Percutaneous interstitial brachytherapy ablation for targeting oligometastatic gynecologic cancers.

INTRODUCTION: Treatment of recurrent oligometastatic gynecologic malignancy may involve targeted surgery, thermal ablation, or CT-guided high-dose-rate interstitial brachytherapy ablation (CT-HDR-IBTA). The purpose of this study was to describe the safety and efficacy of CT-HDR-IBTA for oligometastatic gynecologic malignancies. METHODS: With institutional review board approval (IRB) approval and compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliance, we searched our database to assemble a single-arm study cohort of all patients with oligometastatic gynecologic cancers who underwent CT-HDR-IBTA from 2012-2022 with follow-up. The electronic record was reviewed to determine relevant clinicopathological variables including patient demographics, prior treatments, clinical course, local control, and local and distant recurrence with follow-up imaging. RESULTS: The study cohort comprised 37 lesions in 34 patients treated with CT-HDR-IBTA for recurrent oligometastatic uterine (n = 17), cervix (n = 1), or ovarian cancer (n = 16) with an average lesion size of 2.5 cm with an average patient age of 61.4 years. Each lesion was treated with an average radiation dose of 23.8 Gy in 1.8 fractions and a median follow-up time of 24.0 months. The primary efficacy of CT HDR ITBA was 73% with a median progression-free survival of 8.0 months (95% CI 3.6-12.8 months) and with 58% of patients still alive at 43 months with median overall survival not reached. The rate of Grade 1 adverse events was 22% without any Grade 2, 3 or 4 events. CONCLUSIONS: CT HDR IBTA was safe and effective for treating oligometastatic gynecologic cancers in a heavily pretreated cohort.

RECIST 1.1 Target Lesion Categorical Response in Metastatic Renal Cell Carcinoma: A Comparison of Conventional versus Volumetric Assessment.

Purpose To investigate Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) approximations of target lesion tumor burden by comparing categorical treatment response according to conventional RECIST versus actual tumor volume measurements of RECIST target lesions. Materials and Methods This is a retrospective cohort study of individuals with metastatic renal cell carcinoma enrolled in a clinical trial (from 2003 to 2017) and includes individuals who underwent baseline and at least one follow-up chest, abdominal, and pelvic CT study and with at least one target lesion. Target lesion volume was assessed by (a) Vmodel, a spherical model of conventional RECIST 1.1, which was extrapolated from RECIST diameter, and (b) Vactual, manually contoured volume. Volumetric responses were determined by the sum of target lesion volumes (Vmodel-sum TL and Vactual-sum TL, respectively). Categorical volumetric thresholds were extrapolated from RECIST. McNemar tests were used to compare categorical volume responses. Results Target lesions were assessed at baseline (638 participants), week 9 (593 participants), and week 17 (508 participants). Vmodel-sum TL classified more participants as having progressive disease (PD), compared with Vactual-sum TL at week 9 (52 vs 31 participants) and week 17 (57 vs 39 participants), with significant overall response discordance (P < .001). At week 9, 25 (48%) of 52 participants labeled with PD by Vmodel-sum TL were classified as having stable disease by Vactual-sum TL. Conclusion A model of RECIST 1.1 based on a single diameter measurement more frequently classified PD compared with response assessment by actual measured tumor volume. Keywords: Urinary, Kidney, Metastases, Oncology, Tumor Response, Volume Analysis, Outcomes Analysis ClinicalTrials.gov registration no. NCT01865747 © RSNA, 2023 Supplemental material is available for this article.

A Multicenter Assessment of Interreader Reliability of LI-RADS Version 2018 for MRI and CT.

