.0) of follow-up, eGFR had declined further (from 114±25 mL/min/1.73m² to 99±23 mL/min/1.73m², p=0.001) and reduced renal function was present in 18/49 patients (36.7%). Children who developed AKI after pediatric cardiac surgery show persistent markers of renal injury. Detection and treatment of CKD, proteinuria, and hypertension in children is critical because these are risk factors for cardiovascular diseases and progressive renal damage in adults. Patients with CHD are especially high-risk for long-term cardiac events, and the superposition of comorbidities such as coronary artery disease, diabetes, smoking, and hypertension in adulthood leads to an excess of healthcare utilization in ACHD. We therefore suggest a structured renal follow-up in this vulnerable population and recommend that prevention of renal disease should start in childhood to ensure optimal outcomes in the growing population of ACHD.

Postnatal Repair of Open Neural Tube Defects: A Single Center with 90-Month Interdisciplinary Follow-Up.

After publication of the Management of Myelomeningocele Study (MOMS) there is confusion regarding which treatment of open neural tube defects (NTD) is best. We report our results of postnatally repaired open NTDs born between 2007–2018 (n = 36) in critical reflection of the MOMS study. Neurosurgical, orthopedic, and urologic data were assessed. We also introduce a new entity: “status post prenatal repair”. FU ranged from 29 to 161 months (mean: 89.1 m) in 7 cases of myeloschisis and 24 myelomeningoceles in the final collective n = 31. The shunt rate was 41.9%, and the endoscopic third ventriculostomy rate was 16.1%. Hydrocephalus requiring treatment was not associated with the anatomical level, but with premature birth (p = 0.048). Myeloschisis was associated with shunt placement (p = 0.008). ROC analysis revealed birth <38.5th week predicts the necessity for hydrocephalus treatment (sensitivity: 89%; specificity: 77%; AUC= 0.71; p = 0.055). Eight (25.8%), patients are wheelchair-bound, 2 (6.5%) ambulate with a posterior walker, 10 (32.3%) with orthosis and 11 (35.5%) independently. One (3.2%) patient underwent detethering at 5.5 years. A total of three patients underwent five Chiari decompressions (9.6%). Further, nineteen orthopedic procedures were performed in nine patients (29.0%). A total of 17 (54.8%) patients self-catheterize, which was associated with an anatomical lesion at L3 or below (p = 0.032) and 23 (74.2%) take anticholinergic medication. In conclusion, shunt dependency is associated with myeloschisis, not with the anatomical defect level. Hydrocephalus treatment is associated with premature birth. In this postnatal cohort with significantly longer follow-up data than the MOMs study, the ambulation rate is better, the shunt rate lower and the secondary tethered cord rate better compared to the MOMS study.

How to fill the GAPS-I in secondary prevention: application of a strategy based on GLP1 analogues, antithrombotic agents, PCSK9 inhibitors, SGLT2 inhibitors and immunomodulators

The continuous progress in cardiovascular risk prevention strategies has led to an impressive reduction in mortality and recurrent ischemic events in patients with coronary artery disease (CAD). However, the control of several cardiovascular risk factors remains suboptimal in many CAD patients, with a high rate of recurrent events, underlying the need for more new prevention strategies. The GAPS-I (glucagon-like peptide 1 analogues, antithrombotic agents, proprotein convertase subtilisin/kexin type 9 inhibitors, sodium glucose cotransporter type 2 inhibitors and immunomodulators) strategy offers a promising potential in patients with a high-residual cardiovascular risk, who are frequently encountered in daily practice, by offering an individualized and structured approach to addressing their individual risk factors. The current review summarizes the evidence to date on each of its components, with respect to clinical outcomes and economic feasibility. The current evidence points to an efficacy of GAPS-I in reducing major adverse cardiovascular events and mortality, without a compromise on safety, albeit with the need for longer follow-up data.

Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: a systematic review and meta-analysis.

