Node Tumor Burden Research Articles

PD35-04 QUANTITATIVE PIFLUFOLASTAT F18 (PSMA) SCAN INDICES AS A RESPONSE IMAGING-BIOMARKER TO ANDROGEN DEPRIVATION THERAPY IN VETERANS WITH NEWLY DIAGNOSED METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022PD35-04 QUANTITATIVE PIFLUFOLASTAT F18 (PSMA) SCAN INDICES AS A RESPONSE IMAGING-BIOMARKER TO ANDROGEN DEPRIVATION THERAPY IN VETERANS WITH NEWLY DIAGNOSED METASTATIC PROSTATE CANCER Nicholas Nickols, Gholam Berenji, Nathanael Kane, Karl Sjöstrand, Aseem Anand, Clayton Smith, Jeremie Calais, and Matthew Rettig Nicholas NickolsNicholas Nickols More articles by this author , Gholam BerenjiGholam Berenji More articles by this author , Nathanael KaneNathanael Kane More articles by this author , Karl SjöstrandKarl Sjöstrand More articles by this author , Aseem AnandAseem Anand More articles by this author , Clayton SmithClayton Smith More articles by this author , Jeremie CalaisJeremie Calais More articles by this author , and Matthew RettigMatthew Rettig More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002593.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Standardized quantitative assessment is necessary to associate PSMA imaging with clinical outcome and to establish its clinical utility in management of prostate cancer patients. Assessing changes in bone metastases is a particular challenge with conventional imaging modalities. In this study, we associated the quantitative changes in total PSMA tumor burden in lymph nodes and bone with that of prostate specific antigen (PSA). METHODS: Twenty-one newly diagnosed prostate cancer patients who underwent androgen deprivation therapy with or without radiation were included in this retrospective analysis. A PSMA scan was performed before initiation of treatment with androgen deprivation therapy, with or without radiation. A second PSMA scan was performed at least three months post initiation of treatment in follow-up. As recommended by E-PSMA guidelines, the quantitative metastatic disease burden (of lymph node and bone disease) relative to physiological uptake in blood pool and liver, were calculated using the PROMISE criteria. A deep learning enabled software as a medical device, known as aPROMISE, was used to locate PSMA-avid lesions and track changes over time. The continuous change in quantitative PSMA indices were compared with that of PSA. RESULTS: The DICOM PSMA PET-CT images of all twenty-one patients were successfully analyzed by aPROMISE. The median time between the baseline and post-treatment scan was 20 weeks (IQR 12 to 36 weeks). Fourteen (67%) patients had bone and/or lymph node disease, five (24%) had lymph node only disease, and two did not show metastatic PSMA avid lesions in pre-treatment scan. At treatment follow-up, patients had an average PSA response decline of 97% (median PSA 0.02). Concurrently, the changes in total PSMA indices in lymph node (average decline 80%; IQR: 62% to 100%) and in bone (average decline: 51%; IQR: 14% to 87%) were found to be significantly associated with PSA decline (r=0.74; p=0.0001). CONCLUSIONS: The study demonstrated that the change in the automated PSMA scan indices in bone and lymph node were both significantly associated to the PSA response in androgen deprivation therapy. The PSMA scan index may be a useful measurement of treatment response in bone, which is not feasible with conventional imaging. Source of Funding: Lantheus © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e628 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicholas Nickols More articles by this author Gholam Berenji More articles by this author Nathanael Kane More articles by this author Karl Sjöstrand More articles by this author Aseem Anand More articles by this author Clayton Smith More articles by this author Jeremie Calais More articles by this author Matthew Rettig More articles by this author Expand All Advertisement PDF DownloadLoading ...

Risk Stratification of Prostatic Adenocarcinoma Metastatic to the Lymph Nodes.

