Presence Of Metastases Research Articles

Lymphatic flow mapping using near-infrared fluorescence imaging with indocyanine green helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer not treated with neoadjuvant chemotherapy

BackgroundLymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for the intraoperative prediction of lymph node metastasis in esophageal or esophagogastric junction cancer. However, a consistent method that yields sufficient diagnostic quality is yet to be confirmed. This study explored the diagnostic utility of our newly established lymphatic flow mapping protocol for predicting lymph node metastasis in patients with esophageal or esophagogastric junction cancer.MethodsWe injected 0.5 mL of ICG (500 μg/mL) into the submucosal layer at four peritumoral points on the day before surgery for 54 patients. We performed lymphatic flow mapping intraoperatively using NIR imaging. After determining the NIR status and presence of metastases, evaluable lymph node stations on in vivo imaging and all resected lymph nodes were divided into four categories: ICG+meta+ (true positive), ICG+meta− (false positive), ICG−meta+ (false negative), and ICG−meta− (true negative).ResultsThe distribution of ICG+ and meta+ lymph node stations differed according to the primary tumor site. Sensitivity and specificity for predicting meta+ lymph nodes among ICG+ ones were 50% (95% CI 41–59%) and 75% (73–76%), respectively. Predicting meta+ lymph node stations among ICG+ stations improved these values to 66% (54–77%) and 77% (74–79%), respectively. Undergoing neoadjuvant chemotherapy was an independent risk factor for having meta+ lymph nodes with false-negative diagnoses (odds ratio 4.82; 95% CI 1.28–18.19). The sensitivity of our technique for predicting meta+ lymph nodes and meta+ lymph node stations in patients who did not undergo neoadjuvant chemotherapy was 79% (63–90%) and 83% (61–94%), respectively.ConclusionOur protocol potentially helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer undergoing esophagectomy who did not undergo neoadjuvant chemotherapy.Graphical abstract

Pathomorphological analysis of budding in colorectal carcinomas

Morbidity and mortality from colorectal cancer (CRC) remains a current problem of modern oncology. Intensive budding is an important prognostic factor for a worse clinical course of CRC and may influence clinical decision-making regarding the use of extended interventions in pT1 and stage II, according to the conclusion of the 2016 International Consensus Conference on Tumor Budding. The aim of the work is to evaluate the prognostic significance of budding depending on the clinical and morphological characteristics of colorectal carcinomas. Materials and methods. The article deals with clinical and anatomical material of 31 patients with CRC (14 women and 17 men) who were treated in the 2nd surgical department of the SE “Dnipropetrovsk Regional Clinical Hospital” in the period from 2019 to 2021. The age of the patients varied of 27–84 years old (average age – 62.3 ± 14.8 years old). A histological examination of CRC samples was carried out with an assessment of “hot areas” of the invasive front and an immunohistochemical examination with РАН CK АЕ 1/3, Ki-67, MUC2, caspase-3, β-catenin to calculate the number of tumor cell clusters. Results. In one third of the number of samples, differences were determined not only in the number of clusters, but also in the budding category when stained by routine and immunohistochemical methods. Peritumoral budding of the invasive front with category Bd3 was always accompanied by intratumoral budding of varying degrees of intensity. The analysis of the distribution of gradations of budding of colorectal carcinomas by gender, age, location, histological degree of differentiation, and the presence of metastases did not show a statistically significant difference (p > 0.05), which may indicate the independence of this factor on the prognosis of patient survival. The intensity of budding of colorectal carcinomas depending on the expression of markers Ki-67, caspase-3 and β-catenin did not show a significant difference in subgroups (p > 0.05) but showed tendencies to increase the number of budding with an increase in the proliferation index and a decrease in the activity of the proapoptotic enzyme caspase-3. Conclusions. If the number of buds on the border of categories Bd1 and Bd2, or Bd2 and Bd3, determined by the standardized method of H & E staining is doubtful, the degree of budding may be underestimated in comparison with staining by the immunohistochemical method, due to the exclusion of falsely interpreted morphological objects as tumor clusters; the most reliable immunohistochemical marker for contrast separation of buds is a cocktail of cytokeratins.

