Delaying anterior cruciate ligament reconstruction for more than 3 or 6 months results in lower risk of revision surgery.

BACKGROUND: The objective of this study is to investigate the risk of revision surgery when delaying anterior cruciate ligament reconstruction (ACLR) past 3 months or 6 months after injury. MATERIALS AND METHODS: A total of 30,280 patients with isolated ACLR were identified in the Danish Knee Ligament Reconstruction Registry and divided into four groups; ACLR < 3 months, > 3 months, < 6 months, or > 6 months after injury. Primary outcome was revision surgery and secondary outcome were objective and subjective clinical outcome. The 2 year relative risk, crude, and adjusted hazard ratio (HR) were calculated. RESULTS: Comparing ACLR < 3 months to ACLR > 3 months of injury the 2 year relative risk of revision surgery was found to be 1.81 (95% CI 1.46-2.23; P < 0.001) with an adjusted hazard ratio (HR) of 1.27 (95% CI 1.12-1.44; P < 0.001). Comparing ACLR < 6 months to ACLR > 6 months of injury the 2 year relative risk of revision surgery was found to be 1.61 (95% CI 1.34-1.92; P < 0.001) with an adjusted HR of 1.27 (95% CI 1.15-1.40; P < 0.001). CONCLUSION: The risk of revision ACLR surgery was found to be increased when ACLR was performed within 3 months or 6 months of injury compared with later surgery. The 1 year postoperative objective knee laxity and the subjective patient-related outcome was found to be without a clinically significant difference; however, those with early ACLR (< 3 months or < 6 months) were found to have a higher activity level 1 year postoperatively. The information about increased risk of revision when having early surgery should be informed to patients when deciding timing of ACLR treatment. LEVEL OF EVIDENCE: II.

Seven percent of primary anterior crucial ligament reconstruction patients have arthroscopic resection of cyclops lesions within 2 years: A cohort study of 2556 patients.

PURPOSE: After anterior cruciate ligament reconstruction (ACL-R), a localised scar tissue called cyclops lesion may develop anterior to the graft causing knee extension deficits, pain, oedema, clicking and reduced knee function. This study determined the incidence of arthroscopic resection of a cyclops lesion within 2 years after ACL-R and investigated the associations of patient characteristics and surgical techniques with the need for arthroscopic resection of a cyclops lesion. METHODS: This study included patients who underwent primary ACL-R with adult surgical technique from 2005 to 2019 at Aarhus University Hospital, Denmark. The cohort was identified in a national registry. To identify patients who had resected a cyclops lesion within the first 2 years after ACL-R, patients' surgical records were reviewed. RESULTS: In 2005-2019, 2556 patients underwent primary ACL-R; 176 developed cyclops lesions that were resected within 2 years, equivalent to an incidence of 6.9% (95% confidence interval [CI]: 5.9-7.9). When stratified by the femoral drilling technique used, this incidence was 8.9% (95% CI: 7.7-10.3) with the anteromedial technique and 1.9% (95% CI: 1.0-3.1) with the transtibial technique. The incidence was 8.5% (95% CI: 6.8-10.3) in women and 5.7% (95% CI: 4.6-7.1) in men. Age, graft choice and the presence of cartilage or meniscal lesions did not affect the incidence. CONCLUSION: The overall incidence of a cyclops lesion removal within 2 years post-ACL-R was 6.9%. This was five times higher with the anteromedial femoral drilling technique than with the transtibial technique. Women had a 47% higher incidence of cyclops lesion removal than men. This is relevant for the surgeon when planning an ACL-R. LEVEL OF EVIDENCE: Level II.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Efficacy of intravenous high-dose methotrexate in preventing relapse to the central nervous system in R-CHOP(-like)-treated, high-risk, diffuse large B-cell lymphoma patients and its effect on mortality: a systematic review and meta-analysis.