The pathologic nodal staging of prostatic adenocarcinoma is binary for regional lymph nodes. Stages pN0 and pN1 indicate the absence or presence of regional nodal metastasis, respectively, whereas patients with metastasis to nonregional lymph nodes are staged as pM1a. To determine the risk of recurrence of pN1 prostatic adenocarcinoma patients based on the extent of nodal tumor burden. We retrospectively reviewed pN1 patients with prostatic adenocarcinoma managed with radical prostatectomy seen between 2011 and 2019. Kaplan-Meier and Cox regression analyses were performed to compare disease-free survival. Ninety-six patients were included (median [interquartile range] age, 62 years [57-67 years]; 70 of 96 [73%] White). On univariate analysis, age >65 years (P = .008), ≥2 positive regional lymph nodes (P < .001), and a maximum size of the tumor deposit ≥2 mm (P = .004) were significantly associated with an unfavorable outcome. Controlling for age, stage, metastatic deposit size, margin status, and the presence of extranodal extension, patients with ≥2 positive regional lymph nodes were 3.03 times more likely (95% confidence interval, 1.39-6.60; P = .005) to have an unfavorable outcome. Patients with pN1M1a stage showed a disease-free survival similar to that of pN1M0 patients, after controlling for the number of positive regional lymph nodes (P = .36). Overall, pN1 patients with ≥2 positive regional lymph nodes are 3 times more likely to have an unfavorable outcome. The results suggest a benefit in further stratifying patients with metastatic prostatic adenocarcinoma to the lymph nodes into prognostically significant risk categories that could help the treating clinicians tailor subsequent patient follow-up and therapy.

Research Progress of Ultrasound Radiomics in Predicting Axillary Lymph Node Metastasis of Breast Cancer

Breast cancer, as the most common malignant tumor in women worldwide, has become the focus of global attention. Axillary lymph node tumor burden is an important prognostic indicator of it. Ultrasound is the most commonly used imaging method, but its sensitivity is not high, especially for the diagnosis of small and micro lymph node metastasis. In recent years, the emerging Radiomics in machine learning field has been widely used in the field of medical imaging. Because it can extract high-level information of images that is difficult to be recognized by human eyes, it has been used to establish clinical prediction models. This paper introduced the value of preoperative sonography, sketched Radiomics, and summarized the research progress of this method in predicting lymph node metastasis of breast cancer. This new method is expected to provide a reliable basis for individualized and accurate diagnosis and treatment of breast cancer.

Clinical and ultrasound features correlated with a heavy axillary nodal tumor burden in colon cancer.

Aim: This study aimed to investigate the correlation between the pathologic and ultrasound (US) characteristics of colon cancer and the heavy axillary nodal burden. Methods: In total, 631 patients diagnosed with invasive colon cancer were recruited with ethical ratification. Results: The unitary pathologic features correlated with heavy axillary lymph nodal burden included the age of patient (p=0.035), tumor size (p=0.001), lymph node metastasis (p=0.001), lymphovascular invasion (p=0.020) and pathology type (p=0.012). The independent US characteristics correlated with heavy axillary nodal burden included posterior acoustic enhancement (p=0.006). Heavy axillary nodal burden was correlated with tumor size, lymph node metastasis, lymphovascular invasion and pathology type. Conclusion: Tumor size, lymph node metastasis and posterior acoustic can be used to predict the axillary lymph node tumor burden.

The sentinel node invasion level (SNIL) as a prognostic parameter in melanoma

Sentinel lymph node (SN) tumor burden is becoming increasingly important and is likely to be included in future N classifications in melanoma. Our aim was to investigate the prognostic significance of melanoma infiltration of various anatomically defined lymph node substructures. This retrospective cohort study included 1250 consecutive patients with SN biopsy. The pathology protocol required description of metastatic infiltration of each of the following lymph node substructures: intracapsular lymph vessels, subcapsular and transverse sinuses, cortex, paracortex, medulla, and capsule. Within the SN with the highest tumor burden, the SN invasion level (SNIL) was defined as follows: SNIL 1 = melanoma cells confined to intracapsular lymph vessels, subcapsular or transverse sinuses; SNIL 2 = melanoma infiltrating the cortex or paracortex; SNIL 3 = melanoma infiltrating the medulla or capsule. We classified 338 SN-positive patients according to the non-metric SNIL. Using Kaplan–Meier estimates and Cox models, recurrence-free survival (RFS), melanoma-specific survival (MSS) and nodal basin recurrence rates were analyzed. The median follow-up time was 75 months. The SNIL divided the SN-positive population into three groups with significantly different RFS, MSS, and nodal basin recurrence probabilities. The MSS of patients with SNIL 1 was virtually identical to that of SN-negative patients, whereas outgrowth of the metastasis from the parenchyma into the fibrous capsule or the medulla of the lymph node indicated a very poor prognosis. Thus, the SNIL may help to better assess the benefit-risk ratio of adjuvant therapies in patients with different SN metastasis patterns.