278 Ewing's Sarcoma of the Duodenum: A Rare Case Presentation and Review of Literature

Abstract Introduction Ewing's sarcoma (ES) is a rare tumour with a tendency to metastasise early and recur. It commonly affects paediatric patients. The most common subdivision comprising 70% of all ES is Ewing's sarcoma of the bone. A review of the literature identified only 5 cases worldwide of primary ES arising from the duodenum. Case presentation We present a case of a 42-year-old man with no prior medical history who presented with right-sided abdominal pain. A computed tomography scan of the abdomen demonstrated a 7.7cm heterogeneous mass arising from the second part of the duodenum. Oesophagogastroduodenoscopy confirmed a malignant appearing duodenal lesion with biopsy showing features consistent with small cell carcinoma. The patient underwent three cycles of neoadjuvant chemotherapy followed by elective Kausch-Whipple pancreaticoduodenectomy. A combination of immunohistochemistry and molecular studies confirmed the diagnosis of a rare Ewing sarcoma tumour originating from the duodenum with invasion into the duodenal lumen. The patient recovered well from surgery and remains disease-free 18 months following resection. Discussion Literature search revealed this to be an extremely rare case. The optimal treatment strategy for patients with intestinal ES is unclear, with the results of the literature search demonstrating poor outcomes following surgical resection. The long-term prognosis of intestinal ES is unknown due to its rarity. Determinants of poor outcome include tumour size >5cm, tumours involving the pelvic site, old age, non-response to chemotherapy and presence of metastases. In the case we report, the combination of neoadjuvant chemotherapy and surgery led to a good short-term post-operative outcome.

164. INTRAOPERATIVE LYMPHATIC FLOW MAPPING USING INDOCYANINE GREEN PREDICTS LYMPH NODE METASTASIS IN ESOPHAGEAL CANCER PATIENTS NOT TREATED WITH NEOADJUVANT CHEMOTHERAPY

Abstract Background Lymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for the intraoperative prediction of lymph node metastasis (LNM) in various cancers. Previous studies examined the feasibility of applying this technique to patients with esophageal cancer. However, a consistent method that yields sufficient diagnostic quality has yet to be confirmed. This study explored the diagnostic utility of our established lymphatic flow mapping protocol for predicting LNM in esophageal cancer. Methods We injected 0.5 mL of ICG (500 μg/mL) into the submucosal layer at four peritumoral points on the day before surgery for 54 patients. We performed lymphatic flow mapping intraoperatively using NIR imaging. After determining the NIR status and presence of metastases, evaluable lymph node stations on intraoperative NIR imaging and all resected lymph nodes were divided into four categories: ICG + meta+ (true positive), ICG + meta− (false positive), ICG − meta+ (false negative), and ICG − meta− (true negative). Logistic regression models were used to investigate the characteristics of patients with LNs or LN stations associated with high false-negative rates. Results The distribution of ICG+ and meta+ lymph node stations differed according to the primary tumor site. Sensitivity and specificity for predicting meta+ lymph nodes among ICG+ ones were 50% and 75%, respectively. Predicting meta+ lymph node stations among ICG+ stations improved these values to 66% and 77%, respectively. Undergoing neoadjuvant chemotherapy was an independent risk factor for having meta+ lymph nodes with false-negative diagnoses (odds ratio: 4.82; 95% confidence interval: 1.28–18.19). The sensitivity of our technique for predicting meta+ lymph nodes and meta+ lymph node stations in patients who did not undergo neoadjuvant chemotherapy was 79% and 83%, respectively. Conclusion Our NIR imaging protocol potentially helps to predict lymph node metastasis intraoperatively in patients with esophageal cancer undergoing esophagectomy who had not undergone neoadjuvant chemotherapy. This technique may effectively serve as a parameter for assessing the need for dissecting LNs in each station and determining whether it is applicable to reduce the extent of lymphadenectomy.

