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.).

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.

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.

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.

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.

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.

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.

Next generation sequencing in routine diagnostics of mature non-Hodgkin's B-cell lymphomas.

INTRODUCTION: Integration of molecular characterization of lymphomas in clinical diagnostics may improve subclassification and risk-stratification, and we implemented a next generation sequencing (NGS) analysis as part of routine diagnostic work-up of all mature B-cell non-Hodgkin's lymphoma (B-NHL). Here, we present data of mutational profiles with potential complementary diagnostic, prognostic, and predictive value detected in our consecutive non-selected cohort of B-NHL patients. METHODS: NGS results from 298 patients with both newly diagnosed and relapsed/refractory disease were included as a single center study. NGS was performed as routine analysis together with standard diagnostic work-up using a custom-made amplicon PCR-based multiplex NGS panel covering all coding exons and consensus splice sites in 59 genes. RESULTS: Mutations were detected in 94% of the 298 samples. Most lymphomas could be classified definitively, but 24 cases were classified as small B-cell lymphomas without defining characteristics. Of these, 50% (12/24 cases) could retrospectively be assigned a likely diagnostic subtype according to mutational findings. CONCLUSION: Implementation of a 59 gene exome sequencing panel added diagnostic value to 50% of unclassified cases and provided in 94% of the cases possible biomarkers for disease monitoring as well as potential diagnostic, prognostic, and predictive markers for future studies.

Outcome of limited-stage peripheral T-Cell lymphoma after CHOP(-like) therapy: A population based study of 239 patients from the Nordic lymphoma epidemiology group.

Peripheral T-Cell Lymphomas (PTCLs) are rare, aggressive lymphomas with poor outcomes, but limited-stage disease is infrequent and not well-described. This study reports outcomes and prognostic factors in limited-stage nodal PTCLs in a binational population-based setting. Patients were identified from the Danish and Swedish lymphoma registries. Adults diagnosed with limited-stage nodal PTCL (stage I-II) and treated with CHOP(-like) therapy ±radiotherapy between 2000 and 2014 were included. Medical records were reviewed by local investigators. A total of 239 patients with a median age of 62 years were included; 67% received 6-8 cycles of CHOP(-like) therapy and 22% received 3-4 cycles, of which 59% also received radiotherapy. Autologous stem cell transplant consolidation was administered to 16% of all patients. Median follow-up was 127 months with 5-years overall survival (OS) of 58% (95% CI: 53-65) and progression-free survival (PFS) of 53% (95% CI: 47-59). In multivariable analysis, age ≥ 60 years and B-symptoms were unfavorable and ALK+ anaplastic large cell T-Cell lymphoma was favorable for survival outcomes. There was no difference in treatment-specific outcome (3-4 cycles vs. 6-8 cycles of CHOP(-like) ± radiotherapy). Low-risk patients (age < 60 without B-symptoms) had a 5-year OS of 77% (95% CI 67-89%). In the present study of limited-stage nodal PTCL, survival after curative intent chemotherapy +/- radiotherapy was inferior to that of limited-stage diffuse large B-cell lymphoma, but a subgroup of young patients without B-symptoms had very good outcomes. Treatment outcomes after 3-4 cycles versus 6-8 cycles of CHOP(-like) therapy were comparable.

A systematic review and meta-analysis of beta-blockers and renin-angiotensin system inhibitors for preventing left ventricular dysfunction due to anthracyclines or trastuzumab in patients with breast cancer.

AIMS: Trastuzumab and anthracyclines, often used in the treatment of breast cancer, may impair myocardial function, and reduce left ventricular ejection fraction (LVEF), potentially causing heart failure. Randomized controlled trials (RCTs) have evaluated the effects of beta-blockers (BBs), angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACEI) on trastuzumab- and anthracycline-associated cardiotoxicity. We report a meta-analysis of these RCTs in patients with breast cancer. METHODS AND RESULTS: The primary analysis was on the effect of BBs and ACEI/ARBs on LVEF in patients treated with either trastuzumab or anthracyclines. A secondary analysis was done investigating the effect of BBs or ACEI/ARBs on LVEF in trastuzumab and anthracycline treatments. Only RCTs were included using the search term 'ARBs, ACEIs, BBs, anthracyclines, trastuzumab, and breast cancer' in PubMed, Embase, and CENTRAL up to 31 March 2021. A meta-analysis was conducted to estimate the mean difference (MD) in LVEF between intervention and placebo groups at follow-up. A total of nine RCTs (n = 1362) were included in the analysis. All patients were women. BBs and ACEI/ARBs were shown to attenuate the decline in LVEF during trastuzumab and anthracycline treatments [MD: 2.4; 95% confidence interval (CI): 0.3-4.2 and MD: 1.5; 95% CI: -0.6 to 3.7]. Compared with placebo, LVEF was significantly higher in patients assigned to BB or ACEI/ARB on trastuzumab (MD: 2.3; 95% CI: 0.0-4.6) but not on anthracyclines (MD: 1.9; 95% CI: -0.5 to 4.2). CONCLUSION: Both BB and ACEI/ARB therapies were associated with the preservation of LVEF during trastuzumab and anthracycline-containing regimens as compared with placebo, suggesting both to be beneficial.