Safety, Efficacy and MRD Negativity of a Combination of Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

Safety, Efficacy and MRD Negativity of a Combination of Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

Delphi, a Data Warehouse to Discover Associations between Variables in Clinical Trials: Application to the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial

Background and aims. Data collection in clinical trials is becoming complex, with huge amount of clinical and biological variables that need to be recorded, verified and analyzed to confirm obvious and identify unexpected associations. Outside the medical field, data warehouses (DWs) are widely employed to achieve these objectives. To verify whether DWs might be useful for data quality and association analysis, a team of clinicians, biologists, statisticians and biomedical engineers developed DELPHI (“Data ELaboration to Predict Hypothetical assocIations”). The tool has been suited to a large clinical trial from the Fondazione Italiana Linfomi (FIL), including all the clinical, biological and mutational features collected both in the trial and in the ancillary studies. Herein we present the first results, related to baseline variables: 1) creation of a broad DW (including 350 variables for 300 patients, thus > 105data); 2) data harmonization and quality control; 3) discovery of unexpected associations and (in a later phase) outcome correlations; 4) results visualization.Methods. Data were retrieved from electronic case reporting forms (eCRF) of the phase III, multicenter “FIL-MCL0208” trial (NCT02354313) for younger, untreated mantle cell lymphoma patients [Cortelazzo, EHA 2015], now at the second interim analysis. DW was created with Mysql®, a relational database management system, already used in many apps. DW filling, data cleaning and statistical analysis were performed via Matlab®. For this preliminary analysis 62 baseline features from 300 subjects were organized in groups of demographics, clinical, laboratory, pathological, minimal residual disease, gene expression profiling (GEP) and mutational variables. A first data quality control was performed. Secondly, a team of 3 lymphoma experts claimed the expected associations among about 1860 couples of features conveniently categorized. The original series was randomly divided in two subsets (200 vs 100 subjects): the first used for discovery and the second as a validation set. For each subset, couples were screened by Chi-square and Fisher's test as appropriate (p<0.05), then Cramer's V coefficients were calculated to assess the statistical strength of association. Couples from discovery set confirmed by validation-set were selected. Hence, selected couples were overlapped to the previously declared “clinical expectations” to extrapolate the unexpected ones, suggested by the analysis. Data visualization was performed via Circos [Krzywinski, Gen Res 2009].Results. Quality Control: DELPHI allowed cross comparison analysis and detected many incongruities in eCRF, prompting request for queries to clinical centers, which allowed data corrections - e.g. data quality increase has been recorded for classical laboratory (+7%), biological (+40%) and clinical data (up to 99.6% of correctness). Testing associations: DELPHI identified 231/1860 (12%) associations in the discovery set, of whom 64% (149/231) were confirmed in the validation set. Among these mismatches, main contribution is imputed to associations between clinical and laboratory data with baseline tumor burden by quantitative PCR, qPCR, (n=21) and mutational data (n=11). The clinical team classified as “expected” 242/1860 variables matches (13%), 54% of whom were confirmed by DELPHI (Figure 1A). The thickest ribbons have V>0.5: among these, bone marrow tumor invasion (BMinf) by immunohistochemistry with nodal (NLTB) and extra-nodal (ENLTB) tumor burden at CT scan; Lymphocytes with BMinf by Flow cytometry (Flow). TP53 mutations and blastoid histology with a V=0.39. Finally, discovery of novel associations is shown in Figure 1B. 54 of 1860 (3%) matches were identified by DELPHI as statistically significant unexpected associations: the thickest ribbons have V>0.35. Among these, MIPI, albumin and LDH with Hemoglobin; BMinf by qPCR with MIPIc. Moreover, TP53 mutations and GammaGT (V=0.34), as well as NOTCH1 mutations with ALkaline-Phosphatase (V=0.35) and MIPIb with Beta2 Microglobulin, B2M (V=0.33).Discussion. DELPHI DW is a powerful tool that identifies novel putative associations between clinical and biological features. In order to consider confounding interactions and multiple comparison issues, every association needs further validation on independent data series. The association of baseline data with post-treatment outcomes is ongoing. [Display omitted] DisclosuresGalimberti:Novartis: Speakers Bureau; Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Gaidano:AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Boccadoro:AbbVie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding.

