Nodal Sites Research Articles

Cytological diagnosis of follicular dendritic cell sarcoma with a unique pattern of D2-40 immunoexpression.

Fine needle aspiration procedure is routinely used for cytological diagnosis of nodal or extra nodal lesions. Follicular dendritic cell sarcoma (FDCS) is a rare mesenchymal neoplasm arising from follicular dendritic cells of lymphoid follicles at nodal and extranodal sites. Multimodal therapies have emerged for FDCS, necessitating its accurate pathologic diagnosis with additional ancillary testing for directing clinical management. By immunohistochemical analysis, FDCS is positive for the complement receptors CD21, CD23, and CD35. In addition, D2-40 is reported to be highly sensitive for FDCS with a strong membranous pattern of expression. In this study, we present the cytological diagnosis of a case of FDCS in retroperitoneal lymph nodes with an emphasis on a unique staining pattern of D2-40 which showed a strong nuclear pattern in tumor cells comparable to the membranous pattern of D2-40 on the control tissue and other surgical cases of FDCS in our comparative study.

Risk of second primary cancers in nodal non-Hodgkin lymphoma patients by primary lymph node location: a retrospective cohort population-based study.

Non-Hodgkin lymphoma (NHL) is a diverse group of blood cancers with increasing incidence and survival rates due to advancements in treatment and early detection. However, NHL survivors are at significant risk of developing second primary cancers, which can adversely impact their long-term survival. This retrospective population-based cohort study utilized data from the Surveillance, Epidemiology, and End Results database, covering 17 geographic areas in the United States from 2000 to 2021. The authors included patients diagnosed with nodal NHL as a first primary cancer and excluded those diagnosed at autopsy or via death certificate only. Standardized Incidence Ratios, Absolute Excess Risks, and Person-Years at Risk were calculated to evaluate the risk of developing SPCs according to the primary lymph node site and stratified by latency periods following the initial NHL diagnosis. The cohort included 54012 NHL patients. The authors' results showed that for most SPCs, the risk of development was different for different primary NHL lymph node locations. The highest risks were observed for thyroid cancer, acute myeloid leukemia, and Hodgkin lymphoma. Notably, the risk for thyroid cancer was highest in the first year post-diagnosis, while hematological malignancies such as acute myeloid leukemia and Hodgkin lymphoma showed elevated risks in the intermediate and late latency periods. NHL survivors are at an increased risk of developing SPCs, influenced by the primary lymph node site and latency period. These findings highlight the need for tailored surveillance strategies and preventive measures to mitigate the long-term risks of SPCs in NHL survivors. Further research is necessary to elucidate the underlying mechanisms and to develop targeted interventions for this high-risk population.

A Case of Idiopathic Multicentric Castleman Disease Developing in a Patient with a History of Biopsy Proven Membranous Nephropathy

Abstract Introduction/Objective Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder involving two or more lymph node sites. It is usually associated with systemic inflammatory symptoms and organ dysfunction related to hypercytokinemia. Renal involvement in iMCD has only been described in a limited number of studies and case reports. Of note, only one previous case report has described results from renal biopsies taken prior to the development of iMCD. Methods/Case Report Our patient is a 43 year old female who was first diagnosed with membranous nephropathy in early 2020. She had PLA2 R negative and Exostosin-2 positive disease. Age appropriate screening for malignancy was unremarkable. She had positive ANA titres and normal complement levels but did not meet criteria for SLE per rheumatology. Her proteinuria was improved and maintained on Lisinopril for 3 years. In October 2023, her proteinuria suddenly increased. Repeat renal biopsy was unchanged from the initial biopsy. This time, she also noticed acute swelling over her subpectoral region. PET-CT scan revealed multiple areas of avid lymphadenopathy on either sides of the diaphragm but the highest yield PET- avidity was in the subpectoral region. Biopsy of the right subpectoral lymph node was performed. According to the WHO Classification, 5th edition, diagnostic criteria for iMCD-NOS was met with the histological features displaying grade 3 plasmacytosis, grade 2 regressed germinal centers, follicular dendritic cell prominence, increased hyperplastic follicles and increased vascularity. Immunohistochemical staining for CD138 highlighted abundant plasma cells, CD21 highlighted follicular dendritic cell prominence. Vascular proliferation was seen by CD34 staining. Kappa and Lambda- ISH demonstrated polytypic staining pattern and HHV-8 was negative. Results (if a Case Study enter NA) NA Conclusion There is a significant clinical, histologic and immunologic overlap between iMCD, autoimmune or infectious disorders and malignancy. HHV-8 negative/iMCD is less well understood and has no specific biomarkers. It is important to follow the available clinicopathologic diagnostic criteria for early diagnosis, follow up and treatment. Timely recognition can help prevent multiple organ system dysfunction, systemic inflammatory symptoms, cytopenias and polyclonal lymphoproliferation. Although the pathophysiology maybe unclear, this case may also suggest that in patients with a previously diagnosed membranous nephropathy, iMCD may play a role in recurrence and worsening of the disease.