Adjustable-loop implants are non-inferior to fixed-loop implants for femoral fixation in anterior cruciate ligament reconstruction.

PURPOSE: Button implants with an adjustable-loop device (ALD) are often used in anterior cruciate ligament reconstruction (ACLR). Clinical research comparing ALDs with fixed-loop devices (FLD) has mainly been conducted in small patient populations with short follow-up times. To determine whether ALDs are safe to use in ACLR, a non-inferiority study with a large sample population and a long follow-up period would be beneficial. This study compared ALDs with FLDs to determine non-inferior revision surgery rates, knee stability, and patient-reported outcomes (PROM) in ACLRs. METHODS: This non-inferiority register-based cohort study was conducted using data from the Danish Knee Ligament Reconstruction Registry (DKRR). A total of 12,723 patients > 15 years of age with primary ACLR using hamstring tendon autografts and either an FLD or ALD for femoral fixation were included: 9719 patients were in the FLD group, and 3014 patients were in the ALD group. The primary outcome was revision ACLR with a non-inferiority margin for ALDs at 4% at the 2-year follow-up. The secondary outcomes were anterior and rotatory knee stability and PROMs based on the Knee Injury and Osteoarthritis Outcome Score (KOOS) at the 1-year follow-up. RESULTS: The crude cumulative revision rates in ALD implants at 2 and 5 years were 2.1% (95% CI 1.62-2.68) and 5.0% (95% CI 4.22-5.96), respectively. In the FLD group, the rates were 2.2% (95% CI 1.89-2.48) at 2 years and 4.7% (95% CI 4.31-5.20) at 5 years. The 1-year side-to-side differences were 0.97 mm (95% CI 0.90-1.03) in the ALD group and 1.45 mm (95% CI 1.41-1.49) in the FLD group. In the FLD group, 13% had a positive pivot shift, and in the ALD group, 6% had a positive pivot shift. There were no differences in KOOS. CONCLUSION: ALDs were non-inferior to FLDs regarding revision rates, knee stability, and patient-reported outcomes. Based on this conclusion, ALDs are safe to use for femoral fixation in ACLR. LEVEL OF EVIDENCE: III.

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.

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.

Advances in sarcoma molecular diagnostics.

Sarcomas are cancers of mesenchymal origin with the potential to arise in diverse anatomic locations. With over 80 subtypes, which often demonstrate overlapping morphologies, sarcomas frequently require ancillary testing to enable accurate classification. Pathognomonic driver mutations can often be leveraged for diagnostic purposes and include fusion genes, amplification events, and recurrent point mutations. Until relatively recently, the major clinical molecular diagnostic tests have been karyotyping, fluorescence in situ hybridization, and polymerase chain reaction; however, these techniques have a number of limitations. Recent technological advances have led to the development of more comprehensive assays with higher throughput, thereby replacing the need for a suite of single gene tests. These approaches include next-generation sequencing, fluorescent bar code hybridization, and DNA methylation profiling, among others. Herein, we review the application of recently developed techniques relevant to the diagnosis of sarcomas, and emerging assays with the potential for future development and clinical implementation.

Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study.

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error (p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections (p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.

SRY-box transcription factor 10 is a highly specific biomarker of basal-like breast cancer.