CNS relapse in patients with diffuse large B-cell lymphoma (DLBCL) carries a dismal prognosis with most clinical guidelines recommending CNS prophylaxis to patients deemed at high risk for CNS relapse. However, results from observational studies investigating the effect of CNS prophylaxis have yielded conflicting results. OBJECTIVES: To evaluate: 1) whether addition of prophylactic intravenous HD-MTX reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar and 2) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. METHODS: A systematic search of MEDLINE/PubMed and EMBASE on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar receiving HD-MTX as intervention and a comparator arm receiving no prophylaxis and/or IT prophylaxis. Risk of Bias was estimated using the ROBINS-I tool and the quality of the evidence by the GRADE approach. Finally, a meta-analysis based on the systematic review was conducted. RESULTS: A total of 1812 studies were screened. No RCT's were identified. Seven observational studies comprising 1661 patients met inclusion criteria. We found a statistically non-significant relative risk of 0.54 [0.27-1.07, 95% CI] of CNS relapse for patients receiving HD-MTX vs. controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 [0.44-1.11, 95% CI] for HD-MTX treated vs. controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as low. CONCLUSION: Our data indicate that HD-MTX does not prevent, or at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.

Mutational landscape in Waldenström macroglobulinemia evaluated using a next-generation sequencing lymphoma panel in routine clinical practice.

Next-generation sequencing (NGS) affords comprehensive insights into the genomic landscape of lymphomas. We examined the mutational pattern in patients with Waldenström macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL) as well as the diagnostic and clinical utility of a tailored NGS lymphoma panel. A consecutive series of 45 patients was reviewed and NGS analysis was performed as part of a routine diagnostic setup. The custom designed NGS panel assayed all coding sequences of 59 genes of known clinical significance in lymphoid neoplasms. The most frequently mutated genes were MYD88, CXCR4, BIRC3, CD79B, and ARID1A. Additional somatic mutations were detected in 17 genes with four mutations categorized as pathogenic or likely pathogenic. BIRC3 and TP53 mutations were associated with adverse clinical phenotypes. NGS performance for the MYD88L265P variant was 96% when compared to qPCR. In conclusion, targeted NGS provided important diagnostic and prognostic information in a routine clinical setting.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

LUMINA: Using molecular biomarkers to guide decision making for breast radiotherapy.

In this opinion piece, we respond to comments about the LUMINA trial by Meattini and colleagues in the Journal. LUMINA was a prospective cohort study which evaluated the omission of radiotherapy after breast conserving surgery (BCS) in patients treated with endocrine therapy with low risk clinico-pathologic features and luminal A breast cancer. We address their areas of concern including the single cohort design that required careful patient selection, the relatively short follow-up period of 5 years, and the limited follow-up on younger patients. The Ki67 biomarker was key to defining the luminal A phenotype. We clarify the evidence supporting the Ki67 criteria used. The compliance with endocrine therapy was high and similar to other contemporary trials. Based on the results of LUMINA, and mounting evidence from other trials, we feel comfortable offering our patients the option of no radiotherapy after BCS if they fit the trial eligibility criteria from LUMINA and have decided to receive adjuvant endocrine therapy. We concur that a patient-centered approach to treatment decision making should be used to make patients aware of all available information including the results of the LUMINA trial when deciding on post-operative breast radiotherapy.

Single- or two-stage revision after failed ACL reconstruction: No differences in re-revision rates and clinical outcomes.

PURPOSE: The surgeons' choice of a single-stage or a two-stage procedure in revision anterior cruciate ligament reconstruction (ACLr) is based on the possibility of reuse of the tibia and femoral bone tunnels after primary ACLr. The purpose of this study was to compare failure rates and clinical outcomes following single-stage and two-stage ACL revisions in a cohort of patients from The Danish Knee Ligament Reconstruction Registry. METHODS: Patients identified from 2005 to 2022 with ACL revision and met the following criteria: minimum 2-year follow-up, isolated ACL revision and registered single- or two-stage ACL revision. The primary outcome was ACL re-revision rate. Secondary outcomes were arthrometer sagittal knee laxity (side-to-side difference) and pivot shift (rotational stability difference) evaluated at 1-year follow up. RESULTS: One thousand five hundred seventy-four ACL revisions were included in the study (1331 = single-stage and 243 = two stage). Baseline characteristics showed no difference in relation to age, gender, knee laxity, pivot shift, meniscus injury, cartilage damage or injury mechanism between the two groups. Significant differences were found in relation to the type of graft. No statistical difference in 2-years revision rates between single-stage group 2.79 (95% CI 2.03-3.84) and two-stage group 2.93 (95% CI 1.41-6.05) was found. No significant difference was seen in knee laxity and pivot shift between stage-groups at 1-year follow up. Both groups demonstrated significant improvements in knee stability from baseline to 1-year follow-up. CONCLUSION: The present study found that ACL revision outcomes were similar in terms of rerevision rates and knee laxity for patients managed with a single- or a two-stage surgical strategy. LEVEL OF EVIDENCE: Level III.