ALK-positive Anaplastic Large Cell Lymphoma Involving the Spinal Cord

Abstract Introduction/Objective ALK-positive anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for approximately 3% of non-Hodgkin lymphoma cases in the adult population. Lymph node involvement is most commonly seen, followed by extra-nodal involvement of the skin, soft tissue, and bone. Central nervous system involvement is rare at the time of diagnosis. This case study features a patient with systemic ALK-positive ALCL involving multiple nodal and extra-nodal sites, most notably the spinal cord. Methods/Case Report A 22-year-old female presented to the hospital with worsening back pain accompanied by neurological symptoms. MRI scans of her spine revealed extensive patchy abnormal marrow signal with enhancement of the thoracolumbar vertebrae (T1-L2) and adjacent extension into the spinal canal (T3-T7, T10-L1, L3-S1) and paraspinal soft tissues. A laminectomy of the T5-T7 and T11-T12 levels was performed for surgical decompression, and epidural and paraspinal resection specimens were submitted. These specimens, along with an excisional axillary lymph node biopsy, demonstrated ALK-positive ALCL after comprehensive immunohistochemical studies. In-situ hybridization for EBV was negative. CHOP therapy was initiated, but treatment was complicated by Candidemia and disseminated intravascular coagulation. The patient rapidly declined and passed away less than a month after hospital admission. At autopsy, enlargement of lymph nodes, the left ovary (17.8 g), and spleen (383.6 g) were noted on gross examination. A solid, white-tan lesion (2.1 x 0.9 x 0.8 cm) was found in the left ovary. Necrosis and infiltrates of large, pleomorphic lymphoid cells with irregular nuclear contours and prominent nucleoli were seen on microscopic examination of the spinal cord and leptomeninges, vertebral bone marrow, mediastinal lymph nodes, spleen, and left ovary. Consistent with previously submitted surgical specimens, the viable neoplastic cells stained strongly positive for ALK-1, CD4, and CD30. Results (if a Case Study enter NA) NA Conclusion This case study highlights an atypical presentation of ALCL with a fatal outcome. Given the availability of effective treatment options, prompt diagnosis is crucial to improving survival outcomes. Additional research is necessary to elucidate the clinical and pathological features of ALCL. The differential for back pain is broad, but including this entity for patients with similarly insidious clinical presentations can prevent a delay in diagnosis that allows for rapid progression of disease.