Background Various limitations have impacted research evaluating reader agreement for Liver Imaging Reporting and Data System (LI-RADS). Purpose To assess reader agreement of LI-RADS in an international multicenter multireader setting using scrollable images. Materials and Methods This retrospective study used deidentified clinical multiphase CT and MRI and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 to August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS version 2018 category was computed as a rescored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1, definitely benign; LR-2, probably benign; LR-3, intermediate probability of malignancy; LR-4, probably hepatocellular carcinoma [HCC]; LR-5, definitely HCC; LR-M, probably malignant but not HCC specific; and LR-TIV, tumor in vein) was computed using intraclass correlation coefficients (ICCs). Agreement was also computed for dichotomized malignancy (LR-4, LR-5, LR-M, and LR-TIV), LR-5, and LR-M. Agreement was compared between research-versus-research reads and research-versus-clinical reads. Results The study population consisted of 484 patients (mean age, 62 years ± 10 [SD]; 156 women; 93 CT examinations, 391 MRI examinations). ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.61, 0.73), 0.63 (95% CI: 0.55, 0.70), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs 0.62, respectively; P = .03) and for dichotomized malignancy (ICC, 0.63 vs 0.53, respectively; P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion There was moderate agreement for LI-RADS version 2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Johnson and Galgano and Smith in this issue.

Contrast-enhanced ultrasound for abdominal image-guided procedures.

INTRODUCTION: Since FDA approval for contrast-enhanced ultrasound (CEUS), clinical applications have increased to include diagnostic imaging of hepatic, renal, and other abdominal lesions. The modality has also demonstrated utility in certain image-guided procedures. Intravascular ultrasound contrast agents use microbubbles to improve visibility of solid tumors. Lesions not well seen on grayscale or Doppler ultrasound may become amenable to CEUS-guided biopsy or ablation. MATERIALS AND METHODS: This pictorial essay provides eleven examples to illustrate the current use of CEUS in a variety of abdominal image-guided procedures. Hepatic, renal, peritoneal, and soft tissue cases are presented. CONCLUSION: CEUS can improve visualization and targeting in abdominal image-guided procedures, without nephrotoxicity or radiation exposure.

The Use of Machine Learning to Reduce Overtreatment of the Axilla in Breast Cancer: Retrospective Cohort Study.

BACKGROUND: Patients with early breast cancer undergoing primary surgery, who have low axillary nodal burden, can safely forego axillary node clearance (ANC). However, routine use of axillary ultrasound (AUS) leads to 43% of patients in this group having ANC unnecessarily, following a positive AUS. The intersection of machine learning with medicine can provide innovative ways to understand specific risks within large patient data sets, but this has not yet been trialed in the arena of axillary node management in breast cancer. OBJECTIVE: The objective of this study was to assess if machine learning techniques could be used to improve preoperative identification of patients with low and high axillary metastatic burden. METHODS: A single-center retrospective analysis was performed on patients with breast cancer who had a preoperative AUS, and the specificity and sensitivity of AUS were calculated. Standard statistical methods and machine learning methods, including artificial neural network, naive Bayes, support vector machine, and random forest, were applied to the data to see if they could improve the accuracy of preoperative AUS to better discern high and low axillary burden. RESULTS: The study included 459 patients; 142 (31%) had a positive AUS; among this group, 88 (62%) had 2 or fewer macrometastatic nodes at ANC. Logistic regression outperformed AUS (specificity 0.950 vs 0.809). Of all the methods, the artificial neural network had the highest accuracy (0.919). Interestingly, AUS had the highest sensitivity of all methods (0.777), underlining its utility in this setting. CONCLUSIONS: We demonstrated that machine learning improves identification of the important subgroup of patients with no palpable axillary disease, positive ultrasound, and more than 2 metastatically involved nodes. A negative ultrasound in patients with no palpable lymphadenopathy is highly indicative of low axillary burden, and it is unclear whether sentinel node biopsy adds value in this situation. Further studies with larger patient numbers focusing on specific breast cancer subgroups are required to refine these techniques in this setting.

Pretreatment visceral metastases in castration resistant metastatic prostate cancer: role in prediction versus actual site of disease progression.