AimsThe value of elective coronary revascularisation plus medical therapy over medical therapy alone in managing stable patients with coronary artery disease is debated. We reviewed all trials comparing the two strategies in this population.Methods and resultsFrom inception through November 2020, MEDLINE, EMBASE, Google Scholar, and other databases were searched for randomised trials comparing revascularisation against medical therapy alone in clinically stable coronary artery disease patients. Treatment effects were measured by rate ratios (RRs) with 95% confidence intervals, using random-effects models. Cardiac mortality was the pre-specified primary endpoint. Spontaneous myocardial infarction (MI) and its association with cardiac mortality were secondary endpoints. Further endpoints included all-cause mortality, any MI, and stroke. Longest follow-up data were abstracted. The study is registered with PROSPERO (CRD42021225598). Twenty-five trials involving 19 806 patients (10 023 randomised to revascularisation plus medical therapy and 9783 to medical therapy alone) were included. Compared with medical therapy alone, revascularisation yielded a lower risk of cardiac death [RR 0.79 (0.67–0.93), P < 0.01] and spontaneous MI [RR 0.74 (0.64–0.86), P < 0.01]. By meta-regression, the cardiac death risk reduction after revascularisation, compared with medical therapy alone, was linearly associated with follow-up duration [RR per 4-year follow-up: 0.81 (0.69–0.96), P = 0.008], spontaneous MI absolute difference (P = 0.01) and percentage of multivessel disease at baseline (P = 0.004). Trial sequential and sensitivity analyses confirmed the reliability of the cardiac mortality findings. All-cause mortality [0.94 (0.87–1.01), P = 0.11], any MI (P = 0.14), and stroke risk (P = 0.30) did not differ significantly between strategies.ConclusionIn stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared with medical therapy alone. The cardiac survival benefit after revascularisation improved with longer follow-up times and was associated with fewer spontaneous MIs.

Longer follow-up data of circulating miR371a-3p expression across the spectrum of germ cell tumors (GCT).

379 Background: miR371a-3p (miR371) is overexpressed in seminoma (S) and nonseminoma (NS) active germ cell malignancy (aGCM) and easily detectable in blood. We previously described1 a remarkably high accuracy of miR371 in detecting aGCM in early and advanced stages germ cell tumor (GCT) patients (pts). We here present the updated miR371 expression data with a longer follow-up, particularly relevant to assess miR371 clinical utility to predict GCT relapse in clinical stage I (CSI) and stage IIA pts. Methods:119 samples from 99 pts enrolled in the GU biobank program at the British Columbia Cancer – Vancouver were analyzed. The pts were divided according to their risk of aGCM in low (CSIA NS and CSI S), moderate (CSIB NS, stage IIA markers negative/low elevated S and NS), and high risk (definitively metastatic aGCM) groups. Blood of the low and moderate risk pts was collected post orchiectomy and at the time of the clinical relapse; prior to/post-chemotherapy in the high risk group. Plasma miR371 expression was evaluated by RT-PCR and quantified by ΔΔCT method. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC of the ROC curve were analyzed. Results: Five (2 moderate - 3 low risks) pts were lost at follow-up and 1 high risk pt had deceased. Overall, 113 samples (50, 36, 27 in the low, moderate, and high risk groups, respectively) were analyzed. The median follow-up from study entry was 30 (6-51), 28 (20-52), and 29 (7-53) months for the low, moderate and high risk, respectively. Seven more relapses occurred: 4 in the low risk (3 S and 1 NS) and 3 in the moderate risk groups (2 NS and 1 S). miR371 was found falsely negative post-orchiectomy in 4 pts and truly negative in 3 relapsed pts (2 pure teratoma and 1 unconfirmed relapse). Serial analysis of the false negative relapsed pts showed that miR371 became detectable at the time of clinical relapse. The operating characteristics of miR371 are summarized in the table below. Conclusions: Our follow-up has exceeded the expected time of relapse even in the low risk pts. The high accuracy of miR371 in detecting aGCM was confirmed with a longer follow up. However, the few false negatives in relapsed pts and the serial analysis suggest a lack of sensitivity in the detection of microscopic disease post-orchiectomy with the current methodology while miR371 high sensitivity was confirmed in presence of radiologic measurable disease (≥ 1 cm). The definitive operating characteristics of miR371 post-orchiectomy and during the follow-up of stages I/ IIA pts will be prospectively validated by the S1823 study that is actively recruiting pts. [Table: see text]

Endoscopically controlled surgery with open hemilaminectomy for the treatment of intradural extramedullary tumors: an operative technique and short-term outcomes of 20 consecutive cases