Rare Case of Cutaneous Rosai Dorfman Disease Involving the Nail

Abstract Introduction/Objective Rosia-Dorfman Disease (RDD) is a rare benign non-Langerhans cell histiocytic disorder of unknown etiology with heterogeneous clinical features. RDD was first described by Destombes in 1965 under the term “adenitis with lipid excess.” However, it is named after Rosai and Dorfman, who characterized the further histopathological features of the disease in 1969. The characteristic presentation of RDD is lymphadenopathy, and extra nodal sites include bone, upper respiratory tract, central nervous system, retroperitoneum, and skin. The management of RDD depends on the site of involvement and the presence or absence of the symptoms. Multifocal and refractory diseases require systemic treatment. Surgical resection can be considered in symptomatic and resect- able diseases. Methods/Case Report A 16-year-old Asian female with no significant past medical history presented with a painful verrucous lesion on the left 5th finger for one year with bleeding and purulent discharge. Excision was performed, and histologically, there was extensive infiltration of large histocytes in the dermis with occasional lymphocytes and plasma cells. The histiocytes were engulfing the intact inflammatory cells, exhibiting the emperipolesis phenomenon. Immunohistochemically, S100 and CD68 were positive in the large histiocytes, and leukocyte common antigen (LCA) was positive in the background lymphocytes. Based on histology and immunohistochemistry, RDD diagnosis was rendered. Results (if a Case Study enter NA) N/A Conclusion RDD is a rare condition that poses challenges in diagnosis and management. The key diagnostic factors are histological features and immunohistochemistry to exclude other pathological disorders. Treatment should be tailored according to the needs of each patient and as required to optimize the outcome. We recommend an appropriate diagnosis of this entity in a timely manner to prevent any further long-term complications.

Comprehensive Review of Post-treatment Imaging in Head and Neck Cancers: From expected to unexpected and beyond.

Head and neck cancer management requires multidisciplinary approach in which radical surgery with or without flap reconstructions and neck dissection, along with radiotherapy (RT)/chemoradiotherapy (CRT) serve as the key components. Neoadjuvant chemotherapy (NACT) and immunotherapy are used in selected cases based on the institutional preference. Knowledge of expected posttreatment changes on imaging is essential to differentiate it from recurrence. In addition, awareness of various posttreatment complications is imperative for their early detection on imaging. Distorted anatomy after treatment poses diagnostic challenge, hence, proper choice of imaging modality and appropriate timing of scan is pertinent for accurate posttreatment evaluation. In this article, we have provided a comprehensive review on expected imaging appearances post RT/CRT and after major types of head and neck squamous cell carcinoma (HNSCC) surgeries. In addition, we have extensively reviewed the imaging appearances of various posttreatment complications, and recurrences at the primary and lymph nodal sites. We have also delved into the patterns of recurrence in human papillomavirus (HPV) positive HNSCC in this article. Furthermore, we have provided flowcharts and discussed recommendations on the site-specific and treatment related imaging modalities to be used along with their appropriate timing, for adequate evaluation of HNSCC after treatment. We have also reviewed posttreatment reporting of imaging findings using Neck Imaging Reporting and Data Systems (NIRADS) and Hopkins criteria. In addition, we have also touched upon the role of advanced imaging techniques for posttreatment HNSCC evaluation.

The clinical significance of the lymph node ratio as a recurrence indicator in ampullary cancer after curative pancreaticoduodenectomy.

The clinical significance of the lymph node ratio (LNR), the number of metastatic lymph nodes per dissected lymph node, has not been sufficiently clarified in ampullary cancer. Among patients diagnosed histopathologically with ampullary cancer between 1980 and 2018, the study included 106 who underwent pathological radical resection by pancreaticoduodenectomy. The relationships between the LNR and metastatic lymph node sites and prognosis were examined. Multivariate analysis revealed that sex and lymph node metastasis were independent prognostic factors. In the 46 patients (43%) with metastatic lymph nodes, the LNR in the recurrence group was significantly higher than that in the non-recurrence group (0.15 ± 0.11 vs. 0.089 ± 0.071, p = 0.025). The receiver operating characteristic curve demonstrated that the LNR cut-off value, 0.07 (area under the curve = 0.70, sensitivity 81%, specificity 56%), was a significant indicator for recurrence (22% vs. 61%, p = 0.016) and prognosis (5-year survival: 48% vs. 83%, p = 0.028). Among the metastatic lymph node sites in the 46 positive cases, lymph node metastases developed from the peripancreatic head region (80%, 37/46) to the superior mesenteric artery (33%, 15/46) and para-aortic (11%, 5/46) regions. Lymph node metastasis is an independent prognostic factor, and the LNR is a significant indicator for recurrence and prognosis in patients with ampullary cancer.