BACKGROUND: To evaluate the anatomic site(s) of initial disease progression in patients with castration resistant metastatic prostate cancer (mCRPC) in the presence or absence of pre-treatment visceral metastases while on systemic therapy. METHODS: This is a retrospective cohort study of mCRPC patients who have baseline and at least one follow up bone scan and CT chest, abdomen and pelvis (CAP). Disease progression was determined by RECIST and/or ≥ 30% increase in automated bone scan lesion area score. Kaplan-Meier plot was used to estimate the median progression free survival and log-rank tests were used to compare anatomic sites. RESULTS: Of 203 patients, 61 (30%) had pre-treatment visceral metastases. Patients with baseline visceral disease were 1.5 times more likely to develop disease progression (HR = 1.53; 95% CI, 1.03-2.26). Disease progression was a result of worsening bone scan disease (42% (16/38)) versus visceral (32% (12/38)) or lymph node disease (3% (1/38)) by CT or a combination thereof (23% (9/38)). Median time to progression (TTP) did not differ by anatomic location of initial progression (p = 0.86). Development of new lesions occurred in 50% of those visceral patients with soft tissue only progression and was associated with a significantly longer TTP (3.1 months (2.8-4.3 months) than those with worsening of pre-existing lesions (1.8 months (1.6-2.7 months); p = 0.04. CONCLUSIONS: Patients with pre-treatment visceral metastases in mCRPC are more likely to experience disease progression of bone disease with the initial anatomic site of progression similar to those without baseline visceral involvement.

The Effect Modification of Ultrasound Risk Classification on Molecular Testing in Predicting the Risk of Malignancy in Cytologically Indeterminate Thyroid Nodules.

Background: Thyroid nodules with indeterminate cytology are increasingly subjected to molecular testing. We evaluated the diagnostic performances of Afirma Genomic Sequencing Classifier (GSC) and ThyroSeq v3 in thyroid nodules with high versus low/intermediate suspicion ultrasound classification. Methods: In this prospective cohort study, we analyzed all Bethesda III and IV thyroid nodules that underwent fine-needle aspiration biopsies in the University of California Los Angeles Health System from July 2017 to April 2020. All patients underwent molecular testing with Afirma GSC or ThyroSeq v3 as part of an institutional randomized trial (NCT02681328). Nodules were categorized according to the American Thyroid Association (ATA) ultrasound risk classification. The benign call rate and the positive predictive value of molecular testing were compared between ATA high suspicion versus all other categories. Results: A total of 343 patients with 375 indeterminate thyroid nodules were included. The malignancy rate in ATA high suspicion nodules was not significantly increased by a suspicious Afirma GSC result (77.8% for all ATA high suspicion nodules vs. 87.5% for nodules with ATA high suspicion and suspicious Afirma GSC results, positive likelihood ratio [LR] = 2.0, 95% confidence interval [CI 0.5-8.0], p = 1.0) or by a positive ThyroSeq v3 result (80.0% vs. 80.0%, positive LR = 1.0 [CI 1.0-1.0], p = 1.0). The rate of malignancy in ATA low/intermediate suspicion nodules increased from 21.0% to 56.3% with a suspicious Afirma GSC result (positive LR = 4.8 [CI 3.4-6.9], p < 0.0001) and decreased to 3.8% with a benign Afirma GSC result (negative LR = 0.1 [CI 0.07-0.3], p < 0.0001). Similarly, the rate of malignancy in ATA low/intermediate suspicion nodules increased from 24.3% to 66.7% with a positive ThyroSeq v3 result (positive LR = 6.2 [CI 4.0-9.7], p < 0.0001) and decreased to 2.1% with a negative ThyroSeq v3 result (negative LR = 0.07 [CI 0.02-0.3], p < 0.0001). Conclusions: Afirma GSC and ThyroSeq v3 performed well in ruling out malignancy in sonographically low/intermediate suspicion thyroid nodules but has limited diagnostic value in sonographically high suspicion nodules. Molecular testing can prognosticate more aggressive thyroid cancers, which can inform treatment decisions.

Breast MRI in patients after breast conserving surgery with sentinel node procedure using a superparamagnetic tracer.