Men treated with BEACOPP for Hodgkin lymphoma may be at increased risk of testosterone deficiency.

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors.

Breast Cancer Histopathology in the Age of Molecular Oncology.

For more than a century, microscopic histology has been the cornerstone for cancer diagnosis, and breast carcinoma is no exception. In recent years, clinical biomarkers, gene expression profiles, and other molecular tests have shown increasing utility for identifying the key biological features that guide prognosis and treatment of breast cancer. Indeed, the most common histologic pattern-invasive ductal carcinoma of no special type-provides relatively little guidance to management beyond triggering grading, biomarker testing, and clinical staging. However, many less common histologic patterns can be recognized by trained pathologists, which in many cases can be linked to characteristic biomarker and gene expression patterns, underlying mutations, prognosis, and therapy. Herein we describe more than a dozen such histomorphologic subtypes (including lobular, metaplastic, salivary analog, and several good prognosis special types of breast cancer) in the context of their molecular and clinical features.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

The Risk of Growth Disturbance Is Low After Pediatric Anterior Cruciate Ligament Reconstruction With a Femoral Growth Plate Sparing Technique.

Purpose: To evaluate radiological tibial and femoral length and axis growth disturbances, as well as clinical outcome in skeletal immature anterior cruciate ligament reconstruction (ACLR) patients treated with a femoral growth plate-sparing ACLR technique. Methods: Skeletally immature patients who underwent operation between 2013 to 2019 with ALCR using the femoral growth plate-sparing technique were investigated with follow-up after growth plate closure. The inclusion criteria were isolated ACL rupture in patients with open physis in the distal femur and proximal tibia seen at plain radiography. The minimum follow-up time was 29 months. Patients were evaluated with full extremity radiographs measuring limb length discrepancy and coronal knee alignment compared to contralateral leg, as well as clinical evaluation with Rolimeter measurements and the Knee Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee subjective knee form (IKDC), and Tegner Activity Scale scores. Results: Sixty-five patients were examined with radiography, and 52 patients were assessed with clinical examination. The mean follow-up time was 68 (range, 29-148) months. No limb-length discrepancy (-0.65 mm [confidence interval {CI}, -2.21 to 0.92]) or angular deformity at tibia (-0.25° [CI, -0.78° to 0.28°]) was found. There was a small but statistically significant different angular deformity at the distal femur compared to the contralateral leg (-1.51° [CI, -2.31 to -0.72]) at follow-up. The side-to-side difference in knee laxity at follow-up was 2.4 mm. At follow-up the KOOS Sport, KOOS Quality of Life (QoL), IKDC, and Tegner scores were 80, 75, 86, and 5, respectively. Sixty-seven percent of the patients met the Patient Acceptable Symptom State, and 52% reported results exceeding the KOOS Sport MCID Level and 69% the KOOS QoL level. Conclusions: Femoral physis-sparing ALCR is associated with a low risk of alignment and length disturbances. The technique provides otherwise good subjective clinical outcome and knee stability. Level of Evidence: Level IV, therapeutic case series.

Low-load exercises with concurrent blood flow restriction as rehabilitation for unspecific knee pain to a former American football player: A case report.

Former athlete, 30 years of age, suffered several months of moderate anterior knee pain during daily life activities where daily life activities such as negotiating stairs and lifting heavy objects were moderately painful. Magnetic resonance imaging showed normal meniscus and cruciate ligaments and no extra joint fluid. The patient was referred to a physiotherapist who introduced a strengthening program. Low-load resistance training with concurrent blood flow restriction can induce significant gains in maximal muscle strength and mass with minimal exacerbation of knee-joint pain. We describe the outcome of 12 weeks low-load resistance training with concurrent blood flow restriction as a rehabilitation method for anterior knee pain. The patient performed low-load resistance training with concurrent blood flow restriction for the lower limbs (goblet squat, single-leg knee extensions and flexions). After the low-load resistance training with concurrent blood flow restriction, the patient increased isometric knee extensor muscle strength (31%), single-leg hop test performance (23%), obtained clinically relevant improvements in patient-reported outcomes and was able to return to his usual high-loading training regime. Low-load resistance training with concurrent blood flow restriction seems promising to transition patients back to a healthy lifestyle of training and being physically active.

Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability.

The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.

Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes.

PURPOSE: To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression-based "intrinsic" subtypes luminal A, luminal B, HER2-enriched, and basal-like. METHODS: A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. RESULTS: The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for the combined model (subtype and tumor size) was a significant improvement on either the clinicopathologic model or subtype model alone. The intrinsic subtype model predicted neoadjuvant chemotherapy efficacy with a negative predictive value for pCR of 97%. CONCLUSION: Diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer. The prognostic properties of the continuous risk score will be of value for the management of node-negative breast cancers. The subtypes and risk score can also be used to assess the likelihood of efficacy from neoadjuvant chemotherapy.

Combined anterior cruciate ligament revision with reconstruction of the antero-lateral ligament does not improve outcome at 2-year follow-up compared to isolated acl revision; a randomized controlled trial.

PURPOSE: It is essential to obtain rotational stability of the knee after anterior cruciate ligament reconstruction (ACL-R) and it is suggested that a supplementary reconstruction of the antero-lateral ligament (ALL-R) may supports this. Theoretically, ALL-R may be particularly advantageous to support revision of failed ACL-Rs. It was hypothesized that ACL revision combined with ALL-R will result in superior outcome compared to isolated ACL revision. METHODS: The study was designed as a randomized controlled trial. Patients eligible for first time ACL revision were randomized to either isolated ACL revision (- ALL group) or ACL revision combined with a single-stranded allograft ALL-reconstruction (+ ALL group). Patient reported outcomes and function were evaluated at two-year follow-up by KNEES-ACL, KOOS, and Tegner activity scale. Objective knee laxity was evaluated at one-year follow-up using an instrumented Rolimeter test, the pivot shift test, and a manual Lachman test. RESULTS: A total of 103 patients were enrolled with 49 patients randomized to the + ALL group and 54 patients in the - ALL group. There were no differences at baseline between groups regarding age, gender, body mass index, preoperative patient reported outcome scores and concomitant meniscus or cartilage injury. The ACL revision was performed with an allograft in 10 patients (20%) in the + ALL group and 8 patients (15%) in the -ALL group. At follow-up there was no significant difference between the groups in patient reported outcome scores and clinical knee laxity. CONCLUSION: Supplementary ALL-R does not improve subjective outcome of first time ACL revision at two-years and clinical knee stability at one-year follow-up compared to isolated ACL revision. LEVEL OF EVIDENCE: Level I.

Ki67 assessment protocol as an integral biomarker for avoiding radiotherapy in the LUMINA breast cancer trial.

AIMS: The LUMINA trial demonstrated a very low local recurrence rate in women ≥55 years with low-risk luminal A breast cancer (defined as grade I-II, T1N0, hormone receptor positive, HER2 negative and Ki67 index ≤13.25%) treated with breast-conserving surgery and endocrine therapy (but no other systemic therapy), supporting the safe omission of radiation in these women. Here we describe the protocol for Ki67 assessment, the companion diagnostic used to guide omission of adjuvant radiotherapy. METHODS: Ki67 immunohistochemistry was performed on full-face sections at one of three regional labs. Pathologists trained in the International Ki67 in Breast Cancer Working Group (IKWG) method demarcated tumour areas on scanned slides and scored 100 nuclei from each of at least five randomly selected 1-mm fields. For cases with high Ki67 heterogeneity, further virtual cores were selected and scored in order to confidently assign a case as luminal A (≤13.25%) or B (>13.25%). Interlaboratory variability was assessed through an annual quality assurance programme during the study period. RESULTS: From the quality assurance programme, the mean Ki67 index across all cases/labs was 13%. The observed intraclass correlation coefficient (ICC) and kappa statistics were ≥0.9 and ≥0.7, respectively, indicating a substantial level of agreement. Median scoring time was 4 min per case. The IKWG-recommended scoring method, performed directly from slides, requiring up to four scored fields, is concordant with the LUMINA scoring method (ICC ≥ 0.9). CONCLUSION: Ki67 is a practical, reproducible, and inexpensive biomarker that can identify low-risk luminal A breast cancers as potential candidates for radiation de-escalation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01791829.