Establishment and Validation of Prognostic Nomograms for Nonmetastatic Melanoma of the Limbs—A SEER-Based Study

Background Malignant melanoma, a highly aggressive skin cancer, has remarkable incidence and mortality nowadays. This study aims to explore prognostic factors associated with nonmetastatic cutaneous melanoma of the limbs and to develop nomograms for predicting overall survival (OS) and cancer-specific survival (CSS). Methods The study cohort was derived from the Surveillance, Epidemiology, and End Results database. Univariate Cox regression, Lasso regression, and multivariate Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The receiver operating characteristic (ROC) curve, time-dependent C-index, calibration curve, decision curve analysis (DCA) and Kaplan-Meier method were used to evaluate the accuracy and clinical applicability of the nomograms. Results A total of 15,606 patients were enrolled. Multivariate analysis identified several prognostic factors for OS and CSS including age, sex, histologic type, N stage, tumor thickness, depth of invasion, mitotic rate, ulceration, surgery of primary site, systemic therapy, race, and number of lymph nodes examined. A nomogram incorporating 12 independent predictors for OS was developed, with a C-index of 0.866 (95% confidence interval [CI]: 0.858–0.874) in the training cohort and 0.853 (95% CI: 0.839–0.867) in validation. For CSS, 10 independent predictors and one related factor were included, yielding a C-index of 0.913 (95% CI: 0.903–0.923) in the training cohort and 0.922 (95% CI: 0.908–0.936) in validation. The ROC curve, time-dependent C-index, calibration curve, DCA, and K-M plot demonstrated favorable discrimination, calibration, and clinical utility. Conclusion The developed nomograms provide a precise and personalized predictive tool for risk management of patients with nonmetastatic limb melanoma.

Coexpression of MYC and BCL2 oncoproteins in primary nodal versus primary extranodal diffuse large B-cell lymphoma

Objectives: Diffuse large B-cell lymphoma (DLBCL) is a morphologically and molecularly diversified disease with aggressive biological behavior. The double expression of MYC/BCL2 proteins portends a poorer prognosis. This study aims to evaluate the frequency, describe the clinicopathological features of the double-expressor phenotype of DLBCL in primary nodal (PN) versus primary extranodal (PEN) sites, and investigate their associations. Materials and Methods: A total of 48 patients with the double-expressor phenotype of lymphoma (DEPL) in a tertiary care hospital were included over three years. Clinicopathological parameters and associations were investigated based on the primary site. Statistical Analysis: Data were documented and analyzed using appropriate statistical tests. Results: The incidence of DEPL in our study was 28.7%. The median age of all DEPL patients was 56 years, with a predominance of men (69%). DEPL cases were further subcategorized as PN-DEPL (n = 33) and PEN-DEPL (n=15). Males were affected almost equally in both groups. More PN-DEPL patients exhibited B symptoms (82%), elevated lactate dehydrogenase (LDH) levels (73%), III/IV stage disease (71%), and maximum revised international prognostic index (R-IPI) score (64%) compared to PEN-DEPL patients. On the other hand, bone marrow (BM) involvement (87%), activated B-cell-type phenotype (80%), pathologic stage I/II (67%), and Ki67 index >90% (93%) were more common in PEN-DEPL patients. Conclusions: Significant differences were observed between PN-DEPL and PEN-DEPL in terms of B symptoms, LDH levels, stage at presentation, BM involvement, pathological subtype, Ki67 index, and R-IPI score. This study provides an estimate of the burden of this aggressive entity and encourages further prognostic studies and therapeutic trials.

NIRADS-based case assessment of post-treatment head and neck cancer and its clinical correlation: A validation study

