Individual Lymph Nodes Research Articles

Representativeness of the Index Lymph Node for Total Nodal Basin in Pathologic Response Assessment After Neoadjuvant Checkpoint Inhibitor Therapy in Patients With Stage III Melanoma

Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen. To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population. Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021. Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen. A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted. The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.

Survival impact of compliance in extra-perigastric lymphadenectomy for gastric cancer: 20 years of real-world data from a single institution

BackgroundCompliance in lymphadenectomy was first introduced as part of quality control in a Dutch clinical trial. Although a few studies have investigated compliance, no studies have evaluated the survival impact at individual lymph node stations. MethodsIn total, 2,932 patients who underwent radical gastrectomy between 1996 and 2014 at the Korea University Guro Hospital in Seoul, South Korea were retrospectively reviewed. We compared survival outcomes among the compliance, noncompliance, and metastatic groups. ResultsThe highest compliance among extra-perigastric stations was recorded for #8a (86.6%), followed by #7 (76.6%) and #9 (68.3%). Stations #11 and #12 showed low compliance rates of 28.9% and 31.0%, respectively. Compliance at #7, #8a, and #9 was related to better 5-year relapse-free survival rates (74.5%, 72.8%, and 71.3%, respectively) than noncompliance (61.9% [hazard ratio, 1.72; 95% confidence interval, 1.40–2.11], 61.0% [hazard ratio, 1.6; 95% confidence interval 1.26–2.04], 65.3% [hazard ratio, 1.25; 95% confidence interval 1.04–1.51], respectively). At #11 and #12, there were no significant differences in relapse-free survival between compliance (69.1% and 70.2%, respectively) and noncompliance (67.4% [hazard ratio, 0.85; 95% confidence interval 0.53–1.36], 65.1% [hazard ratio, 1.13; 95% confidence interval 0.71–1.81], respectively). In multivariable analysis, stations #7 and #8 alone showed an increased hazard ratio of relapse-free survival in the noncompliance group relative to the compliance group. ConclusionWe showed a survival benefit of compliance during lymphadenectomy for gastric cancer. Although further prospective trials to validate our results are warranted, compliance could be adopted in real-world practice to achieve better survival among patients with gastric cancer.

Radiomics signature based on computed tomography images for the preoperative prediction of lymph node metastasis at individual stations in gastric cancer: A multicenter study

BackgroundSpecific diagnosis and treatment of gastric cancer (GC) require accurate preoperative predictions of lymph node metastasis (LNM) at individual stations, such as estimating the extent of lymph node dissection. This study aimed to develop a radiomics signature based on preoperative computed tomography (CT) images, for predicting the LNM status at each individual station. MethodsWe enrolled 1506 GC patients retrospectively from two centers as training (531) and external (975) validation cohorts, and recruited 112 patients prospectively from a single center as prospective validation cohort. Radiomics features were extracted from preoperative CT images and integrated with clinical characteristics to construct nomograms for LNM prediction at individual lymph node stations. Performance of the nomograms was assessed through calibration, discrimination and clinical usefulness. ResultsIn training, external and prospective validation cohorts, radiomics signature was significantly associated with LNM status. Moreover, radiomics signature was an independent predictor of LNM status in the multivariable logistic regression analysis. The radiomics nomograms revealed good prediction performances, with AUCs of 0.716–0.871 in the training cohort, 0.678–0.768 in the external validation cohort and 0.700–0.841 in the prospective validation cohort for 12 nodal stations. The nomograms demonstrated a significant agreement between the actual probability and predictive probability in calibration curves. Decision curve analysis showed that nomograms had better net benefit than clinicopathologic characteristics. ConclusionRadiomics nomograms for individual lymph node stations presented good prediction accuracy, which could provide important information for individual diagnosis and treatment of gastric cancer.