Sentinel node tumor burden in cutaneous melanoma. Survival with competing risk analysis and influence in relapses and non-sentinel node status: retrospective cohort study with long follow-up in a Spanish population.

Several authors have studied the potential of sentinel lymph node (SLN) tumor burden as prognostic factor but the microscopic classifications used in different study groups were variable. We examined the prognostic role of tumor burden in SLN on melanoma specific-survival and competing causes of death. We also analysed clinical and histological factors as predictors of disease relapses and additional non sentinel lymph node (NSLN) metastases. We included all patients with cutaneous melanoma that underwent SLN biopsy between 2002 and 2012 at Complejo Hospitalario de Navarra (Spain). The study end-points were death due to melanoma, melanoma relapse and involvement of NSLN. We used Fine-Gray test for competing risk analysis. A logistic regression model was performed to predict the risk of involvement of NSLN. Between 2002 and 2012, there were 348 patients who underwent SLN biopsy in our centre (308 were eligible for the study). 26.9% patients positive SLN. 88 patients died during the follow-up period and 66 (75%) died from melanoma. The 5-year cumulative incidence of melanoma death was 15.33% (95 % CI 15.25-15.42). The cumulative probability of death from melanoma was associated with gender, histological subtype, Breslow thickness, mitotic rate, ulceration and SLN tumor burden. In multivariable analysis, Breslow thickness and SLN tumor burden remained as independent prognostic factors. SLN tumor burden appears to be an important prognostic factor. It is very important reporting these characteristics in pathological reports. More prospective studies would be necessary to analyze these variables and to be able to make recommendations in management of melanoma patients.

Lymph Node Tumor Burden Correlates With Tumor Budding and Poorly Differentiated Clusters: A New Prognostic Factor in Colorectal Carcinoma?

INTRODUCTION:Molecular lymph node (LN) staging in early colorectal cancer (CRC) has demonstrated to be more precise than conventional histopathology pN staging. Tumor budding (TB) and poorly differentiated clusters (PDCs) are associated with LN metastases, recurrences, and lower survival in CRC. We evaluated the correlation between the total tumor load (TTL) in LNs from CRC surgical specimens with patient outcome, TB, and PDC.METHODS:In this retrospective multicentre study, 5,931 LNs from 342 stage I–III CRC were analyzed by both hematoxylin and eosin and molecular detection of tumor cytokeratin 19 mRNA by one-step nucleic acid amplification. TB and PDC were evaluated by hematoxylin and eosin and cytokeratin 19 immunohistochemistry.Results:One-step nucleic acid was positive in 38.3% patients (n = 131). Tumor Budding was low in 45% cases, intermediate in 25%, and high in 30%. Poorly Differentiated Clusters were low-grade G1 in 53%, G2 in 32%, and G3 in 15%. TB and PDC correlated with TTL, high-grade, lymphovascular and perineural invasion, pT, pN and stage (P < 0.001). TB, PDC, and TTL ≥ 6,000 copies/µL were associated with worse overall survival (P = 0.002, P = 0.013, and P = 0.046) and disease-free survival (P < 0.001).Discussion:The implementation of more sensitive molecular methods to assess LN status is a promising alternative approach to pN staging, which could be integrated to other factors to help risk stratification and management of patients with early-stage CRC. This study demonstrates the correlation of the amount of LN tumor burden with TB and PDCs. TTL is related to the outcome and could be used as a new prognostic factor in CRC (see Visual , Supplementary Digital Content 2, http://links.lww.com/CTG/A512).

Radiomics Analysis for 177Lu-DOTAGA-(l-y)fk(Sub-KuE) Targeted Radioligand Therapy Dosimetry in Metastatic Prostate Cancer-A Model Based on Clinical Example.