Introduction: The neck imaging reporting and data system (NIRADS) lexicon is aimed at surveillance of head and neck cancer during post-treatment follow-up using either a CECT or PET-CT scan. These recommendations standardize management, reduce interobserver variability, and standardizes scientific communication. Objectives: The primary aim of this study was to validate the correlation between the NI-RADS category and disease status on clinical follow-up and histopathological analysis. The other objective was to assess the status of primary as well as nodal site at least 8 to 12 weeks after definitive treatment on first post-treatment imaging as per NI-RADS. Materials and Methods: We did a retrospective review of maintained a database of patients treated with curative intent radiotherapy or chemoradiotherapy. The diagnostic accuracy of NIRADS was compared with the clinical follow-up and histopathological findings. Data was recorded using the NIRADS lexicon and analyzed using SPSS 25. Result: In our study, 37 cases were followed with CECT, whereas 111 were followed with PET-CT. We observed no significant difference between CECT and PET-CT for predicting recurrence in any of the NIRADS category. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of NIRADS to predict recurrence for the primary site is 61.54%, 75.21%, 34.8%, 90.1%, and 72.79%, respectively, whereas for the neck, it is 69.54%, 75.41%, 37.5%, 92%, and 74.32%. Conclusion: NIRADS score is strongly associated with positive disease in as Neck as well as primary. Increased use of NIRADS will lead to a uniform reporting system and improved patient outcome.

Interdigitating Dendritic Cell Tumour: A Rare Case Report with Review of Literature

Background and Aims: Interdigitating dendritic cell tumour/sarcoma (IDCS) is an exceedingly uncommon and aggressive tumour with a dismal prognosis. IDCS arises from antigen-presenting cells, which involve nodal and extranodal sites. The aim of the study is to evaluate a case of IDCS and its diagnostic challenges. Methods: A 21-year-old female with no comorbidities, a bone marrow aspirate and biopsy and an excision biopsy of the lymph node shows atypical mononuclear infiltrates that were immunohistochemically positive for S100-diffuse, CD68, LCA and Ki67. Results: Here, we report a single case of IDCS with a tumour arising from the lymph node and bone marrow infiltration. Discussion: IDCS is an aggressive disease with uncertain behaviour; strong suspicion is required to establish a diagnosis.

Identification of genetic subtypes in follicular lymphoma

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Port Site Metastasis in Women with Low- or Intermediate-Risk Endometrial Carcinoma: A Systematic Review of Literature.

Background: Port site metastasis (PSM) has been reported as a rare metastasis in women with endometrial carcinoma (EC). However, even more rarely, it has also been described in patients with low- or intermediate-risk EC. Unfortunately, knowledge appears limited on the topic. Objectives: Our objective was to systematically review the literature on PSM in low- or intermediate-risk EC. Search Strategy: A systematic review of the literature was performed by searching six electronic databases from their inception to January 2023. Selection Criteria: We included in our research all peer-reviewed studies which reported PSM in low- or intermediate-risk EC women. Data Collection and Analysis: Data on PSM were collected from the included studies and compared. Results: Seven studies with 13 patients (including our case) were included in the systematic review. PSM was reported in patients with low- or intermediate-risk EC independently from tumor histologic characteristics, endoscopic approach, lymph node staging type, number and site of the port, route of specimen removal, prevention strategies for PSM, and concomitant metastases. Among several proposed treatments, local resection and radiotherapy with or without chemotherapy might be the most appropriate ones. Nevertheless, the prognosis appears poor. Conclusions: In patients with low- or intermediate-risk EC, PSM can occur as a rare metastasis, regardless of tumor characteristics or surgical strategy. Unfortunately, no consensus has been reached regarding treatment, and the prognosis appears poor. Additional cases are needed in order to confirm and further explore this rare EC metastasis.

Prospective investigation of amino acid transport and PSMA-targeted positron emission tomography for metastatic lobular breast carcinoma.