Quantitate Image Responses in High Risk p16+ Oropharyngeal Cancer Patients Treated With Definitive ChemoRT and Concurrent Nivolumab Compared to ChemoRT Alone

Biomarkers of immunotherapy response are increasingly important in oropharyngeal cancer with the rapid expansion of treatment in the R/M population and many ongoing upfront trials. CPS score is the most commonly used method to quantify immune infiltration and predict response to immunotherapy, although limited by its static nature and sampling error. Previous studies show that pre-RT to mid-treatment changes in MRI-derived blood volume (BV) and apparent diffusion coefficient (ADC) as well as FDG-PET derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG) serve as imaging markers for pattern failure of HNC treated by CRT. The goal of this study is to evaluate changes in image metrics during concurrent immunotherapy and CRT compared to those from CRT.MRI and FDG-PET scans were acquired pre- and mid-treatment (fx 10) from 75 patients with high risk p16+ OPSCC (AJCC stage 3 or "matted nodes") who were treated with definitive concurrent CRT on 2 prospective institutional trials. The patients included: 1) the first 15 patients treated with definitive CRT 70Gy/concurrent carboplatin/taxol and concurrent nivolumab (iCRT) and 2) 60 patients treated with 70-80Gy/concurrent weekly cisplatin/carboplatin (CRT). Changes in quantitative image metrics from pre- to mid-treatment of primary tumors and individual lymph nodes were evaluated: gross tumor volume (GTV), MTV at 50% max SUV, TLG, mean SUV, mean BV and ADC between the two treatment groups using unpaired t test.Clinical characteristics and baseline quantitative image metrics were similar between CRT and iCRT groups, except the iCRT group had a lower BV value of primary tumors and a greater MTV of nodal tumors than CRT group (P = 0.05). However, at mid-treatment, iCRT patients had: 1) significantly greater increases in mean BV and ADC of primary tumors than CRT patients (49% vs. 23% and 21% vs. 12%, P < 0.007 and 0.03, respectively); but 2) less decreases in MTV, TLG and mean SUV of primary tumors than CRT patients, for which 11% of the TLG decrease was significantly different from 43% decrease of CRT group (P < 0.05); and 3) 12% decrease in mean SUV of nodal tumors that was significantly less than 25% in CRT group (P < 0.0001). With a mean follow-up of 11 months in the iCRT group, there has been only 1 DM in a patient with persistent low BV in the primary tumor, consistent with our previous findings in CRT patients.This analysis suggests that high risk p16+ OPSCC patients treated with iCRT had larger increases in BV and ADC and a smaller decrease in TLG in primary tumors mid-treatment compared to CRT group. Increases in BV and ADC have been identified to be associated with improved tumor control by previous studies of CRT. The minimal reduction of FDG metrics of iCRT group may be due to inflammatory response to anti-PD1. These findings warrant further investigation as predictive biomarkers for iCRT response to treatment.

Magnetic resonance guided elective neck irradiation targeting individual lymph nodes: A new concept.

Conventional elective neck irradiation (ENI) in head and neck cancer consists of radiotherapy (RT) to the regional lymph node (LN) levels contoured on computed tomography. Hybrid Magnetic Resonance (MR) - RT modalities, such as combined magnetic resonance imaging - linear accelerators (MRLs), might enable new ENI strategies in which individual non-suspect lymph nodes (i-LNs) are targeted. In this treatment planning study, new MR-based strategies targeting i-LNs (i-ENI) were compared to conventional treatment. All i-LNs were delineated on MR images of ten retrospectively selected patients with T2-4aN0M0 laryngeal cancer. Three strategies were considered. Strategy A: Conventional ENI delivered with a conventional linear accelerator (35x 1.55Gy). Strategy B: MRL-based i-ENI (35x 1.55Gy) to the individual lymph nodes including a background dose to the conventional elective neck volumes (35x 1.03Gy). Strategy C: Same as Strategy B, but without background dose. In all plans the dose prescription to the primary tumor was 35x 2Gy. Mean dose (D mean) reductions in the organs at risk (OAR) were compared using the Wilcoxon signed rank test. Compared to conventional ENI (strategy A), significant D mean reductions of 6.0Gy and 8.0Gy were observed in the submandibular glands, of 9.4Gy and 13Gy in the carotid arteries and of 9.9Gy and 19.4Gy in the thyroid for strategy B and C, respectively. Large inter-patient variations of D mean reductions were observed in all OARs. MRL-based i-ENI is a new promising concept that could reduce the mean dose to OARs in the neck significantly for patients with laryngeal cancer.