BACKGROUND: A procedure for sentinel lymph node biopsy (SLNB) using superparamagnetic iron-oxide (SPIO) nanoparticles and intraoperative sentinel lymph node (SLN) detection was developed to overcome drawbacks associated with the current standard-of-care SLNB. However, residual SPIO nanoparticles can result in void artefacts at follow-up magnetic resonance imaging (MRI) scans. We present a grading protocol to quantitatively assess the severity of these artefacts and offer an option to minimise the impact of SPIO nanoparticles on diagnostic imaging. METHODS: Follow-up mammography and MRI of two patient groups after a magnetic SLNB were included in the study. They received a 2-mL subareolar dose of SPIO (high-dose, HD) or a 0.1-mL intratumoural dose of SPIO (low-dose, LD). Follow-up mammography and MRI after magnetic SLNB were acquired within 4 years after breast conserving surgery (BCS). Two radiologists with over 10-year experience in breast imaging assessed the images and analysed the void artefacts and their impact on diagnostic follow-up. RESULTS: A total of 19 patients were included (HD, n = 13; LD, n = 6). In the HD group, 9/13 patients displayed an artefact on T1-weighted images up to 3.6 years after the procedure, while no impact of the SPIO remnants was observed in the LD group. CONCLUSIONS: SLNB using a 2-mL subareolar dose of magnetic tracer in patients undergoing BCS resulted in residual artefacts in the breast in the majority of patients, which may hamper follow-up MRI. This can be avoided by using a 0.1-mL intratumoural dose.

A Randomized Phase II Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab in Patients with Advanced Gastrointestinal Stromal Tumors.

PURPOSE: Most gastrointestinal stromal tumors (GIST) are driven by KIT/PDGFRa mutations. Tyrosine kinase inhibitor benefit is progressively less after imatinib failure. This phase II trial analyzed the efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in patients with refractory GIST. PATIENTS AND METHODS: Patients with advanced/metastatic GIST refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded phase II trial of N (240 mg every 2 weeks) or N + I (240 mg every 2 weeks + 1 mg/kg every 6 weeks). The primary endpoint was the objective response rate of N alone or N+I by RECIST 1.1 in the intent-to-treat population. RESULTS: A total of 36 patients with a median of 3 (1-6) prior lines of therapies were enrolled. Ten of 19 (52.6%) patients had stable disease (SD) for a clinical benefit rate (CBR) of 52.6% in the N arm and the median progression-free survival (PFS) was 11.7 weeks [95% confidence interval (CI), 7.0-17.4]. In the N+I arm, 1 of 16 (6.7%) patients had a complete response (CR) and 4/16 (25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3 weeks (95% CI, 5.6-22.2). The 4- and 6-month PFS were 42.1% and 26.3%, respectively for N, and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AE) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were nine total attributable grade 3-4 AEs. CONCLUSIONS: The primary endpoint of response rate > 15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long-term disease control with both N and N+I were observed. No new safety signals have been observed.

Optimization of SPIO Injection for Sentinel Lymph Node Dissection in a Rat Model.

The magnetic technique, consisting of a magnetic tracer and a handheld magnetometer, is a promising alternative technique for sentinel lymph node dissection (SLND) and was shown to be non-inferior to the standard technique in terms of identification rates. In this study, injection characteristics (iron dose, dilution, time course and massaging) were evaluated to optimize magnetic tracer uptake in the sentinel lymph nodes (SLN) in a rat hindleg model. 202 successful SLNDs were performed. Iron uptake in the SLN is proportional (10% utilization rate) to the injection dose between 20 and 200 µg, showing a plateau uptake of 80 µg in the SLN around 1000 µg injection. Linear regression showed that time had a higher impact than dilution, on the SLN iron uptake. Massaging showed no significant change in iron uptake. The amount of residual iron at the injection site was also proportional to the injection dose without any plateau. Time was a significant factor for wash-out of residual iron. From these results, preoperative injection may be advantageous for SLN detection as well as reduction in residual iron at the injection site by potential decrease in required injection dose.

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.