To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or 18F-FDG positron-emission-tomography (PET)-CT]. 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with 18F-fluciclovine and 68Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and 18F-FDG PET-CT in 7 patients). Results were correlated to a composite standard of truth. Confirmed detection rate (cDR) was compared using McNemar's test. Mean SUVmax of 18F-fluciclovine and 68Ga-PSMA-11 in the most avid lesion for each true positive metastatic region and intact primary lesion were compared by t-test. The cDR for standard-of-care imaging was 5/20 patients in 5/60 regions. 68Ga-PSMA-11 PET-CT detected metastasis in 7/20 patients in 7/60 regions. 18F-fluciclovine PET-CT detected metastasis in 9/20 patients in 12/60 regions. The cDR for 18F-fluciclovine PET-CT was significantly higher versus standard-of-care imaging on the patient and combined region levels, while there were no significant differences between 68Ga-PSMA-11 and standard-of care imaging. 18F-fluciclovine cDR was also significantly higher than 68Ga-PSMA-11 on the combined region level. Mean SUVmax for true positive metastatic and primary lesions with 18F-fluciclovine (n = 18) was significantly greater than for 68Ga-PSMA-11 (n = 11) [5.5 ± 1.8 versus 3.5 ± 2.7 respectively, p = 0.021]. In this exploratory trial, 18F-fluciclovine PET-CT has a significantly higher cDR for ILC metastases compared to standard-of-care imaging and to 68Ga-PSMA-11. Mean SUVmax for true positive malignancy was significantly higher with 18F-fluciclovine than for 68Ga-PSMA-11. Exploratory data from this trial suggests that molecular imaging of amino acid metabolism in patients with ILC deserves further study. Early phase (I-II) clinical trial (NCT04750473) funded by the National Institutes of Health (R21CA256280).

Case report: A rare case of isolated sigmoid Rosai-Dorfman disease on contrast-enhanced CT and 18F-FDG PET/CT

Rosai-Dorfman disease (RDD) is an uncommon histiocytic disorder that occurs in nodal and/or extranodal sites. Extranodal RDD exhibits a wide range of clinical and radiological presentations, frequently leading to misdiagnoses. Involvement of the gastrointestinal (GI) system is uncommon, accounting for less than 1% of the reported cases. Here we present a case of a 54-year-old male who complained of abdominal distention and was diagnosed with RDD affecting the sigmoid colon, manifesting as a sigmoid mass. The patient had a past medical history of liver transplantation due to hepatocellular carcinoma (HC). This report details the multiphase contrast-enhanced computed tomography (CT) and fluorodeoxyglucose (18F-FDG) positron emission tomography (PET-CT) imaging findings of RDD involving the sigmoid colon without lymphadenopathy, and a review of the relevant literature is provided.

Comparison of tumor immune microenvironments (TIMEs) between primary and metastatic sites (Mets) in triple-negative breast cancer (TNBC).

1097 Background: The TIME is critical in determining response to immune checkpoint inhibitors (ICIs), but TIME differences across primary and mets in TNBC are not well understood. Since ICIs are standard of care for patients with TNBC, we studied the TIMEs of primary TNBC and mets to investigate how immune composition may affect ICI efficacy. Secondary analysis stratified cohorts by race and disease sites to compare TIMEs in Black or African American (B/AA) with White patients, since TNBC has a high prevalence of B/AA women who are underrepresented in studies and have a worse prognosis. Methods: We retrospectively analyzed de-identified next-generation sequencing data from TNBC patients (n=1,044) in the Tempus Database. Tumors from primary breast (PB, n=553), liver (n=153), lymph node (LN, n=174), lung (n=111), and bone (n=53) sites were sequenced with the Tempus xT DNA (648-gene panel) and xR RNA assays. Histologies included invasive ductal carcinoma (82%), lobular carcinoma (2.2%), mixed ductal and lobular carcinoma (1.7%), and other (14%). Demographics, TMB, MSI, PD-L1, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared across sites. LN were used as a positive control. Chi-squared/Fisher’s exact or Kruskal-Wallis tests were used to assess statistical significance (two-sided, evaluated at the 0.05 alpha level). Results: The cohort (median age=57 years, IQR 46-66) comprised a diverse population (65% White, 23% B/AA, 2.8% Asian, and 9.3% other). Liver exhibited a lower percentage of B cells and higher percentage of macrophages compared to PB (p<0.0001 for both), lung (p<0.0001 for both), and bone (B cells p<0.0001, macrophages p<0.05). Liver also exhibited lower percentages of CD8+ T cells compared to PB (p<0.05) and CD4+ and NK cells compared to lung (CD4+ cells p<0.01, NK cells p<0.0001). Bone had lower percentages of CD8+ cells compared to PB (p<0.0001), lung (p<0.001), and liver (p<0.01). Compared to lung, bone had a lower percentage of CD4+ cells (p<0.0001) and higher percentage of macrophages (p<0.01). PD-L1 positivity, TMB, and MSI exhibited no differences across sites. Secondary analysis compared the TIME between B/AA and White cohorts in PB (B/AA n=85 vs White n=204: %B cells, 15 vs 11, p=0.017; %CD8 cells, 4.9 vs 7.3, p=0.025), liver (B/AA n=15 vs White n=48: %B cells, 8 vs 4, p=0.2; %CD4, 23 vs 14, p=0.2; %CD8, 7.2 vs 4.6, p=0.07), and lung (B/AA n=9 vs White n=33: %B cells, 22 vs 11, p=0.021; %CD8, 7.9 vs 5.2, p=0.5). Conclusions: Compared to PB and lung, liver and bone had immune cell infiltrates indicating a less immunogenic TIME in the overall TNBC population. Although limited by sample size, this is one of the first studies to assess the TIME across race and sites of disease. These findings are hypothesis generating and provide further rationale to better understand how the TIME across disease sites and race may alter the efficacy of ICIs in TNBC.