COVID‐19 associated Kikuchi‐Fujimoto disease

We discuss the case of a 17-year-old male who presented with painful lymphadenopathy, fevers, weight loss, anorexia and a history of preceding anosmia. Histological features on lymph node biopsy were in-keeping with Kikuchi-Fujimoto disease (KFD). We later confirmed SARS-CoV-2 (COVID-19) infection on antibody testing. This case describes an atypical presentation of COVID-19 in a young patient and highlights an association between the virus and this rare disease.

Preoperative detection of papillary and medullary thyroid cancer metastases in the lymph nodes of the neck lateral cellular tissue using a molecular classifier

Introduction.The main method of preoperative diagnosis of thyroid tumors and the identification of possible metastasis is a cytological examination of smears obtained by fine-needle aspiration biopsy. However, the cytological material of the lymph nodes may not be adequate, and the detection of metastases faces a number of difficulties. In our recent study, we described a variant of the molecular classifier that allows the detection and typing of malignant thyroid tumors by analyzing several molecular markers in cytological preparations.The study objectivewas to assess the applicability of the developed method for the preoperative detection of metastases of papillary and medullary thyroid cancer in the lymph nodes of the neck lateral cellular tissue.Materials and methods.A total of 86 cytological samples were used, obtained from individual lymph nodes of 62 patients who had a diagnosis – thyroid cancer. Samples were analyzed by real-time polymerase chain reaction regarding the preselected set of molecular markers: the BRAF V600E mutation, the normalized concentration of HMGA2, FN1 and SERPINA1 mRNA, 5 miRNAs and the mitochondrial/nuclear DNA ratio. The decision tree-based classifier was used to discriminate between benign and malignant samples.Results.The previously described classifier, based on the analysis of the BRAF V600E mutation, the content of HMGA2 mRNA, 3 miRNAs and the mitochondrial/nuclear DNA ratio, revealed metastases of thyroid cancer with good specificity (98 %) but less sensitivity (83 %). Therefore, a new classifier was built, including three markers – HMGA2 and FN1 mRNA, and miRNA-375, which, with regard to the detection of metastases, showed good sensitivity – 93 % with a slight decrease in specificity (up to 96 %).Conclusion.Thus, we demonstrated the possibility of preoperative detection of thyroid cancer metastases in the lymph nodes of the neck lateral cellular tissue by analyzing several molecular markers in cytological material.

Abstract PO-56: Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients

Abstract Follicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma; however, it remains incurable with conventional therapies and is poorly responsive to checkpoint blockade. Additionally, because FL develops so slowly (and often asymptomatically), a major research focus has been to avoid chemotherapy treatments to limit the potential development of treatment-related side effects and the risk of therapy-related second cancers. The mutational processes that lead to lymphomagenesis and progression also produce tumor-specific mutant antigens (TSMAs) that can be targeted by the immune system to control malignancies. Personalized cancer vaccines designed for these TSMAs represent a promising new strategy for treatment of FL. However, the feasibility of this approach and precisely how to optimize effective vaccine design, informed by next-generation sequencing data, are not fully understood. We hypothesize that (tumor/normal) whole-exome sequencing (WES) and (tumor) RNA sequencing (RNA-Seq) can be used to predict patient HLA typing and neoepitopes to engineer personalized cancer vaccines for FL. DNA and RNA from 58 patients' FL biopsies underwent WES and RNA-Seq. pVACtools and MiXCR predicted potential somatic and B-cell clonotype neoantigens, which were filtered to identify high-quality TSMAs. B-cell oligoclonality was determined by comparison to B-cell receptor (BCR) repertoire profiling of healthy individual lymph nodes. RNA-seq data allowed us to identify expressed TSMAs. Complementary in silico analysis based on mRNA-based peptide reconstruction and custom HLA affinity binding predictions were performed. An average of 52 somatic mutations per patient (range: 2-172) were identified. At least one high-quality TSMA was predicted for 57 of 58 patients. Five or more TSMA candidates were identified for 52 (90%) patients with a mean of 17 predicted peptides per patient (range: 0-45). 81% (813/1,004) of the total predicted TSMA peptides arose from missense mutations, 9% (94/1,004) from indels, and 10% (97/1,004) from BCR. 78% (45/58) of patients have both somatic and BCR vaccine candidates, while 21% (12/58) of patients had only somatic vaccine candidates. No fusion genes were identified within the cohort that could have been a source of neoepitope candidates. Predicted TSMAs were identified in multiple genes recurrently mutated in lymphoma (e.g., BCL2). There was a high prediction concordance with the orthogonal BostonGene Vaccine Module V1 pipeline. These preclinical results led to a first-in-human pilot trial of personalized TSMA vaccine combined with anti-PD-1 mAb for rel/ref FL patients (NCT03121677), with one response observed within 4 patients evaluable for response to date. TSMA peptides suitable for cancer vaccines were identified for most FL patients via next-generation sequencing, MiXCR and pVACtools. This preclinical study suggests that FL patients will be candidates for TSMA vaccine clinical trials, and pilot clinical results provide proof of concept for this approach. Citation Format: Cody A. Ramirez, Felix Frenkel, Olga Plotnikova, Vladislav Belousov, Alexander Bagaev, Elena Ocheredko, Susanna Kiwala, Jasreet Hundal, Zachary L. Skidmore, Marcus Watkins, Michelle Becker-Hapak, Thomas B. Mooney, Jason Walker, Catrina Fronick, Robert Fulton, Robert Schreiber, Nancy L. Bartlett, Brad Kahl, Ravshan Ataullakhanov, Malachi Griffith, Obi Griffith, Todd A. Fehniger. Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-56.