BACKGROUND: The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. METHODS: In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. RESULTS: Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091. CONCLUSION: TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. TRIAL REGISTRATION: ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

A Primer on RECIST 1.1 for Oncologic Imaging in Clinical Drug Trials.

Drug discovery and approval in oncology is mediated by the use of imaging to evaluate drug efficacy in clinical trials. Imaging is performed while patients receive therapy to evaluate their response to treatment. Response criteria, specifically Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and can be used at different time points to classify response into the categories of complete response, partial response, stable disease, or disease progression. At the trial level, categorical responses for all patients are summated into image-based trial endpoints. These outcome measures, including objective response rate (ORR) and progression-free survival (PFS), are characteristics that can be derived from imaging and can be used as surrogates for overall survival (OS). Similar to OS, ORR and PFS describe the efficacy of a drug. U.S. Food and Drug Administration (FDA) regulatory approval requires therapies to demonstrate direct evidence of clinical benefit, such as improved OS. However, multiple programs have been created to expedite drug approval for life-threatening illnesses, including advanced cancer. ORR and PFS have been accepted by the FDA as adequate predictors of OS on which to base drug approval decisions, thus substantially shortening the time and cost of drug development (1). Use of imaging surrogate markers for drug approval has become increasingly common, accounting for more than 90% of approvals through the Accelerated Approval Program and allowing for use of many therapies which have altered the course of cancer. Keywords: Oncology, Tumor Response RSNA, 2021.

A systematic review of neo-adjuvant radiotherapy in the treatment of breast cancer.

INTRODUCTION: The use of neo-adjuvant radiotherapy (NRT) has been proven effective at improving cancer related outcome measures, including overall-survival (OS) in the management of solid cancers. However, its utilisation in breast cancer has not been explored to the extent of neo-adjuvant chemotherapy (NAC). The evidence for the application of NRT in breast cancer is evaluated. METHODS: PubMed, Embase and the Cochrane Library databases were searched systematically in August 2020 for studies that addressed the role of NRT in the treatment of breast cancer. Studies were deemed eligible if they reported on objective outcome measurements of OS, disease free-survival (DFS) or pathological complete response (pCR) and attained a satisfactory quality assessment. FINDINGS: A total of 23 studies reported upon 3,766 patients who had received NRT of which 3,233 also received NAC concurrently (neo-adjuvant chemo-radiotherapy (NCRT)). The pCR values ranged from 14% to 42%, 5-year DFS 61.4% to 81% and 5-year OS 71.6% to 84.2%. Complications were confined to radiation dermatitis with no cases of implant loss reported during breast reconstruction. The application of NRCT alone showed no significant difference in OS or DFS compared to NCRT followed by surgery. INTERPRETATION: Numbers of patients receiving exclusively NRT is small. However, NCRT is oncologically safe with a low side-effect profile including preceding breast reconstruction. Potential benefits include precise cancer volume targeting, chemosensitisation, elimination of delays in adjuvant therapies and alternatives to chemotherapy in oestrogen receptor positive patients. These factors warrant further exploration within randomised controlled-trials.

Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules: A Randomized Clinical Trial.