177Lu-DOTAGA-(l-y)fk(Sub-KuE) a.k.a. 177Lu-PSMA I&T is currently used for radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) in several centers in Europe. Background: Dosimetry is mandatory according to EU guidelines, although routine methods for dosimetry, i.e., absorbed radiation dose calculations for radiopharmaceuticals, are missing. Methods: We created a model of dosimetric analysis utilizing voxel-based dosimetry and intra-lesion radiomics to assess their practicality in routine dosimetry. Results: As an example for the model, our patient with mCRPC had excellent therapy response; quantitatively more than 97% of the metastatic tumor burden in local and distant lymph nodes and skeleton was destroyed by four cycles of RLT. The absorbed radiation doses in metastases decreased towards later cycles of RLT. Besides the change of prostate-specific membrane antigen (PSMA) concentration and absorbed doses in the tumor, further response to RLT could be predicted from biomarker changes, such as LDH and PSA. Conclusions: Individual dosimetry is needed to understand large variations in tumor doses and mixed responses; for that purpose, routine tools should be developed. The Dosimetry Research Tool (DRT) fluently performed automated organ delineation and absorbed radiation dose calculations in normal organs, and the results in our patient were in good concordance with the published studies on 177Lu-PSMA dosimetry. At the same time, we experienced considerable challenges in voxel-based dosimetry of tumor lesions. Measurements of 177Lu-PSMA activity concentrations instead of absorbed radiation dose calculations could make routine dosimetry more flexible. The first cycle of RLT seems to have quantitatively the biggest impact on the therapy effect. Radiomics analyses could probably aid in the treatment optimization, but it should be tested in large patient populations.

Residual lymph node tumour burden following removal of a single axillary sentinel lymph with macrometastatic disease in women with screen-detected invasive breast cancer.

BackgroundWomen with screen-detected invasive breast cancer who have macrometastatic disease on axillary sentinel lymph node biopsy (SLNB) are usually offered either surgical axillary node clearance (ANC) or axillary radiotherapy. These treatments can lead to significant complications for patients. The aim of this study was to identify a group of patients who may not require completion ANC.MethodsData from the NHS Breast Screening Programme between 1 April 2012 and 31 March 2017 were interrogated to identify women with invasive breast carcinoma and a single sentinel lymph node (SLN) with macrometastatic disease who subsequently proceeded to completion ANC. Univariable and multivariable analyses were performed to identify patients with a single positive SLN who had no further lymph node metastasis on ANC.ResultsOf the 2401 women included in the cohort, the presence of non-sentinel node disease was significantly affected by: the number of nodes obtained at SLNB (odds ratio (OR) 0.49 for retrieval of more than 1 node), invasive size of tumour (OR 1.63 for size greater than 20 mm), surgical treatment (OR 1.34 for mastectomy), human epidermal growth factor receptor (HER) 2 status (OR 0.71 for HER2 positivity), and patient age (OR 1.10 for age less than 50 years; OR 1.46 for age greater than 70 years). Patients aged less than 70 years, with tumour size smaller than 2 cm, more than one node retrieved on SLNB, and who had breast-conserving surgery had a lower chance of positive non-sentinel nodes on completion ANC compared with other patients.ConclusionThis study, of a purely screen-detected breast cancer cohort, identified a subset of patients who may be spared completion ANC in the event of a single axillary SLN with macrometastasis.

Nomogram based on radiomics analysis of primary breast cancer ultrasound images: prediction of axillary lymph node tumor burden in patients.

To establish a prediction model for evaluating the axillary lymph node (ALN) status of patients with T1/T2 invasive breast cancer based on radiomics analysis of US images of primary breast lesions. Between August 2016 and November 2018, a total of 343 patients with histologically proven malignant breast tumors were included in this study and randomly assigned to the training and validation groups at a ratio of 7:3. ALN tumor burden was defined as low (< 3 metastatic ALNs) or high (≥ 3 metastatic ALNs). Radiomics features were obtained using the PyRadiomics package, and the radiomics score was established by least absolute shrinkage and selection operator regression. A nomogram combining the breast cancer US radiomics score with patient age and lesion size was generated based on the multivariate logistic regression results. In the training and validation cohorts, 29.1% (69/237) and 32.08% (34/106) of patients were pathologically diagnosed with more than 2 metastatic ALNs, respectively. The radiomics score consisted of 16 US features, and patient age and lesion diameter identified by US were included to construct the model. The AUC of the model was 0.846 (95% CI, 0.790-0.902) for the training cohort and 0.733 (95% CI, 0.613-0.852) for the validation cohort. The calibration curves showed good agreement between the predictions and observations. Our novel nomogram demonstrates high accuracy in predicting ALN tumor burden in breast cancer patients. We also suggest further development of PyRadiomics to improve US radiomics. • A nomogram based on US was developed to predict ALN tumor burden (low, < 3 metastatic ALNs; high, ≥ 3 metastatic ALNs). • The nomogram could assist clinicians in evaluating treatment strategies for T1/T2 invasive breast cancer.