Defined Intestinal Regions Are Drained by Specific Lymph Nodes That Mount Distinct Th1 and Th2 Responses Against Schistosoma mansoni Eggs.

The balance of type 1 and type 2 immune responses plays a crucial role in anti-helminth immunity and can either support chronic infection or drive type 2 mediated expulsion of the parasite. Helminth antigens and secreted molecules directly influence this balance and induce a favorable immunological environment for the parasite’s survival. However, less is known if the site of infection also influences the balance of type 1 and type 2 immunity. Here, we report that tissue-specific immune responses are mounted against helminth antigens, which elicited strong IL-4 responses when injected into the skin, while the same antigen, delivered into the intestinal subserosa, induced increased IFN-γ and reduced Th2 responses. Immune responses in individual mesenteric lymph nodes that drain defined regions of the intestine furthermore displayed a site-specific pattern of type 1 and type 2 immunity after Schistosoma mansoni or Heligmosomoides polygyrus infection. S. mansoni egg-specific Th2 responses were detectable in all mesenteric lymph nodes but Th1 responses were only present in those draining the colon, while H. polygyrus infection elicited mixed Th1 and Th2 responses in the lymph nodes associated with the site of infection. Similar site-specific type 1 and type 2 immune responses were observed in the draining lymph nodes after the controlled delivery of S. mansoni eggs into different segments of the small and large intestine using microsurgical techniques. Different subsets of intestinal dendritic cells were hereby responsible for the uptake and priming of Th1 and Th2 responses against helminth antigens. Migratory CD11b+CD103− and especially CD11b+CD103+ DC2s transported S. mansoni egg antigens to the draining lymph nodes to induce Th1 and Th2 responses, while CD103+ DC1s induced only IFN-γ responses. In contrast, H. polygyrus antigens were predominantly transported by CD11b+CD103− DC2s and CD103+ DC1s and all DC subsets induced similar Th1 but weaker Th2 responses, compared to S. mansoni egg antigens. The development of adaptive anti-helminth immune responses is therefore influenced by the antigen itself, the uptake and priming characteristics of antigen-positive dendritic cell subsets and the site of infection, which shape the level of Th1 and Th2 responses in order to create a favorable immunological environment for the parasite.

Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients.