Evaluating tumor inflammation and PD-L1 expression in sequential biopsies of real-world primary and metastatic breast cancer.

e13035 Background: Biomarkers for measuring immunogenicity of tumors such as PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB), and immune gene expression have been studied in many cancers including breast cancer. How these biomarkers change over time and how their detection differs with sequential testing in the real-world clinical setting has been studied to a lesser extent but is an important consideration for optimal patient care. Methods: We performed an analysis of 30 patients with primary and metastatic breast cancer sequentially tested by comprehensive genomic and immune profiling (CGIP) at two time points during routine clinical care to observe temporal changes in immunotherapy markers and immune gene expression. Genomic variants and TMB were assessed with DNA-seq, while immune gene expression was assessed with RNA-seq. PD-L1 expression was determined using IHC. Immune gene expression signatures characterizing the tumor microenvironment (TME) were calculated, including tumor inflammation (TIGS), cell proliferation (CP), and cancer testis antigen burden (CTAB). Differences between sequential tests were tested for using linear mixed effect models. Results: Time between biopsies for sequential tests ranged from the same day to 4.5 years, with 40% of specimens being collected within 30 days of the first. Sequential specimens were collected from breast (27%), non-breast (40%), or a mix of breast and non-breast (33%) tissue. Non-breast tissue types included sites from lymph node (18%), GI tract (15%), skin (10%), thorax (7%), and musculoskeletal sites (7%). Overall, TMB, PD-L1 IHC, and gene expression signatures were relatively stable between sequential tests (P > 0.05); however, trends were noted for second tests detecting lower tumor inflammation (TIGS score) and PD-L1 IHC (P = 0.1). Further, second tests detected significantly lower levels of tumor inflammation when both were performed on non-breast tissue (P = 0.04), but not when performed on all breast (P = 0.7) or a mix of breast and non-breast (P = 0.6) tissues. An opposite trend was noted for PD-L1 where second tests detected lower levels of PD-L1 IHC when both tests were performed on breast tissue (P = 0.1), but not when performed on all non-breast (P = 0.4) or a mix of breast and non-breast (P = 0.5) tissue. Tissue-dependent trends were still present even when excluding lymph node specimens (P = 0.1). Conclusions: Changes in immunotherapy markers and immune gene expression signatures, on average, remained relatively stable over time, except for tumor inflammation and PD-L1 IHC when sequentially testing all non-breast or breast tissue, respectively. These observations highlight the utility of clinical CGIP testing in revealing temporal changes of the TME, which may help inform clinical trial or treatment strategies occurring over time for primary and metastatic breast cancer.

A randomized, open-label phase II/III efficacy and safety study of atezolizumab in combination with FLOT versus FLOT alone in patients with gastric cancer and adenocarcinoma of the oesophagogastric junction and high immune responsiveness: The IKF633/DANTE trial, a trial of AIO in collaboration with SAKK.