BackgroundTo present a surgical technique for the treatment of intradural extramedullary (IDEM) tumors by using endoscopically controlled surgery with open hemilaminectomy technique.MethodsIn this study, 20 patients with 22 IDEM tumors were enrolled. An endoscopically controlled surgery with open hemilaminectomy was employed to remove the tumors. Data related to clinical symptoms and medical images before and after surgery were collected for perioperative evaluation and follow-up analysis.ResultsAll the tumors in 20 patients were well removed. The clinical symptoms were significantly reduced in all the patients as well. The short-term follow-up data showed that there was no tumor recurrence or spinal deformity.ConclusionThe endoscopically controlled surgery with open hemilaminectomy technique provided favorable exposure and satisfactory resection to the IDEM tumors. It may be an effective surgical method for treating IDEM tumors. Larger samples and longer follow-up data are needed to verify its long-term effectiveness.

PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinoma and Tumor-associated Immune Cells: Differences Between MLH1 Methylated and Nonmethylated Subgroups.

Mismatch repair (MMR)-deficient endometrial carcinomas show increased programmed cell death-ligand 1 (PD-L1) expression compared with MMR-intact endometrial carcinomas, but there are limited data regarding PD-L1 expression between sporadic and inherited carcinomas exhibiting MMR loss. Most of the studies investigating PD-L1 expression in endometrial carcinoma have used tissue microarrays and did not examine all tumor blocks. In this study, we analyzed the expression of PD-L1 in resection specimens of 176 consecutive endometrial carcinomas using all tumor blocks; we compared PD-L1 expression in MMR-deficient endometrial carcinomas, including the MLH1 and PMS2-loss subgroup, and the other MMR-loss subgroups (MSH2 and MSH6, isolated PMS2, and isolated MSH6), with the MMR-intact subgroup. MLH1 methylation was performed in tumors with MLH1 and PMS2 loss. Tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 positivity with a 1% cutoff was observed in 21% (n=37) and 66.5% (n=117) of cases, respectively, and with a 5% cutoff in 5.1% (n=9) and 39.8% (n=70) of cases, respectively. MMR protein deficiency was a statistically significant parameter associated with IC PD-L1 positivity, with 1% and 5% cutoffs on multivariate analysis [odds ratio (OR)=5.236, 95% confidence interval (CI)=2.075-13.211, P=0.001, and OR=3.702, 95% CI=1.759-7.791, P=0.001, respectively]. The multivariate analysis showed that IC PD-L1 positivity, using both 1% and 5% cutoffs, was significantly associated with the MLH1 and PMS2 loss compared with the MMR protein-intact subgroup (MLH1 and PMS2 loss for 1% cutoff: OR=5.104, 95% CI=1.876-13.881, P=0.001, and for 5% cutoff: OR=3.322, 95% CI=1.540-7.166, P=0.002). Squamous differentiation was an independent predictor for TC PD-L1 positivity, with a 5% cutoff (OR=6.102, 95% CI=1.280-10.096, P=0.026). Larger tumor size was an independent predictive factor for IC PD-L1 positivity with a 1% cutoff (OR=6.757, 95% CI=1.569-29.109, P=0.010). Overall, 48 (92.3%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 1% cutoff, and 34 (65.4%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 5% cutoff. Our results show a higher rate of IC PD-L1 positivity than in previous studies. This is likely due in part to the use of all tumor blocks. MLH1 and PMS2 loss was an independent predictive factor for IC PD-L1 positivity, with both 1% and 5% cutoffs. Using univariate analysis, we observed decreased disease-free survival for IC PD-L1 positivity ≥5%. Our study results should now be tested and proven in larger cohorts, with longer follow-up data.

Subcutaneous Epcoritamab Induces Complete Responses with an Encouraging Safety Profile across Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Subtypes, Including Patients with Prior CAR-T Therapy: Updated Dose Escalation Data

Subcutaneous Epcoritamab Induces Complete Responses with an Encouraging Safety Profile across Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Subtypes, Including Patients with Prior CAR-T Therapy: Updated Dose Escalation Data

Analysis of the serial circulating tumor cell count during neoadjuvant chemotherapy in breast cancer patients

We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80–63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26–155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.

A Shifting Paradigm in Diagnosis and Management of Hepatic Adenoma.