8054 Background: Follicular lymphoma (FL) is incurable with conventional therapies and poorly responsive to immune checkpoint blockade. There is a need for new therapies without long-term complications of chemotherapy and with curative potential. We hypothesize that FL contains tumor-specific mutant antigens (TSMAs) that can be targeted by the immune system by vaccination. Recent reports have highlighted the potential for unique immunoglobulin peptides to elicit immune response in lymphomas. We utilized whole exome sequencing (WES) and RNA sequencing (RNA-Seq) of FL patient samples to infer HLA genotype, and predict TSMAs with the goal of designing a personalized cancer vaccine, supported by recent reports of this approach in solid cancers. Methods: DNA and RNA from 58 patients’ FL biopsies underwent WES and RNA-Seq. pVACtools and MiXCR predicted potential somatic and B-cell clonotype neoantigens, which were filtered to identify high quality TSMAs. B-cell oligoclonality was determined by comparison to B-cell receptor (BCR) repertoire profiling of healthy individual lymph nodes. RNA-seq data allowed us to identify expressed TSMAs. Complementary in silico analysis based on mRNA-based peptide reconstruction and custom HLA affinity binding predictions were performed. Results: An average of 52 somatic mutations per patient (range: 2-172) were identified. At least one high quality TSMA was predicted for 57 of 58 patients. Five or more TSMA candidates were identified for 52 (90%) patients with a mean of 17 predicted peptides per patient (range: 0-45). 81% (813/1,004) of the total predicted TSMA peptides arose from missense mutations, 9% (94/1,004) from indels, and 10% (97/1,004) from BCR. 78% (45/58) of patients have both somatic and BCR vaccine candidates, while 21% (12/58) of patients had only somatic vaccine candidates. Predicted TSMAs were identified in multiple genes recurrently mutated in lymphoma (e.g., BCL2). There was a high prediction concordance with the orthogonal BostonGene Vaccine Module V1 pipeline. These pre-clinical results led to a first-in-human pilot trial of personalized TSMA vaccine combined with anti-PD-1 mAb for rel/ref FL patients (NCT03121677), with one response observed within 4 patients evaluable for response to date. Conclusions: TSMA peptides suitable for cancer vaccines were identified for most FL patients via next-generation sequencing, MiXCR and pVACtools. This pre-clinical study suggests that FL patients will be candidates for TSMA vaccine clinical trials and pilot clinical results provide proof of concept for this approach.

A highly potent lymphatic system‐targeting nanoparticle‐cyclosporine with efficacy in a lupus mouse model

A highly potent lymphatic system‐targeting nanoparticle‐cyclosporine with efficacy in a lupus mouse model

Lymph Node Predictive Model with in Vitro Ultrasound Features for Breast Cancer Lymph Node Metastasis

Ultrasound diagnosis of axillary lymph nodes has the advantages of ease, convenience and low cost; however, most previous studies evaluated lymph node metastasis of the entire axilla rather than the association between the ultrasound features of a single lymph node and its pathology. This prospective study was performed to explore the ultrasound features of lymph nodes observed in bionic medium in vitro and to develop a lymph node-specific model for prediction of metastasis based on analysis of the association between the ultrasound features and pathology of each lymph node. From November 1, 2017 to December 19, 2017, 373 nodes (54 patients) were enrolled into the modeling group; from December 20, 2017 to January 12, 2018, 139 lymph nodes (22 patients) were enrolled into the validation group. Lymph nodes from sentinel lymph node biopsy or axillary lymph node dissection were enrolled. Individual lymph nodes were placed in bionic medium and observed separately using ultrasound. Traditional ultrasound features of metastatic nodes (long axis, short axis, cortical thickness and hilum loss) were recorded, and the longitudinal-to-transverse axis ratio (L/T) and cortical proportion were calculated. Pathologic results specific to each lymph node were recorded. On the basis of two-level binary logistic regression, independent predictors of lymph node metastasis in the modeling group were lymph node long axis (p = 0.004), short axis (p < 0.001), L/T (p = 0.006), cortical thickness (p = 0.001) and hilum loss (p < 0.001). When analysis was done at the node level, the areas under the curve of the modeling and validation groups were 0.97 and 0.75, respectively. When validation was done at the patient level, the areas under the curve of the modeling and validation groups were 0.96 and 0.93, respectively. The model for prediction of metastasis based on the ultrasound features and pathology of each lymph node is of good predictive value for lymph node metastasis.