IMPORTANCE: Approximately 20% of thyroid nodules display indeterminate cytology. Molecular testing can refine the risk of malignancy and reduce the need for diagnostic hemithyroidectomy. OBJECTIVE: To compare the diagnostic performance between an RNA test (Afirma genomic sequencing classifier) and DNA-RNA test (ThyroSeq v3 multigene genomic classifier). DESIGN, SETTING, AND PARTICIPANTS: This parallel randomized clinical trial of monthly block randomization included patients in the UCLA Health system who underwent thyroid biopsy from August 2017 to January 2020 with indeterminate cytology (Bethesda System for Reporting Thyroid Cytopathology category III or IV). INTERVENTIONS: Molecular testing with the RNA test or DNA-RNA test. MAIN OUTCOMES AND MEASURES: Diagnostic test performance of the RNA test compared with the DNA-RNA test. The secondary outcome was comparison of test performance with prior versions of the molecular tests. RESULTS: Of 2368 patients, 397 were eligible for inclusion based on indeterminate cytology, and 346 (median [interquartile range] age, 55 [44-67] years; 266 [76.9%] women) were randomized to 1 of the 2 tests. In the total cohort assessed for eligibility, 3140 thyroid nodules were assessed, and 427 (13.6%) nodules were cytologically indeterminate. The prevalence of malignancy was 20% among indeterminate nodules. The benign call rate was 53% (95% CI, 47%-61%) for the RNA test and 61% (95% CI, 53%-68%) for the DNA-RNA test. The specificities of the RNA test and DNA-RNA test were 80% (95% CI, 72%-86%) and 85% (95% CI, 77%-91%), respectively (P = .33); the positive predictive values (PPV) of the RNA test and DNA-RNA test were 53% (95% CI, 40%-67%) and 63% (95% CI, 48%-77%), respectively (P = .33). The RNA test exhibited a higher PPV compared with the prior test version (Afirma gene expression classifier) (54% [95% CI, 40%-67%] vs 38% [95% CI, 27%-48%]; P = .01). The DNA-RNA test had no statistically significant difference in PPV compared with its prior version (ThyroSeq v2 next-generation sequencing) (63% [95% CI, 48%-77%] vs 58% [95% CI, 43%-73%]; P = .75). Diagnostic thyroidectomy was avoided in 87 (51%) patients tested with the RNA test and 83 (49%) patients tested with the DNA-RNA test. Surveillance ultrasonography was available for 90 nodules, of which 85 (94%) remained stable over a median of 12 months follow-up. CONCLUSIONS AND RELEVANCE: Both the RNA test and DNA-RNA test displayed high specificity and allowed 49% of patients with indeterminate nodules to avoid diagnostic surgery. Although previous trials demonstrated that the prior version of the DNA-RNA test was more specific than the prior version of the RNA test, the current molecular test techniques have no statistically significant difference in performance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02681328.

Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.

OBJECTIVE: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer. DESIGN: Prospective, open label, randomised controlled clinical trial. SETTING: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada. PARTICIPANTS: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT). INTERVENTIONS: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients). MAIN OUTCOME MEASURES: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes. RESULTS: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005). CONCLUSION: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned. TRIAL REGISTRATION: ISRCTN34086741, NCT00983684.

Diagnostic Value of Molecular Testing in Sonographically Suspicious Thyroid Nodules.

OBJECTIVE: Molecular testing can refine the diagnosis for the 20% of thyroid fine-needle aspiration biopsies that have indeterminate cytology. We assessed the diagnostic accuracy of molecular testing based on ultrasound risk classification. METHODS: This retrospective cohort study analyzed all thyroid nodules with indeterminate cytology at an academic US medical center (2012-2016). All indeterminate nodules underwent reflexive molecular testing with the Afirma Gene Expression Classifier (GEC). Radiologists performed blinded reviews to categorize each nodule according to the American Thyroid Association (ATA) ultrasound classification and the American College of Radiology Thyroid Imaging, Reporting and Data System. GEC results and diagnostic performance were compared across ultrasound risk categories. RESULTS: Of 297 nodules, histopathology confirmed malignancy in 65 (22%). Nodules by ATA classification were 8% high suspicion, 44% intermediate, and 48% low/very low suspicion. A suspicious GEC result was more likely in ATA high-suspicion nodules (81%) than in nodules of all other ATA categories (57%; P = .04). The positive predictive value (PPV) of GEC remained consistent across ultrasound categories (ATA high suspicion, 64% vs all other ATA categories, 48%; P = .39). The ATA high-suspicion category had higher specificity than a suspicious GEC result (93% vs 51%; P < .01). A suspicious GEC result did not increase specificity for the ATA high-suspicion category. CONCLUSION: The PPV of molecular testing remained consistent across ultrasound risk categories. However, a suspicious GEC result was very likely in ATA high-suspicion nodules and did not improve specificity in this sonographic category.