SPIRITUAL SUPPORT FOR SYNOVIAL SARCOMA WITH GRIEF AND LOSS: BARGAINING PHASE

Background: Synovial sarcoma is a rare high-grade soft tissue tumor, which is about 5% to 10% of the total soft tissue sarcoma and can occur at various ages. The prognosis in patients with synovial sarcoma is influenced by many characteristics of the disease, namely tumor size, invade locality, histologic type, presence of metastases and lymph node involvement, and successful surgery. Surgery can have an impact, namely the problem of grieving in sufferers. Spirituality is an important indicator of quality of life and an aspect that reduces the negative impact of an ineffective grieving process. In helping patients cope with grieving responses, spiritual support is provided not only by religious practices. Spiritual support also refers to activities that provide a calm atmosphere, provide entertainment, listen to patients, provide and respect privacy, and support patients' search for meaning and purpose in life. Objective: The aim of the research was to apply nursing care which includes assessment, determination of diagnoses, interventions based on evidence-based practice, implementation and evaluation of nursing. Methods: The research methods used are interviews, observation and documentation studies. The design of this research is a case study with synovial sarcoma patient respondents who were given spiritual support nursing interventions. Result: Based on the results of the nursing evaluation, there was a decrease in the level of grieving in patients after being given spiritual support. Conclusion: Thus, the patient's care plan is continued by the ward nurse and encourages the patient and family to use spiritual support as a step to overcome feelings of grief.

Metastatic Malignant Glomus Jugulare Tumor: A Rare Case Report with Clinical Manifestations and Treatment Approach.

BACKGROUND Paragangliomas are neuroendocrine neoplasms derived from paraganglia of the sympathetic and parasympathetic nervous systems. Parasympathetic ganglia-derived tumors, also called non-chromaffin, are located almost exclusively in the neck and skull base and are usually non-secretory and inactive. A case of malignant glomus jugulare with a metastatic cervical lymph node is described here. CASE REPORT A 24-year-old woman was referred to an otolaryngology clinic for concern of voice change for 1 month, which was associated with right progressive hearing loss, pulsating tinnitus, and right facial weakness. A clinical examination revealed a reddish mass in the right ear behind an intact tympanic membrane with right facial weakness of House-Brackmann grade VI. A bedside flexible nasopharyngoscopy revealed an immobile right vocal fold. A computed tomography scan of the brain revealed a destructive lesion within the right jugular foramen. The patient underwent embolization followed by glomus tumor resection via infra-temporal fossa with Fisch type A approach. Pathology revealed that the tumor was an infiltrative epithelioid tumor with a spindle and nesting pattern separated by fibrovascular stroma. The submitted lateral neck lymph node revealed a metastatic tumor. CONCLUSIONS Glomus jugulare tumors are uncommon paragangliomas, and malignant behavior with metastasis is extremely rare. Metastatic tumors are often associated with facial and vagal nerves palsy. There are no histological features that distinguish malignant glomus jugulare tumors. Malignant neoplasms are characterized by the presence of metastases. Tumors of the glomus jugulare that are malignant are treated with surgery, radiotherapy, or both. However, our search of the literature revealed no clear guidelines, given the scarcity of cases. Moreover, the presence of metastasis increases the risk of death.

Impact of Time to Metastasis (Synchronous vs. Metachronous) on Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with First Line Immune-Checkpoint Inhibitors (ICI)-based Combinations

Abstract Background Metastatic renal cell carcinoma (RCC) can present as synchronous metastatic disease, where primary metastases are detected at the time of diagnosis, or metachronous disease, where metastases appear during follow-up after initial RCC diagnosis. The effect of time to metastasis on patient outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assess the differences in clinical outcomes between patients with synchronous and metachronous mRCC. Methods Data for mRCC patients treated with first line ICI-based combination therapies between 2014 and 2023 were retrospectively collected from two NCI-designated comprehensive cancer centers. Patients were categorized as having synchronous or metachronous disease based on the time of presentation of metastases. Synchronous disease was defined as the presence of metastases at the time of RCC diagnosis or within 3 months thereafter. The study endpoints were time to treatment failure (TTF), overall survival (OS), and disease control rate (DCR). TTF and OS were estimated by Kaplan-Meier method and compared based on the time of presentation of metastases using log-rank tests. Univariable and multivariable Cox proportional hazard models and logistic regression models were used to examine the impact of sex, IMDC risk score, histology, and age at treatment start on TTF, OS and DCR. Results A total of 223 patients (126 synchronous and 97 metachronous) diagnosed with mRCC were included in the analysis. No significant difference was seen in gender distribution or age at first line treatment between these two groups. Although not statistically significant, the synchronous group had a higher proportion of patients with non-clear cell histology compared to those with metachronous disease (21% vs. 11%, P = 0.057). The median TTF was shorter in patients with synchronous disease but did not reach statistical significance (9 vs. 19.8 months for synchronous and metachronous, respectively, HR 1.37, 95% CI [0.98, 1.92], P = 0.064). Median OS was significantly shorter in patients with synchronous disease (28.0 vs. 50.9 months, adjusted HR 2.23, 95% CI [1.36, 3.65], P = 0.001). Similarly, patients with synchronous mRCC had a lower DCR than patients with metachronous (58.7% vs 78.4%, adjusted odds ratio (OR) 0.29, 95% CI [0.13, 0.64], P = 0.002). In the multivariable analysis, synchronous disease remained an independent factor associated with worse OS and DCR. Conclusions Patients with metastatic disease at the time of RCC diagnosis who were treated with first line ICI-based combinations have a poorer OS, and worse DCR than those who develop metastatic disease during follow-up. Although further validation is needed, these findings could be valuable in designing clinical trials and selecting patients for treatment escalation and closer clinical follow-up. CDMRP DOD Funding: no

