Citations

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(<60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function >grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.

503 Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.

AbstractImmune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objective To analyze the clinical outcomes, knee function, and activity level of patients after treatment of full-thickness cartilage defects involving the patellofemoral compartment of the knee with cryopreserved osteochondral allograft. Design Nineteen patients with cartilage defects involving the patellofemoral compartment were treated. The average age was 31 years (range 15-45 years), including 12 females and 7 males. Patients were prospectively followed using validated clinical outcome measures including Veterans RAND 12-item Health Survey (VR-12), International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Tegner activity scale. Graft incorporation was evaluated by magnetic resonance imaging (MRI) or second-look arthroscopy. Results The cartilage defects included the patella ( n = 16) and the femoral trochlea ( n = 3). Mean VR-12 scores increased from 31.6 to 46.3 ( P < 0.01), mean IKDC increased from 40.0 to 69.7 ( P < 0.01), mean KOOS increased from 53.9 to 80.2 ( P < 0.01), and mean Tegner scores increased from 3.0 to 4.9 ( P < 0.01), at average follow-up of 41.9 months (range 24-62 months). Of the 3 patients who underwent second-look arthroscopy, all demonstrated a well-incorporated graft. Mean MOCART score for the 6 patients with follow-up MRI was 62.5 (range 25-85). The reoperation rate was 21.1% and 2 patients (12.5%) experienced progressive patellofemoral osteoarthritis requiring conversion to patellofemoral arthroplasty. Conclusion Patients with unipolar cartilage defects involving the patellofemoral compartment of the knee can have positive outcomes at minimum 2-year follow-up after surgical treatment with a cryopreserved osteochondral allograft when concomitant pathology is also addressed, but the reoperation rate is high and bipolar cartilage lesions may increase the failure rate.

BackgroundDistal iliotibial band friction syndrome (ITBFS) is a common cause of knee pain in endurance athletes. Nonsurgical treatment is usually successful, but surgery is occasionally required for recalcitrant cases. No published studies to date have evaluated the feasibility of an ultrasound‐guided (USG) partial iliotibial band (ITB) release.ObjectiveTo determine the feasibility of an USG partial ITB release using a cutting wire. A secondary aim was to assess whether adjacent structures were damaged. We hypothesized that the posterior distal ITB could be partially transected with a cutting wire under USG with no injury to adjacent structures.DesignCadaveric study.SettingQuaternary‐care academic institute.ParticipantsTen cadaveric knees ranging from 76‐89 years old with a mean body mass index of 21.9 kg/m2.InterventionsOne physician sonographer performed USG releases of the posterior ITBs at the level of the lateral femoral epicondyle with a cutting wire. Dissection was carried out by an independent second physician to assess for primary and secondary outcomes.Main Outcome Measures(1) Release of the posterior border of the ITB; (2) width of the release; (3) evaluation for any injury to adjacent structures; (4) technical difficulty of the procedure (0 = no difficulty, 10 = most difficult procedure possible); (5) duration of time it took to complete the procedure.ResultsAll 10 knees had the posterior border of the ITB transected. Mean release length was 16 mm (range 15‐17), which was within 1 mm of the target release length of 15 mm. No adjacent structures were damaged.ConclusionA USG release of the posterior ITB utilizing a cutting wire is feasible and safe in a cadaveric model. Translational research is warranted to determine how these results apply to the clinical setting.

6 Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS >0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS >0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC. [Table: see text]

AbstractBuilding on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.

Purpose To determine (1) the demographic characteristics as well as radiographic findings of medial versus lateral meniscal root tears at time of presentation, (2) treatment decisions and clinical outcomes of patients undergoing medial versus lateral root repair, and (3) risk factors for worse clinical and radiographic outcomes. Methods A retrospective review was performed to identify patients with symptomatic, medial, or lateral meniscus posterior root tears with a minimum 2‐year follow‐up. Radiographs were graded using Kellgren‐Lawrence scores. Subanalysis was performed on 62 patients who underwent root repair. Tegner, Lysholm, International Knee Documentation Committee scores, and progression to arthroplasty were analyzed in the repair groups. Patient demographics, radiographic findings, and clinical outcomes were compared between medial meniscus posterior horn root tear (MMRT) and lateral meniscus root repair (LMRT). Results Of the 141 root tears, 109 were MMRTs, 30 were LMRTs, and 2 patients had both. At the time of injury, patients with MMRTs had a significantly higher age (MMRT = 51.4 vs LMRT=24.6, P < .0001), body mass index (MMRT = 32.1 vs LMRT 25.8, P < .0001), Kellgren‐Lawrence score (MMRT = 1.3 vs LMRT=0.6, P < .0001), and higher rate of major meniscal extrusion (MMRT = 72% vs LMRT = 20%, P < .0001). Of the 30 LMRT, 30/30 (100.0%) were treated with meniscal repair. With MMRT, 52/109 (48%) were treated nonoperatively, 27/109 (25%) with partial meniscectomy, and 30/109 (27%) with meniscal repair. Sixty‐two patients underwent meniscus root repair with an average 41‐month follow‐up. LMRT had significantly increased International Knee Documentation Committee (LMRT = 89.5, MMRT = 80.4, P = .02) and Tegner scores (LMRT = 6.5, MMRT = 5.1, P < .05) compared with MMRT. Conclusions Compared with MMRTs, LMRTs occur in younger male patients with lower body mass index, less cartilage degeneration, less extrusion on magnetic resonance imaging, and more commonly with a ligament injury. Although good to excellent clinical outcomes were attained in select patients for both medial and lateral meniscus root repair, LMRTs may have better results after repair, suggesting that differences in injury and patient characteristics may contribute to differences in these outcomes. Level of Evidence Retrospective comparative study, Level III.

AbstractFailed multiligament knee reconstruction is a challenging problem due to recurrent pathologic laxity that is often associated with limb malalignment, meniscus deficiency, articular cartilage insufficiency, decreased motion, compromised bone stock, and a paucity of graft sources. Revision surgical indications and techniques require a comprehensive evaluation of the patient, injury and treatment factors along with a focused physical examination and advanced imaging. A stepwise treatment approach can be effective in the evaluation of revision surgery and also in setting realistic patient goals.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.