New insights into molecular pathogenesis of hepatocellular adenomas (HCA) have allowed sub-classification based on distinct genetic alterations and a fresh look at characterizations of natural history. Clinically, this is important in understanding risk factors for two feared complications: malignant transformation and hemorrhage. PubMed literature search for hepatocellular adenoma over all years, excluding case reports and articles focusing on multiple adenomas or adenomatosis. The β-catenin exon 3 mutated HCA accounts for about 10% of all HCAs and is associated with the highest risk of malignant transformation. The HF1α subtype accounts for 30-40% of all HCAs and has the lowest risk of malignant transformation. Gender has also emerged as an increasingly important risk factor and males with HCA are at considerably higher risk of malignant transformation, regardless of tumor size. The increasing use of gadoxetic-enhanced MRI has allowed for improved differentiation of HCAs from focal nodular hyperplasia, as well as the identification of specific radiologic features of some subtypes, particularly the inflammatory and HF1α HCAs. Classification of HCA by subtype has important implications for patient counseling and treatment given variable risks of malignant transformation and hemorrhage. Males and those with β-catenin exon 3 mutated HCAs are two groups who should always be counselled to undergo surgical resection. On the other hand, in the lower risk HF1α subtype observation is appropriate in lesions <5cm and may even be considered in larger lesions as longer follow-up data is aggregated and tumorigenesis is better understood.

PBI36 REVIEW AND COMPARISON OF OVERALL SURVIVAL EXTRAPOLATION IN HEALTH TECHNOLOGY ASSESSMENTS FOR CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPIES (CAR-TS)

The US Institute for Clinical and Economic Review (ICER) and the UK National Institute for Health and Care Excellence (NICE) recently evaluated chimeric antigen receptor T-cell therapies (CAR-Ts) for pediatric B-cell acute lymphoblastic lymphoma (B-ALL), and diffuse large B-cell lymphoma (DLBCL) in adults. We reviewed and compared assessments of CAR-Ts from ICER and NICE, focusing on the extrapolation of overall survival (OS). One ICER evaluation and three NICE technology assessments (TAs) of the cost effectiveness of CAR-Ts in B-ALL and DLBCL were identified. Methods used for extrapolation of OS were compared. For both B-ALL and DLBCL populations in ICER’s assessment, standard parametric survival curves were extrapolated for 5 years, after which survivors were considered cured and followed general population mortality. In NICE TA559 and TA554, mixture-cure models were used for modelling OS. Here, a cure fraction was derived; cured patients followed general population mortality, whereas patients who were not followed fitted parametric survival curves. The Committee considered this method appropriate, but also found the cure fraction, a key driver of results, to be highly uncertain. The Committee for NICE TA567 considered a 1-knot spline extrapolation appropriate but insisted more long-term data were needed to decide the point after which patients are assumed to follow general population mortality. In all three NICE TAs, CAR-Ts were recommended for the Cancer Drugs Fund due to uncertainties in OS data. While ICER’s assessment yielded favorable cost-effectiveness results, nine of 13 voters stressed the significant uncertainty around long-term clinical benefits. Both ICER and NICE noted the uncertainty with extrapolating short-term survival data beyond trial period for CAR-Ts but appeared to accept the use of mixture-cure and spline models over traditional parametric survival modelling to represent their potential curative nature. Longer follow-up data should be collected to confirm long-term survival benefit of CAR-Ts.

Device profile of the Vici venous stent for chronic iliofemoral venous obstruction recanalization: overview of its safety and efficacy

ABSTRACT Introduction: Endovenous stenting is being increasingly used for the management of iliofemoral venous outflow obstruction due to thrombotic or non-thrombotic iliac vein lesions (NIVL). Dedicated venous stents have replaced re-purposed arterial stents but there are limited data on their relative safety and efficacy. Areas covered: This review looks at the available literature on the safety and efficacy of the Veniti Vici Venous stent (Boston Scientific), a specific venous stent, and compares its outcomes with the other venous stents that are currently available. Reported outcomes include patency, clinical efficacy, and the number of adverse events. Expert opinion: The initial clinical trials of the Vici venous stent have shown both good clinical and safety outcomes at 12–24 months follow-up. Longer follow-up data are pending and further trials comparing available stents are required. Current evidence supports its use in the management of deep venous reconstruction, especially in occlusive post-thrombotic disease. Patients should, however, be made aware of the paucity of long-term data and the need for monitoring within a dedicated surveillance program following stent placement.