Axillary nodal metastatic burden in patients with breast cancer with clinically positive axillary nodes.

The aim of this study was to determine preoperative factors and tumour characteristics related to a high nodal tumour burden in patients with clinically node-positive breast cancer. These findings were used to construct a predictive tool to evaluate the patient-specific risk of having more than two axillary lymph node metastases. Altogether, 507 consecutive patients with breast cancer and axillary lymph node metastasis diagnosed by preoperative ultrasound-guided needle biopsy were reviewed. These patients underwent breast surgery and axillary lymph node dissection at Helsinki University Hospital between 2010 and 2014. Patients were grouped into those with one or two, and those with more than two lymph node metastases. There were 153 patients (30·2 per cent) with one or two lymph node metastases and 354 (69·8 per cent) with more than two metastases. Five-year disease-free survival was poorer for the latter group (P =0·032). Five-year overall survival estimates for patients with one or two and those with more than two lymph node metastases were 87·0 and 81·4 per cent respectively (P =0·215). In multivariable analysis, factors significantly associated with more than two lymph node metastases were: age, tumour size, lymphovascular invasion in the primary tumour, extracapsular extension of metastasis in lymph nodes, and morphology of lymph nodes. These factors were included in a multivariable predictive model, which had an area under the curve of 0·828 (95 per cent c.i. 0·787 to 0·869). The present study provides a patient-specific prediction model for evaluating nodal tumour burden in patients with clinically node-positive breast cancer.

Preoperative Axillary Ultrasound Helps in the Identification of a Limited Nodal Burden in Breast Cancer Patients.

Since the Z0011 trial, the clinical evaluation of axillary status has been redirected to predicting nodal tumor burden rather than nodal metastases. Our study aimed to evaluate the value of clinicopathological factors and axillary ultrasound (US) for the prediction of a high nodal burden (≥3 metastatic lymph nodes) in breast cancer patients. A total of 532 consecutive patients who underwent preoperative axillary US and subsequent surgery for clinical T1-2 breast cancer with a final pathologic analysis were included. Clinical and pathologic variables were retrospectively evaluated. Univariate and multivariate statistical analyses were performed to identify the variables that were associated with a high nodal burden. Among the 532 patients, 110 (20.7%) had a high axillary nodal burden and 422 (79.3%) had a limited nodal burden. The multivariate analysis showed that suspicious axillary US findings (P < 0.001), clinical T2 stage (P = 0.011), the presence of lymphovascular invasion (P < 0.001), and estrogen receptor positivity (P < 0.001) were significantly associated with a high nodal burden. Patients with negative axillary US findings seldom had a high nodal burden, with a negative predictive value of 93.0% (294/316). Patients with suspicious axillary US findings, clinical T2 stage, lymphovascular invasion, and estrogen receptor positivity are more likely to have a high nodal burden, which may provide additional information for the treatment plan of breast cancer patients. Preoperative axillary US helps identify a limited nodal burden in breast cancer patients and has implications for axillary lymph node dissection and adjuvant treatment.

The generalisability of randomised clinical trials: an interim external validity analysis of the ongoing SENOMAC trial in sentinel lymph node-positive breast cancer

PurposeNone of the key randomised trials on the omission of axillary lymph node dissection (ALND) in sentinel lymph-positive breast cancer have reported external validity, even though results indicate selection bias. Our aim was to assess the external validity of the ongoing randomised SENOMAC trial by comparing characteristics of Swedish SENOMAC trial participants with non-included eligible patients registered in the Swedish National Breast Cancer Register (NKBC).MethodsIn the ongoing non-inferiority European SENOMAC trial, clinically node-negative cT1–T3 breast cancer patients with up to two sentinel lymph node macrometastases are randomised to undergo completion ALND or not. Both breast-conserving surgery and mastectomy are eligible interventions. Data from NKBC were extracted for the years 2016 and 2017, and patient and tumour characteristics compared with Swedish trial participants from the same years.ResultsOverall, 306 NKBC cases from non-participating and 847 NKBC cases from participating sites (excluding SENOMAC participants) were compared with 463 SENOMAC trial participants. Patients belonging to the middle age groups (p = 0.015), with smaller tumours (p = 0.013) treated by breast-conserving therapy (50.3 versus 47.1 versus 65.2%, p < 0.001) and less nodal tumour burden (only 1 macrometastasis in 78.8 versus 79.9 versus 87.3%, p = 0.001) were over-represented in the trial population. Time trends indicated, however, that differences may be mitigated over time.ConclusionsThis interim external validity analysis specifically addresses selection mechanisms during an ongoing trial, potentially increasing generalisability by the time full accrual is reached. Similar validity checks should be an integral part of prospective clinical trials.Trial registration: NCT 02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015

Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T Cell Product: Updated Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib

Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T Cell Product: Updated Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib

Prognostic relevance of regional lymph-node distribution in patients with N1-positive non-small cell lung cancer: A retrospective single-center analysis

ObjectiveLymph node (LN) metastases predict survival in patients with non-small cell lung cancer (NSCLC) treated with curative surgery. Nevertheless, prognostic differences within the same nodal (N) status have been reported. Consequently, the International Association for the Study of Lung Cancer (IASLC) proposed to stratify patients with limited nodal disease (pN1) from low (pN1a) to high (pN1b) nodal tumor burden. This study aimed to validate the IASLC proposal in a large single-center surgical cohort of patients with pN1 NSCLC. Material and MethodsData from 317 patients with pN1 NSCLC treated between January 2012 and December 2016, were retrospectively analyzed. Associations between distribution of LN metastases and survival were analyzed for different classification models—toward nodal extension (pN1a: one station involved; pN1b: multiple stations involved) and toward location (pN1 in the hilar [LN#10/11] or peripheral zone [LN#12-14]). ResultsTumor-specific survival (TSS) in the entire pN1 cohort was 67.1% at five years. Five-year TSS rates for pN1a and pN1b patients were comparable (67.6% vs. 66.5%, p = 0.623). Significant survival differences from pN1a to pN1b were observed only in patients with adenocarcinoma histology and completed adjuvant chemotherapy (5-year TSS: pN1a, 80.4% vs. pN1b, 49.6%; p = 0.005). TSS for LN metastases in the hilar zone/peripheral zone or in both zones was 68.2% and 59.9%, respectively (p = 0.068). In multivariate analysis, adjuvant chemotherapy, squamous cell histology, and nodal disease limited to one zone nodal disease were identified as independent beneficial prognostic factors (p < 0.05). ConclusionpN1 in only one region (hilar or lobar) was associated with better outcome than metastatic affection of both regions after surgery and adjuvant therapy. A stratification towards single (pN1a) and multiple (pN1b) N1-metastases was found of prognostic relevance only in adenocarcinoma. Prospective multicenter analysis of prognostic subgroups in N1 NSCLC is required to evaluate its clinical impact for consideration in future TNM classification.

The Effect of Regional Node Irradiation on the Thyroid Gland in the Breast Cancer Patients: The Clinical Significance of Optimization of Radiation Target Volume

Although current international consensus recommends considering regional node irradiation (RNI) even in high-risk early-stage breast cancer, the risk of radiotherapy (RT)-related late toxicities including radiation-induced-hypothyroidism (RIH) has been neglected so far. Here, we investigated the long-term contribution of RNI on the risk of RIH and whether optimizing RT target volumes for supraclavicular (SCV) lymph node could minimize its risk. We identified 4,073 patients who received adjuvant RT after surgery for breast cancer between 2007 and 2016 at a single institution. Patients were divided into three groups by the volume of regional RT field: no RNI (n=2,468), low SCV-RNI (cranial border at the subclavian artery according to ESTRO guideline, n=215), and standard-RNI (cranial border at the cricoid cartilage according to RTOG atlas, n=1,390). Development of subclinical or biochemical RIH was evaluated by medical chart review. The incidences of hypothyroidism were compared among three groups, and the dosimetric analysis was performed to estimate the Dmean to the thyroid in randomly-sampled matching patients (n = 200). At a median of 60 months (range, 5.2-140.2), 89 patients (2.2%) developed RIH (1.5% subclinical, 0.7% biochemical). The time interval from RT to detection of hypothyroidism was mean 30.2±24.0 months, and the 3- and 5-year rates were 1.3% and 2.2%. Patients with RNI had a significantly higher rate of hypothyroidism than patients without RNI (3.4% vs. 1.4%, P<.001). In RNI group (n = 1,605), low SCV-RNI was significantly associated with lowered risk of hypothyroidism than standard-RNI (0.5% vs. 3.8%, P<.001). After adjusting all confounders, standard-RNI was the only independent risk factor for development of RIH (vs. low SCV, HR 1.46, 95% CI, 1.05-2.03). In the dosimetric analysis, mean radiation dose to the thyroid was significantly lowered in low SCV-RNI group than standard-RNI group (2.9±1.9 Gy vs. 9.3±8.4 Gy P<.001). Standard supraclavicular lymph node irradiation increased the risk of newly developed hypothyroidism. However, optimization of RT target volume could reduce the lifelong RIH risk, which further supports adoption of smaller volume for supraclavicular lymph node in breast cancer with limited nodal tumor burden.