AIMS: Basal-like breast cancer is an aggressive molecular subtype associated with younger age and early relapse. Most cases lack expression of oestrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, limiting targeted therapeutic options. Basal-like breast cancer is defined by the expression of genes in the outer/basally located epithelial layer of mammary glands, including those encoding cytokeratin (CK) 5 and CK14, and epidermal growth factor receptor (EGFR). SRY-box transcription factor 10 (SOX10), for which there is a readily available immunohistochemical stain, is expressed in a subset of breast cancers, particularly triple-negative carcinomas. In this study, we sought to: (i) assess the association between SOX10 expression and intrinsic molecular subtypes as defined by Prediction Analysis of Microarray 50 (PAM50) gene expression; and (ii) compare the performance of SOX10 with that of other surrogate markers of the basal-like subtype, including CK5, EGFR, nestin, and inositol polyphosphate 4-phosphatase type II (INPP4B). METHODS AND RESULTS: SOX10 immunostaining was performed on tissue microarrays constructed from a contemporary series enriched for ER-negative and weakly ER-positive cancers that had also undergone PAM50 gene profiling. A total of 211 cases were informative for both SOX10 immunohistochemistry and PAM50 subtype, including 103 basal-like cancers. Staining for SOX10 was positive in 73 of 103 basal-like cancers and in only two of 108 cancers of other subtypes (P < 0.001), resulting in a sensitivity of 70.9% and a specificity of 98.1%. SOX10 was more specific than the other tested basal markers, and the results were independent of ER status. CONCLUSIONS: SOX10 is a moderately sensitive, but highly specific, immunohistochemical biomarker for the basal-like intrinsic subtype of breast cancer, which, unlike other commonly used immunohistochemical biomarkers, is independent of hormone receptor status.

A high level of knee laxity after anterior cruciate ligament reconstruction results in high revision rates.

PURPOSE: The literature indicates a lack of consensus on the correlation between knee laxity after anterior cruciate ligament reconstruction (ACLR) and subjective clinical outcomes and the need for revision surgery. Therefore, using high-volume registry data, this study aimed to describe the relationship between objective knee laxity after ACLR and subjective symptom and functional assessments and the need for revision surgery. The hypothesis was that greater postoperative knee laxity would correlate with inferior patient-reported outcomes and a higher risk for revision surgery. METHODS: In this study, 17,114 patients in the Danish knee ligament reconstruction registry were placed into three groups on the basis of objective side-to-side differences in sagittal laxity one year after surgery: group A (≤ 2 mm), Group B (3-5 mm) and Group C (> 5 mm). The main outcome measure was revision rate within 2 years of primary surgery, further outcome measures were the knee injury and osteoarthritis outcome score (KOOS) as well as Tegner activity score. RESULTS: The study found the risk for revision surgery was more than five times higher for Group C [hazard ratio (HR) = 5.51] than for Group A. The KOOS knee-related Quality of Life (QoL) sub-score exhibited lower values when comparing Groups B or C to Group A. In addition, the KOOS Function in Sport and Recreation (Sport/Rec) sub-score yielded lower values for groups B and C in comparison with Group A. CONCLUSION: These results indicate that increased post-operative sagittal laxity is correlated with an increased risk for revision surgery and might correlate with poorer knee-related QoL, as well as a decreased function in sports. The clinical relevance of the present study is that high knee laxity at 1-year follow-up is a predictor of the risk of revision surgery. LEVEL OF EVIDENCE: III.

A clinical calculator to predict disease outcomes in women with triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by substantial risks of early disease recurrence and mortality. We constructed and validated clinical calculators for predicting recurrence-free survival (RFS) and overall survival (OS) for TNBC. METHODS: Data from 605 women with centrally confirmed TNBC who underwent primary breast cancer surgery at Mayo Clinic during 1985-2012 were used to train risk models. Variables included age, menopausal status, tumor size, nodal status, Nottingham grade, surgery type, adjuvant radiation therapy, adjuvant chemotherapy, Ki67, stromal tumor-infiltrating lymphocytes (sTIL) score, and neutrophil-to-lymphocyte ratio (NLR). Final models were internally validated for calibration and discrimination using ten-fold cross-validation and compared with their base-model counterparts which include only tumor size and nodal status. Independent external validation was performed using data from 478 patients diagnosed with stage II/III invasive TNBC during 1986-1992 in the British Columbia Breast Cancer Outcomes Unit database. RESULTS: Final RFS and OS models were well calibrated and associated with C-indices of 0.72 and 0.73, as compared with 0.64 and 0.62 of the base models (p < 0.001). In external validation, the discriminant ability of the final models was comparable to the base models (C-index: 0.59-0.61). The RFS model demonstrated greater accuracy than the base model both overall and within patient subgroups, but the advantages of the OS model were less profound. CONCLUSIONS: This TNBC clinical calculator can be used to predict patient outcomes and may aid physician's communication with TNBC patients regarding their long-term disease outlook and planning treatment strategies.

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice.

Immune 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.