Elective Endovascular Versus Open Repair of Abdominal Aortic Aneurysm - Current Long-Term Data

Four randomized clinical trials prospectively compared endovascular (EVAR) and open repair (OR) of abdominal aortic aneurysm (AAA): Chronologically these are EVAR 1 (UK), DREAM (Netherlands), OVER (USA) and ACE (France). All of them investigated whether the superior early postoperative outcome of endovascular repair is maintained in the long-term. The longest follow-up data of EVAR 1, with a mean person-years observation (either until death or end of study) of 8 years, clearly question the superiority of EVAR. In this context, open repair of AAA takes on a new significance and the indication for endovascular repair should be critically assessed with regard to the long-term course. Indication for invasive treatment has not changed and should - apart from exceptions - only be given for men with a diameter of 5,5 cm or more. Furthermore, current studies on prophylactic mesh reinforcement after open repair of AAA show that incisional hernias can be safely avoided.

Transanal total mesorectal excision: the Slagelse experience 2013–2019

To describe outcomes after transanal total mesorectal excision (TaTME) 5years from implementation at a large-volume colorectal unit, including local recurrence, distant metastasis, and survival. Transanal total mesorectal excision (TaTME) is a relatively new procedure for mid- and low-rectal cancer, with well-documented safety and feasibility. However, data on long-term results are limited. This study was based on a prospective data collection via a maintained database in a large colorectal unit. The database included patients who underwent TaTME from December 2013 through July 2019. We have updated the database through a review of patient charts, including radiology and pathology reports. Data collection included operative details, intraoperative findings, postoperative complications, pathologic results, and oncologic results. During the study period, two hundred patients underwent TaTME in the study period (men = 147). The mean BMI was 26.7%, and the mean tumor height from the anal verge was 7.86cm. Neoadjuvant treatment was given to 22% of patients. Anastomotic leakage occurred in 9.3% of patients, and the overall rate of postoperative complications was 24.5%. The TME specimen was incomplete in 11% of patients, and the CRM was positive in 5.5% of patients. Local recurrence (LR) occurred in seven patients with a follow-up of at least 2 years (4.7%). Distant metastasis (DM) occurred in 12% of patients. The overall survival was 90% and disease-free survival was 81%. The operating time was reduced in the later period of our experience. This study showed that TaTME is feasible, safe, and had acceptable short-term outcomes and an acceptable rate of LR. The study included, however, one group that was non-randomized, and the follow-up was not long enough for most patients. Studies with longer follow-up data are awaited.

Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update.

11 Background: In the phase 2 CheckMate 142 trial, nivolumab plus low-dose ipilimumab provided robust and durable clinical benefit and was well tolerated as first-line therapy for microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events; 3 (7%) had any grade treatment-related adverse events leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. Nivolumab plus low-dose ipilimumab may represent a new first-line treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

Mitral and aortic paravalvular leaks closure: Insights from the prospective international multicenter FFPP cohort study

Percutaneous paravalvular leak closure (PVLc) has emerged as an alternative to surgery. It remains a technically challenging procedure. We aim to compare outcomes after mitral and aortic PVLc. We analyzed data from PVLc procedures performed over the 2 first years of inclusion in the FFPP (Fermeture de Fuite Périprothétique) study, a prospective observational industry-independent cohort study which started in January 2017. We analyzed 147 PVLc (99 mitral–48 aortic), performed in 127 patients (1 procedure in 109 patients, 2 in 16 and 3 in 2) included in 22 centers among 3 countries (France, Poland and Belgium). Age (69 ± 10 versus 69 ± 11 yo), left ventricular ejection fraction (56 versus 51%), Euroscore2 (9 versus 7.6) and rate of mechanical valve (56.7% versus 41.7%, P = 0.1) were not significantly different among mitral and aortic groups. All patients had heart failure and/or hemolytic anemia. Hemolysis was more common in mitral PVL (62 versus 43%, P = 0.04). A mean of 1.4 (min 1, max 3) and 1.8 (min 1 max 5) devices were respectively required for technically successful aortic and mitral PVLc. No complication was reported in procedures with failure of device implantation. Aortic PVLc were faster than mitral PVLc (1h18 versus 2h20), with a trend towards a higher rate of technical success (96% versus 87%, P = 0.1) and fewer rate of major adverse events (worsening hemolysis, stroke, life threatening events and deaths; 2% versus 14%, P = 0.02). At 1 month follow-up, events were reported in 2% of patients (blood transfusion for hemolysis) versus 26.2% (deaths 3.3%; hemolysis 14.8%; heart failure 3.3%; heart failure and hemolysis 4.9%) after successful aortic and mitral PVLc respectively, P = 0.6. Mitral PVLc is a more complex procedure than aortic PVLc, with a lower success rate and a higher risk of peri-procedural and one-month severe adverse events. Longer follow-up data are expected and will be available from this on-going study.