Pre-treatment radiomic features predict individual lymph node failure for head and neck cancer patients

Background and purposeTo develop and validate a pre-treatment radiomics-based prediction model to identify pathological lymph nodes (pLNs) at risk of failures after definitive radiotherapy in head and neck squamous cell carcinoma patients. Materials and methodsTraining and validation cohorts consisted of 165 patients with 558 pLNs and 112 patients with 467 pLNs, respectively. All patients were primarily treated with definitive radiotherapy, with or without systemic treatment. The endpoint was the cumulative incidence of nodal failure. For each pLN, 82 pre-treatment CT radiomic features and 7 clinical features were included in the Cox proportional-hazard analysis. ResultsThere were 68 and 23 nodal failures in the training and validation cohorts, respectively. Multivariable analysis revealed three clinical features (T-stage, gender and WHO Performance-status) and two radiomic features (Least-axis-length representing nodal size and gray level co-occurrence matrix based - Correlation representing nodal heterogeneity) as independent prognostic factors. The model showed good discrimination with a c-index of 0.80 (0.69–0.91) in the validation cohort, significantly better than models based on clinical features (p < 0.001) or radiomics (p = 0.003) alone. High- and low-risk groups were defined by using thresholds of estimated nodal failure risks at 2-year of 60% and 10%, resulting in positive and negative predictive values of 94.4% and 98.7%, respectively. ConclusionA pre-treatment prediction model was developed and validated, integrating the quantitative radiomic features of individual lymph nodes with generally used clinical features. Using this prediction model, lymph nodes with a high failure risk can be identified prior to treatment, which might be used to select patients for intensified treatment strategies targeted on individual lymph nodes.

Heterogeneous Responses of Axillary Lymph Node Metastases to Neoadjuvant Chemotherapy are Common and Depend on Breast Cancer Subtype.

The objective of this study was to analyze heterogeneous responses of axillary lymph node metastasis to neoadjuvant chemotherapy and to determine to what extent they differ between tumor subtypes (TN, HER2+, HR+/HER2-). This retrospective, monocenter study included 72 consecutive, histologically node-positive breast cancers (cT1-4 cN1-3 cM0) diagnosed in the period from January 2015 to December 2016, who had received axillary lymph node dissection following neoadjuvant chemotherapy. All individual lymph node specimens were re-evaluated for the presence of tumor cells and chemotherapy effects to assess their response to neoadjuvant chemotherapy on an individual lymph node level according to the Sataloff classification. Heterogeneous axillary responses to neoadjuvant chemotherapy occurred in 47.2% of the included 72 patients. The partial response rate was significantly higher in HR+/HER2- tumors (74.2%) than in TN (28.6%) and HER2+ tumors (25.0%) (p < 0.001). The presence of at least one negative, completely responding lymph node in the axillary lymph node dissection specimen had a false-negative rate of 48.8% in predicting ypN0. It dropped below 10% if at least four completely responding negative lymph nodes were identified. Our study shows that axillary heterogeneous response rates differ significantly between tumor subtypes.

Dose Response Relationship and Prognostic Factors of Nodal Control Rate of Metastatic Lymph Nodes in Cervical Cancer