Patient-reported Outcomes and Muscle Strength after a Physiotherapy-led Exercise and Support Brace Intervention in Patients with Acute Injury of the Posterior Cruciate Ligament: A Two-year Follow-up Study.

Background: While outcomes of posterior cruciate ligament (PCL) injuries treated surgically are well described, prospective studies reporting outcomes of exercise interventions are lacking. Purpose: The purpose of this study was to investigate changes in patient-reported outcomes of a physiotherapy-led exercise and support brace intervention in patients with acute injury of the PCL over a two-year follow-up period. Furthermore, this study sought to investigate changes in isometric knee muscle strength over an eight-month follow-up period, and finally to report conversion to surgical reconstruction over a two-year follow-up period. Study design: Case series study, prospective. Methods: Fifty patients with an acute injury of the PCL were treated with a brace and a physiotherapy-led exercise intervention and followed prospectively. Changes in patient-reported outcomes were measured with the International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) and the Knee injury and Osteoarthritis Outcome Score (KOOS) from baseline (diagnosis) to two-year follow-up. Furthermore, changes in isometric knee flexion and extension strength were measured with a static strength dynamometer from 16 weeks after diagnosis to one-year follow-up. Conversion to surgery was prospectively extracted from medical records. Mean changes were analyzed with a mixed effects model with time as a fixed factor. Results: The IKDC-SKF score improved 28 (95%CI 24-33) IKDC points from baseline to two-year follow-up. Isometric knee flexion strength of the injured knee increased 0.18 (95%CI 0.11-0.25) Nm/kg from 16 weeks after diagnosis to one-year follow-up, corresponding to an increase of 16%. In contrast, isometric knee extension strength of the injured knee did not change (0.12 (95%CI 0.00-0.24) Nm/kg, p=0.042). Over two years, seven patients converted to PCL surgical reconstruction. One and two-year follow-up were completed by 46 and 31 patients, respectively. Conclusions: The physiotherapy-led exercise and support brace intervention demonstrated clinically relevant improvements in patient-reported outcomes and knee flexion strength, and the risk of PCL surgical reconstruction was considered low within the first two years. Level of evidence: 3b©The Author(s).

Similar outcomes after anterior cruciate ligament reconstruction in paediatric and adult populations: a 1-year follow-up of 506 paediatric operations in Denmark.

PURPOSE: To present 1-year results after all paediatric anterior cruciate ligament (ACL) reconstructions in Denmark (5.9 M inhabitants) for the 10½ year period, 1 July 2011 to 31 December 2021. METHODS: All children who had an ACL reconstruction were enrolled. They were asked to complete Pedi-IKDC preoperatively and at 1-year follow-up. Independent observers performed pivot shift test and instrumented laxity assessment preoperatively and at 1-year follow-up. RESULTS: The median age of the 506 children (47.2% girls) was 14.3 years (9.3-15.9). The Pedi-IKDC score increased from preoperatively 61.6 ± 15.8 (mean ± SD) to 85.9 ± 13.0 at 1-year follow-up (p < 0.0001). There were concomitant injuries (to meniscus and/or cartilage) in 49.9%, but these children had preoperative and follow-up Pedi-IKDC scores similar to the scores for children with isolated injury to ACL (n. s.). Instrumented anterior laxity was 4.3 ± 1.4 (mean ± SD) mm preoperatively and 1.4 ± 1.4 mm at follow-up (p < 0.0001). Preoperatively, 3% had no pivot shift whilst this was the case for 68% postoperatively (p < 0.0001). Twenty-five children (5.6%) had 4 mm instrumented laxity or more relative to the unoperated knee at follow-up. Two patients (0.4%) had an operatively treated deep infection, three (0.5%) were operated on for reduced range of motion and two (0.4%) had a revision ACL reconstruction. CONCLUSION: ACL reconstruction resulted in a clinically meaningful increase in Pedi-IKDC, an improved instrumented stability, a reduction in the grade of pivot shift and the complication rate was low at 1-year follow-up. The risk of graft insufficiency at 1-year follow-up was the same as in an adult population. LEVEL OF EVIDENCE: II.

Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).