Improved Characterization of Circulating Tumor Cells and Cancer-Associated Fibroblasts in One-Tube Assay in Breast Cancer Patients Using Imaging Flow Cytometry.

Circulating tumor cells (CTCs) and circulating cancer-associated fibroblasts (cCAFs) have been individually considered strong indicators of cancer progression. However, technical limitations have prevented their simultaneous analysis in the context of CTC phenotypes different from epithelial. This study aimed to analyze CTCs and cCAFs simultaneously in the peripheral blood of 210 breast cancer patients using DAPI/pan-keratin (K)/vimentin (V)/alpha-SMA/CD29/CD45/CD31 immunofluorescent staining and novel technology-imaging flow cytometry (imFC). Single and clustered CTCs of different sizes and phenotypes (i.e., epithelial phenotype K+/V- and epithelial-mesenchymal transition (EMT)-related CTCs, such as K+/V+, K-/V+, and K-/V-) were detected in 27.6% of the samples and correlated with metastases. EMT-related CTCs interacted more frequently with normal cells and tended to occur in patients with tumors progressing during therapy, while cCAFs coincided with CTCs (mainly K+/V- and K-/V-) in seven (3.3%) patients and seemed to correlate with the presence of metastases, particularly visceral ones. This study emphasizes the advantages of imFC in the field of liquid biopsy and highlights the importance of multimarker-based analysis of different subpopulations and phenotypes of cancer progression-related cells, i.e., CTCs and cCAFs. The co-detection of CTCs and cCAFs might improve the identification of patients at higher risk of progression and their monitoring during therapy.

Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer

Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.

Apport de l’IRM corps entier au bilan initial du liposarcome myxoïde

IntroductionMyxoid liposarcoma is a soft tissue sarcoma associated with multifocal metastases at diagnosis. These metastases are asymptomatic and occult on CT and FDG-PET and can alter the therapeutic management and prognosis. In this context, we evaluated the contribution of whole-body MRI to the initial workup of patients with myxoid liposarcoma. MethodThis retrospective study was conducted between January 2015 and December 2020 at the Oscar Lambret Center. We enrolled 22 patients who were diagnosed with myxoid liposarcoma and underwent whole-body MRI at diagnosis. The number of metastases at diagnosis, their location, and the visibility of these lesions on CT were evaluated. Associations between clinical features, presence of metastasis, and their impact on management were assessed. ResultsSixteen patients (72.7%) had non-metastatic disease at the initial diagnosis, and 15 of these patients were managed using local treatment. Six patients (27.3%) had metastases at multiple locations and received chemotherapy. The main locations were the bones (n=5) and lungs (n=3). In five patients with metastases, whole-body MRI demonstrated additional lesions that were not visible on CT (bone and soft tissue lesions). Only the presence of a round cell contingent (P=0.009) was found as a criterion associated with the presence of metastases. ConclusionThe patients’ young age, absence of reliable prognostic factors at diagnosis, asymptomatic nature of the lesions, and the benefits of early and targeted therapeutic management encourage the use of whole-body MRI as part of the initial work-up as it seems to provide a better initial staging compared with conventional imaging.

The Prognostic Value of Serum Biomarkers for Survival of Children with Osteosarcoma of the Extremities.