In contrast to excellent local control in definitive aim radiation therapy (RT) of cervical cancer, control rate of metastatic lymph nodes remains insufficient. Therefore, radiation boost to metastatic lymph nodes has been attempted, but little is known about the optimal dose and prognostic factors of regional nodal control. In this study, we retrospectively investigated the dose response relationship of metastatic lymph nodes as well as prognostic factors of nodal control, and attempted to propose optimal dose for individual metastatic lymph nodes. We identified 90 patients (295 lymph nodes) who received definitive aim RT for node positive cervical cancer between 2013 and 2017. Total prescribed dose to each metastatic lymph node was converted to 2 Gy equivalent dose (EQD2, α/β = 10 Gy). Each node was tracked individually from initial diagnosis to any recurrence in the same specific node. Any tumor or treatment factors predictive of nodal control were searched. In addition, we attempted to stratify risk groups in order to find optimal dose for nodal control in a certain risk group. The median number of metastatic lymph nodes per patient was 2 (range, 1-14). Regarding total lymph nodes, the most common pathology was squamous cell carcinoma (85.6%) followed by adenocarcinoma (8.9%) and others (5.6%). The mean nodal volume at initial diagnosis was 5.0 ± 9.2 mL, and the mean total prescribed dose in EQD2 for each node was 55.0 ± 6.8 Gy. With median follow up of 25 months (range, 3-57 months), 32 nodal failures occurred, and 2-year nodal control rate was 89%. In multivariate analysis, neutrophil-to-lymphocyte ratio (NLR) higher than 3.0 (p<0.001), para-aortic nodes (vs. pelvic nodes, p=0.013), larger initial nodal volume (p<0.001) and lower total dose (HR 0.90 for increase of 1 Gy in EQD2; 95% CI 0.85-0.95; p<0.001) were identified as risk factors for poor nodal control. Each node was stratified into two risk groups; low risk group with none or one risk factor, and high risk group with two or three risk factors. For risk group analysis, initial nodal volume was dichotomized (≤ 5.3 mL or > 5.3 mL). ROC curve analysis showed that 53.1 Gy and 62.0 Gy was the optimal cut-off dose for predicting nodal control rate in low and high risk group, respectively. In low risk group, doses higher than 53.1 Gy showed significantly superior nodal control rate (p=0.050) with 2-year nodal control rate of 99% (vs. 93% for ≤ 53.1 Gy). In high risk group, doses equal to or higher than 62.0 Gy showed superior nodal control rate with marginal significance (p=0.053) with 2-year nodal control rate of 80% (vs. 62% for < 62.0 Gy). Our data demonstrated that nodal control depends on the prescribed dose to lymph node, NLR, location of lymph node, and initial nodal volume. Therefore, these factors should be considered to enhance nodal control at the stage of treatment plan.

Lymph Node Station-Based Nodal Staging System for Esophageal Squamous Cell Carcinoma: A Large-Scale Multicenter Study.

The American Joint Committee on Cancer (AJCC) nodal staging for esophageal squamous cell carcinoma (ESCC) has been defined by the number of metastatic lymph nodes (N system). However, the precise counting of individual positive lymph nodes is difficult and unreliable in some clinical settings, which calls for a more available and reliable system. This study examined the performance of a newly proposed nodal staging category, termed the S system, based on the number of metastatic lymph node stations. Using the Kaplan-Meier method and Cox-regression analysis, this study retrospectively analyzed the overall survival (OS) of 2285 ESCC patients who underwent esophagectomy in three major China hospitals. Predictive models were constructed, and C-indices were computed to evaluate the discriminatory power of the S system, and to compare it with the N system. The categories defined by the S system were more homogeneous in terms of OS than those defined by the N system. Overall, the S system had a slightly better C-index (p = 0.659) than the N system ((p = 0.658). Subgroup analyses also showed that the C-index of the S system was slightly better than that of the N system for each subgroup of sex and age, but the two were comparable for each subgroup defined by the tumor location. The S system demonstrated a competing prognostic performance compared with the current AJCC N system. Due to the relatively easy accessibility of the number of metastatic lymph node stations, the S system may offer an easier option for cancer staging without a loss of discriminative power.

Near-infrared fluorescence imaging improves the nodal yield in neck dissection in oral cavity cancer – A randomized study

IntroductionLymph node yield (LNY) in neck dissection has been identified as a prognostic factor in oral cavity cancer. The purpose of this study was to investigate the impact of additional use of optical imaging on LNY in therapeutic ND in oral cancer. MethodsConsecutive patients with oral squamous cell carcinoma with clinical neck metastasis planned for primary tumor resection were randomized to conventional neck dissection or near-infrared fluorescence (NIRF)-guided neck dissection, respectively. In the intervention group, patients were injected with ICG-Nanocoll prior to surgery. Intraoperatively, an optical hand-held camera system was used for lymph node identification. Also, NIRF imaging of the neck specimen was performed, and optical signals were pinned with needle markings to guide the pathological examination. The endpoint of the study was LNY per neck side in levels Ib-III. Results31 patients were included with 18 neck sides in the control group and 18 neck sides in the intervention group for evaluation. During NIRF-guided ND, individual lymph nodes could be identified by a bright fluorescent signal and individual tumor-related drainage patterns could be observed in the neck. The LNY in the intervention group was significantly higher compared to the control group (p = 0.032) with a mean of 24 LN (range: 12–33 LN in levels Ib-III compared to 18 LN (range: 10–36 LN) in the control group, respectively. ConclusionsNIRF-guided ND significantly improved the nodal yield compared to the control group. Intraoperative real-time optical imaging enabled direct visualization of tumor-related drainage patterns within the neck lymphatics.