TPS4184 Background: Despite recent advances, long-term survival of patients with locally advanced, operable esophagogastric adenocarcinoma (EGA) is below 50%. Immune checkpoint inhibitors in the neoadjuvant setting of this tumor type have lately been shown to increase pathological responses in all comers (IKF633/DANTE pII, KEYNOTE-585, Matterhorn), but the effect on survival is still unknown. The IKF633/DANTE pIII trial evaluates the efficacy and clinical activity of atezolizumab (ATZ) with perioperative FLOT in patients (pts) with locally advanced, resectable EGA considered having an immune-responsive profile. Methods: IKF633/DANTE is conducted as a randomized, multinational, multicenter, prospective, investigator-initiated, open label phase II/III trial. For the phase III portion, pts with histologically confirmed EGA of a clinical stage ≥cT2 and/or cN+ without evidence of distant metastases and with at least one immune response criterium (MSI, PD-L1 CPS≥1, TMB ≥10/MB or EBV+) are eligible. Pts are stratified acc. to nodal stage (cN- vs. cN+), tumor site (GEJ type I vs. GEJ type II/III vs. gastric) and PD-L1 expression levels (CPS≥5 vs. CPS<5). Pts are randomized 1:1 to receive 4 pre- and post-operative cycles FLOT/ATZ, followed by 8 cycles ATZ maintenance (Arm A) or 2x4 perioperative cycles FLOT alone (Arm B). In total, 556 pts will be enrolled, thereof 379 pts in phase III. This estimates to a recruitment time of 30 months plus 18 months follow-up for 80% statistical power and a significance level of p<0.05 (two-sided log rank test). The primary endpoint is event-free survival (EFS) with a target hazard ratio of 0.72, reflecting a clinically relevant improvement to 41.65 months in arm A. Main secondary endpoints are pCR, overall survival (OS) also in high immune-responsive subgroups (CPS ≥5/ CPS≥ 10/ MSI), R0 resection rate and safety/tolerability. In addition, a prospective biomarker study with serial circulating tumor DNA (ctDNA) analysis accompanying therapy is performed to explore the prognostic impact of ctDNA on efficacy and survival parameters, as well as on relapse incidence. Recruitment of phase III started in Aug 2023 and is still ongoing. Clinical trial information: NCT03421288 .

Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Pattern of recurrence after stereotactic body radiotherapy of nodal lesions: a single-institution analysis.

Stereotactic body radiotherapy (SBRT) and/or single fraction stereotactic body radiosurgery (SRS) are effective treatment options for the treatment of oligometastatic disease of lymph nodes. Despite the encouraging local control rate, progression-free survival remains unfair due to relapses that might occur in the same district or at other sites. The recurrence pattern analysis after nodal local ablative RT (laRT) in oligometastatic patients is presented in this study. The pattern of failure of patients with nodal metastases who were recruited and treated with SBRT in the Destroy-1 or SRS in the Destroy-2 trials was investigated in this single-institution, retrospective analysis. The different relapsed sites following laRT were recorded. Data on 190 patients who received SBRT or SRS on 269 nodal lesions were reviewed. A relapse rate of 57.2% (154 out of 269 nodal lesions) was registered. The pattern of failure was distant in 88 (57.4%) and loco-regional in 66 (42.6%) patients, respectively. The most frequent primary malignancies among patients experiencing loco-regional failure were genitourinary and gynaecological cancers. Furthermore, the predominant site of loco-regional relapse (62%) was the pelvic area. Only 26% of locoregional relapses occurred contra laterally, with 74% occurring ipsilaterally. The recurrence rates after laRT for nodal disease were more frequent in distant regions compared to locoregional sites. The most common scenarios for locoregional relapse appear to be genitourinary cancer and the pelvic site. In addition, recurrences often occur in the same nodal station or in a nodal station contiguous to the irradiated nodal site. Local ablative radiotherapy is an effective treatment in managing nodal oligometastasis. Despite the high local control rate, the progression free survival remains dismal with recurrences that can occur both loco-regionally or at distance. To understand the pattern of failure could aid the physicians to choose the best treatment strategy. This is the first study that reports the recurrence pattern of a significant number of nodal lesions treated with laRT.