Outcomes Analysis of Endovascular Repair for Giant Abdominal Aortic Aneurysms

Introduction: Aortic aneurysm diameter has been reported to be a predictor of poor outcomes in the long-term follow-up: in particular, previous analysis showed that the risk of complications is increased and outcomes following repair are worse when diameter exceeds 80 mm. Since the more the aorta enlarges the more the anatomy increases in complexity, open surgical repair has been the method of treatment of almost all larger aneurysms reported in Literature so far. The aim of this paper is to report the results of endovascular repair (EVAR) of “giant” abdominal aortic aneurysms (g-AAAs). Methods: This is a multicenter, observational cohort registry-based study with retrospective analysis of all AAAs extrapolated from the 5014 patients enrolled in the Global Registry for Endovascular Aortic Treatment (GREAT). Main outcomes were primary technical success, freedom from aortic-related mortality (ARM), and freedom from device-related reinterventions. Results: One-hundred twenty-eight (2.5%) cases were treated. There were 115 (89.8%) males. All AAAs involved the infrarenal aorta; in 14 (11%) cases the aneurysmal disease involved one common iliac artery at least. Overall, mean age was 74 ± 8 (range, 50-92) and the mean AAA diameter was 91 mm ± 10 (range, 81-150). Primary technical success was achieved in all cases. In-hospital and EVAR-related mortality was never observed. At a mean follow-up of 444 days, neither rupture nor aorto-enteric fistulization was observed. Ten (7.8%) patients required aortic-related reintervention and conversion to open repair occurred in 1 (0.8%) only. An endoleak was detected in 9 (7%) cases (type 2, n = 6; type 1a (n = 3). At 12 months window, aneurysm sac stabilization or shrinkage was observed in 92% of the cases. Conclusion: Preliminary “real-world” experience of EVAR for g-AAAs shows that g-AAA is a rare event, and that EVAR has satisfactory outcomes at short-term follow-up. Although concerns remain for long-term durability, EVAR-related complications rate was acceptably low with no additional aortic-related mortality. Longer follow-up data are expected to confirm durability of these results. Disclosure: Nothing to disclose

Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia

Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia

PCN358 COMPARING AND VALIDATING THE OVERALL SURVIVAL EXTRAPOLATIONS FOR IMMUNO-ONCOLOGY TREATMENTS APPLIED IN HTA'S BY NOMA AND TLV

To compare the extrapolation of overall survival (OS) in reimbursement submissions of Immuno-Oncology (IO) treatments by the Norwegian Medical Agency (NoMA) and the Dental and Pharmaceutical Benefits Board (TLV), and to validate the OS extrapolation using longer-term trial data that have been published after the health technology appraisals (HTA). This study follow the same overall approach as Bullement et al. (2019), who published a review and validation of OS extrapolation in IO assessments published by NICE. Appraisals of programed death-ligand 1 (PD-L1) treatments published by NoMA and TLV were identified from the agencies’ webpage, and Kaplan-Meier curves and extrapolation methods used in the agency base-case were extracted. A targeted literature search was conducted to identify if longer follow-up on OS had been published. This study only included cases that 1) had a published assessment report from both agencies; and 2) had longer follow-up data on OS published after the HTA assessment. Agency base-cases were recreated by digitizing Kaplan-Meier curves, creating pseudo individual patient level data and applying the base-case extrapolations to these data. Comparison and validation of extrapolations were assessed by visual inspection and by investigating how mean OS estimates were affected by applying the base-case extrapolation to the longer-term follow-up data. Seven cases that fulfilled the inclusion criteria were identified. Graphical representation showed significant variation in long-term OS extrapolation between the agencies that mostly underestimated long-term OS. Applying the base case extrapolation methods to later data-cuts resulted in increased long-term OS estimations. This study demonstrate variation in long-term OS extrapolation of NoMA and TLV in IO HTA’s. Standard parametric survival extrapolations do not seem to capture the potential long-term OS, which suggests that alternative approaches to OS extrapolation of IO treatments, e.g. mixture cure or response based models, are needed.