A model system for studying superselective radiotherapy of lymph node metastasis in mice with swollen lymph nodes

Utilizing mice with swollen lymph nodes, we succeeded in irradiating individual metastatic lymph nodes through a hole in a lead shield. This system enabled us to increase the radiation dose to >8 Gy (the lethal dose for total-body irradiation) and evaluate both direct and abscopal antitumor effects.

Individual lymph nodes: “See it and Zap it”

Background and purposeWith magnetic resonance imaging (MRI)-guided radiotherapy systems such as the 1.5T MR-linac the daily anatomy can be visualized before, during and after radiation delivery. With these treatment systems, seeing metastatic nodes with MRI and zapping them with stereotactic body radiotherapy (SBRT) comes into reach. The purpose of this study is to investigate different online treatment planning strategies and to determine the planning target volume (PTV) margin needed for adequate target coverage when treating lymph node oligometastases with SBRT on the 1.5T MR-linac. Materials and methodsTen patients were treated for single pelvic or para-aortic lymph node metastases on the 1.5T MR-linac with a prescribed dose of 5x7Gy with a 3 mm isotropic GTV- PTV margin. Based on the daily MRI and actual contours, a completely new treatment plan was generated for each session (adapt to shape, ATS). These were compared with plans optimized on pre-treatment CT contours after correcting for the online target position (adapt to position, ATP). At the end of each treatment session, a post-radiation delivery MRI was acquired on which the GTV was delineated to evaluate the GTV coverage and PTV margins. ResultsThe median PTV V35Gy was 99.9% [90.7–100%] for the clinically delivered ATS plans compared to 93.6% [76.3–99.7%] when using ATP. The median GTV V35Gy during radiotherapy delivery was 100% [98–100%] on the online planning and post-delivery MRIs for ATS and 100% [93.9–100%] for ATP, respectively. The applied 3 mm isotropic PTV margin is considered adequate. ConclusionFor pelvic and para-aortic metastatic lymph nodes, online MRI-guided adaptive treatment planning results in adequate PTV and GTV coverage when taking the actual patient anatomy into account (ATS). Generally, GTV coverage remained adequate throughout the treatment session for both adaptive planning strategies. “Seeing and zapping” metastatic lymph nodes comes within reach for MRI-guided SBRT.

Inter-fraction movements of the prostate and pelvic lymph nodes during IGRT

ObjectivitiesThe aim of this study was to evaluate inter-fraction movements of lymph node regions that are commonly included in the pelvic clinical target volume (CTV) for high-risk prostate cancer patients. We also aimed to evaluate if the movements affect the planning target volumes.MethodsTen prostate cancer patients were included. The patients underwent six MRI scans, from treatment planning to near end of treatment. The CTV movements were analyzed with deformable registration technique with the CTV divided into sections. The validity of the deformable registration was assessed by comparing the results for individual lymph nodes that were possible to identify in all scans.ResultsUsing repetitive MRI, measurements showed that areas inside the CTV (lymph nodes) in some extreme cases were as mobile as the prostate and not fixed to the bones. The lymph node volumes closest to the prostate did not tend to follow the prostate motion. The more cranial lymph node volumes moved less, but still independently, and they were not necessarily fixed to the pelvic bones. In 95% of the cases, the lymph node motion in the R-L direction was 2–4 mm, in the A-P direction 2–7 mm, and in the C-C direction 2–5 mm depending on the CTV section.ConclusionLymph nodes and prostate were most mobile in the A-P direction, followed by the C-C and R-L directions. This movement should be taken into account when deciding the margins for the planning target volumes (PTV).