Enhancing the prognostic role of melanoma sentinel lymph nodes through microscopic tumour burden characterization: clinical usefulness in patients who do not undergo complete lymph node dissection.

This study aimed to investigate the sentinel lymph node (SLN) tumour burden to predict the non-SLN positivity rate and the survival of melanoma patients to evaluate whether SLN microstaging could predict the prognosis, similar to what is currently performed by examining the lymph nodes excised by complete lymph node dissection. Of 1130 consecutive melanoma patients who underwent SLN biopsy, 226 were tumour-positive and 204 were included in this study. SLN metastases were classified on the basis of dimensional (Rotterdam) and topographic (Dewar) criteria either separately or combined. SLN metastases more than 1 mm in diameter had the highest non-SLN positivity rate (31%) compared with metastases 0.1-1 mm (10%) and less than 0.1 mm (4%). The non-SLN positivity rate was 45% for extensive metastases, 5% for subcapsular metastases and 23-29% for parenchymal, combined and multifocal classes, therefore suggesting a simplification of the parenchymal SLN metastases into only two classes: extensive and 'not extensive'. The dimension of the metastasis was correlated with a different non-SLN positivity rate only when the metastasis was in the parenchyma (20-36%) and not when it was in the subcapsular location (4-7%). Interestingly, the 5-year melanoma-specific survival (MSS) was 89% for patients with subcapsular less than 0.1 mm metastases and 45% for patients with nonsubcapsular more than 1 mm metastases (P=0.017). In the parenchyma, larger metastases (>1 mm) were related to a lower 5-year MSS (46%) than smaller (<1 mm) metastases (MSS 77%). SLN tumour burden characterization can be simplified and it can provide prognostic information on non-SLN positivity and survival, which is especially useful in patients who do not undergo complete lymph node dissection.

Clinicopathologic and Ultrasound Variables Associated With a Heavy Axillary Nodal Tumor Burden in Invasive Breast Carcinoma.

To identify clinicopathologic and ultrasound (US) variables that were associated with a heavy nodal tumor burden, which was defined as 3 or more lymph nodes involved with metastasis to the axilla after invasive breast carcinoma. With ethical approval, 621 patients with a pathologic diagnosis of invasive breast carcinoma were retrospectively analyzed for clinical, pathologic, and US data. Pathologic findings were ascertained by the final paraffin pathologic analysis. Ultrasound characteristics were evaluated on the basis of the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and US variables that were associated with a heavy nodal tumor burden at the axilla. There were 107 cases (17.2%) of invasive breast carcinoma with a heavy tumor burden at the axilla. The independent clinicopathologic variables for a heavy tumor burden at the axilla included a tumor size of 2 to 5 cm (odds ratio [OR], 1.86; P = .036), the presence of lymphovascular invasion (OR, 23.52; P < .001), the presence of papillary invasion (OR, 2.93; P = .043), and a non-triple-negative subtype (OR, 2.34; P = .04). The independent US features of breast tumors that were associated with a heavy tumor burden at the axilla included BI-RADS category 5 (OR, 5.50; P = .024) and a posterior acoustic shadow (OR, 1.94; P = .024). A large tumor size, lymphovascular invasion, papillary invasion, and a non-triple-negative subtype on the pathologic analysis as well as BI-RADS category 5 and a posterior acoustic shadow on a US assessment were associated with a heavy nodal tumor burden at the axilla. These US characteristics of the primary breast carcinoma might provide additional information to axillary US for the prediction of axillary nodal tumor loads.