Osteosarcoma is a highly aggressive malignant bone tumor that affects mainly adolescents and young adults. We analyzed serum biomarkers for their prognostic significance in children with osteosarcoma. In this retrospective study, we investigated the prognostic factors in 210 children who were treated for appendicular osteosarcoma, including patient age and sex, tumor site and size (≥8 cm or <8 cm), presence of metastasis, chemotherapy-induced tumor necrosis, serum levels of alkaline phosphatase (AP), C-reactive protein, serum hemoglobin, lactate dehydrogenase, erythrocyte sedimentation rate (ESR), leukocyte counts, platelet count, and neutrophil-lymphocyte ratio. A multivariate Cox regression model showed that high level of AP [HR of 1.73; 95% CI, 1.02 to 2.94], poor chemotherapy-induced tumor necrosis [HR of 2.40; 95% CI, 1.41 to 4.08] and presence of metastases at presentation [HR of 3.71; 95% CI, 2.19 to 6.29] were associated with poor prognosis at 5 years (p < 0.05). Inadequate surgical margins [HR 11.28; 95% CI, 1.37 to 92.79] and high levels of ESR [HR 3.58; 95% CI, 1.29 to 9.98] showed a greater risk of local recurrence at 5 years follow-up (p < 0.05). AP and ESR can identify osteosarcoma-diagnosed children with a greater risk of death and local recurrence, respectively.

Osteosarcoma as a GES-Listed Pathology: 7-Year Experience at a National Reference Center

Osteosarcoma (OS) is the most frequent malignant primary bone tumor. The explicit health guarantee (GES) plan in Chile, a law that guarantees diagnosis, treatment, and rehabilitation, incorporated OS in 2014. To describe the characteristics of the population over 15 years, with a histopathological diagnosis of OS, to define survival rate and complications, and to identify variables that affect these outcomes. A retrospective study from 2014 to 2020, including all patients affiliated with the public health system diagnosed with OS, with histological confirmation. From clinical records, we extracted demographic data, anatomical OS location, histopathological findings, admission stage, presence of metastases, treatment, complications, and survival. We determined prognostic factors by multivariate analysis. 133 patients, 58.8% men, the average age was 31 years, and the most frequent location was the distal femur (34.9%). 56.4% of the patients were admitted in Enneking stage IIB, and 36.4% presented metastasis at admission. 14.3% presented complications, the most frequent periprosthetic infection (6 cases). 16% of patients evolved with local recurrence. The multivariate model showed that age and metastases at admission constitute independent prognostic variables, with a hazard ratio of 1.017 for age (p = 0.016) and 3.13 for metastases (p = 0.0000). In the subgroup analysis, patients without metastases at diagnosis had a 5-year survival of 54% versus 11% for the group with metastases. Adjusting for age, the 5-year survival for the non-metastatic and metastatic groups was 73% and 22%, respectively. This is our country's first demographic description study of patients with OS. In our series, the age of presentation and the presence of metastases at admission were factors that significantly affect prognosis. When adjusting for age, the survival percentages are comparable to those reported in other international centers specialized in sarcomas.

Validation of the prognostic value of a three-gene signature and clinical parameters-based risk score in prostate cancer patients.

The study aimed to validate the prognostic value of the Prostatype® risk score (P-score), which includes a three-gene signature and conventional risk factors, in a retrospective cohort. All 716 patients diagnosed with prostate cancer from 2008 to 2010 at Skåne University Hospital, Sweden, were included. After excluding patients based on pathological and clinical eligibility criteria, RNA quality, and presence of metastases at diagnosis, a final cohort comprising 316 patients was further analyzed. Expression levels of three genes (IGFBP3, F3, and VGLL3) were measured in archived formalin-fixed paraffin-embedded core needle biopsies. The gene expression data were combined with clinical parameters (Gleason score, prostate-specific antigen, and clinical tumor stage) to calculate the P-score for each patient. Predictive performance of the P-score in terms of prostate cancer-specific mortality (PCSM), distant metastasis and adverse pathological outcomes were investigated. The P-score predicted both PCSM (hazard ratio [HR] = 1.6) and metastasis (HR = 1.46). The P-score had an area under curve (AUC) of 0.93 when predicting the PCSM risk at 10 years (95% confidence interval [CI]: 0.89-0.98), which was significantly better than both D'Amico (AUC: 0.81, 95% CI: 0.72-0.90, p < 0.001) and UCSF-CAPRA (AUC: 0.88, 95% CI: 0.80-0.96, p < 0.05). Decision curve analysis showed a higher net benefit of the P-score compared to both D'Amico and CAPRA. All three risk scores performed similarly in the prediction of distant metastases. For patients who underwent radical prostatectomy (RP), a higher P-score correlated with adverse pathological features such as pathologic tumor stage T3-4 (p < 0.0001) and ≥International Society of Urological Pathology grade group 3 (p < 0.0001). Our findings provide evidence for the prognostic value of the P-score. The P-score predicted the risk for PCSM more accurately than the D'Amico and CAPRA scores. Performance was similar when predicting the risk for development of distant metastases within 10 years. Moreover, the P-score correlated with adverse pathological outcomes in RP specimens. Thus, the P-score could provide useful information for patients and their doctors to make informed decisions at the time of diagnosis.

Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.

Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.

Can we rely on contrast-enhanced CT to identify pancreatic ductal adenocarcinoma? A population-based study in sensitivity and factors associated with false negatives.

To determine the sensitivity of contrast-enhanced computed tomography (CECT) in detecting pancreatic ductal adenocarcinoma (PDAC) and identify factors associated with false negatives (FNs). Patients diagnosed with PDAC in 2014-2015 were retrospectively identified by a cancer registry. CECTs performed during the diagnostic interval were retrospectively classified as true positive (TP), indeterminate, or FN. Sensitivity TP/(TP+FN) was calculated for all CECTs and the following subgroups: protocol (uniphasic vs. biphasic); tumor size (≤ 2 cm vs. > 2 cm); and resectability (potentially resectable vs. unresectable). Multivariate logistic regression was performed to assess which of the following factors were associated with FN: clinical suspicion of PDAC; size >2 cm; presence of metastases; protocol; isoattenuating tumor; and potentially resectable disease on imaging. In total, 176 CECTs (127 uniphasic; 49 biphasic) in 154 patients (90 men, mean age 72 ± 11 years) were included. Sensitivity was 125/149 (83.9%) overall and 87/106 (82.1%) and 38/43 (88.4%) for uniphasic and biphasic protocols, respectively. Sensitivity was decreased for tumors ≤ 2 cm (45.4% vs. 90.6%), no liver metastases (78.0% vs. 95.9%), and potentially resectable disease (65.3% vs. 93.0%). Factors significantly associated with FN were clinical suspicion (OR, 0.24, 95% CI: 0.07-0.75), size>2 cm (OR, 0.10, 95% CI: 0.02-0.44), absence of liver metastases (OR, 4.94, 95% CI: 1.29-22.99), and potentially resectable disease (OR, 4.13, 95% CI: 1.07-16.65). In our population, the overall sensitivity of CECT to detect PDAC is 83.9%; however, this is substantially lower in several scenarios, including patients with potentially resectable disease. This finding has important implications for patient outcomes and efforts to maximize CECT sensitivity should be sought. The sensitivity of CECT to detect PDAC is significantly decreased in the setting of sub-2 cm tumors and potentially resectable disease. A dedicated biphasic pancreatic CECT protocol has higher sensitivity and should be applied in patients with suspected pancreatic disease. • The sensitivities of contrast-enhanced CT for the detection of PDAC were 87/106 (82.1%) and 38/43 (88.4%) for uniphasic and biphasic protocols, respectively. • The sensitivity of contrast-enhanced CT was decreased for small tumors ≤ 2 cm (45.4% vs. 90.6%), if there were no liver metastases (78.0% vs. 95.9%), and with potentially resectable disease (65.3% vs. 93.0%). • Absence of liver metastases (OR, 4.94, 95% CI: 1.29-22.99) and potentially resectable disease (OR, 4.13, 95% CI: 1.07-16.65) were associated with a false--negative (FN) CT result; suspicion of malignancy on the imaging requisition (OR, 0.24, 95% CI: 0.07-0.75) and size > 2 cm (OR, 0.10, 95% CI: 0.02-0.44) were negatively associated with FN.

Abstract A024: Glucocorticoid receptor-induced non-muscle caldesmon regulates growth and metastasis in castration-resistant prostate cancer

Abstract Lethal prostate cancer (PCa) is characterized by the presence of metastases and the development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. The goal of our study was to characterize the potential role of l-CaD in PCa metastases and antiandrogen therapy resistance. In this study, we extracted co-expression data of l-CaD from the largest public PCa patient data sets and identified the common transcripts between the sets. The common co-expression hits were used to recognize biological processes associated with l-CaD in the PCa context. Next, we used in vitro techniques, including 3D culture, cell viability assays, immunofluorescence staining, and Western blotting, to study the role of l-CaD in PCa with a focus on cancer hallmarks and the recognized associated biological processes. Finally, we used in vivo zebrafish and mouse xenograft models to verify the findings observed in silico in PCa patient data and in vitro in PC3, DU145, and VCaP cell lines. Here, we report that in vitro downregulation of l-CaD promotes the epithelial phenotype and reduces the spheroid growth in 3D, which is reflected in vivo in the reduced formation of metastases in a zebrafish PCa xenograft model. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets and that GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation. Citation Format: Verneri Virtanen, Kreetta Paunu, Antti Kukkula, Saana Niva, Ylva Junila, Mervi Toriseva, Terhi Jokilehto, Sari Mäkelä, Riikka Huhtaniemi, Matti Poutanen, Ilkka Paatero, Maria Sundvall. Glucocorticoid receptor-induced non-muscle caldesmon regulates growth and metastasis in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A024.

Concordance between liquid and tissue biopsy in participants with newly diagnosed recurrent breast cancer.

1028 Background: Tissue biopsy is recommended to confirm breast cancer (BC) recurrence. Liquid biopsy [including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA)] is a non-invasive approach for detecting cancer that may provide information to identify treatment choices and replace invasive biopsies. This ongoing study aims to assess the concordance between tissue and liquid biopsy testing in subjects presenting with suspicion of distant recurrence from BC. Methods: Patients with suspected metastatic BC were enrolled; tumour characteristics and treatment were recorded. Blood samples were collected within 30 days before tissue biopsy, or within 7-28 days after tissue biopsy and before any systemic or radiation treatment. Samples were shipped to EPIC Sciences and processed within 96 hours; after plasma isolation, nucleated cells were plated; slides and plasma were banked. CTCs were identified using Epic Sciences digital imaging and machine learning algorithms. Single-cell isolation for genomic ctDNA analysis was performed. Cell free DNA was analyzed using a validated NGS panel to detect ctDNA alterations. The presence of metastases was classified as suspicious, highly suspicious, definitely metastatic BC or other by the treating oncologist based on the patient's clinical presentation and biopsy pathology results. Epic Sciences classified samples into similar categories based on CTC and ctDNA assay results. These classifications were performed independently. Sensitivity of the Epic Sciences methodology to detect metastatic BC (as determined by the treating oncologist), and its false positive rate were calculated. Results: 100 patients were enrolled from June 2020 to October 2022; shipping delays precluded EPIC assays in six patients; 94 patients were analyzed. Of 83 cases deemed suspicious, highly suspicious, or definitely metastatic BC by the treating oncologist, 61 were also deemed so by Epic Sciences (sensitivity of 73.5%, 95% confidence interval, CI 63.1% - 81.9%). Of 66 cases assigned as suspicious, highly suspicious, or definitely metastatic BC by the Epic Sciences, 4 had new primary cancers (3 lung cancer, 1 hepatocarcinoma), for a false positive rate of 6.1% (95% CI 1.9% - 15.0%). One additional case was classified as un-specified adenocarcinoma (possibly breast) by the treating oncologist; resolution awaits further follow-up. Conclusions: Preliminary results show that 73.5% of distant BC recurrences were correctly identified by liquid biopsy. A small number of false positive results occurred in patients with other new primary cancers. Additional analyses with CTC characterization are ongoing. [Table: see text]

Head and neck embryonal rhabdomyosarcoma clinical outcomes determinates: A pooled database analysis.

e23537 Background: Embryonal rhabdomyosarcoma (ERS) is a soft tissue sarcoma of skeletal muscle with mesenchymal precursor cells that involve the genitourinary system or head and neck. Currently, head and neck embryonal rhabdomyosarcoma (HNERS) is considered a similar entity to other ERS subtypes by the Intergroup Rhabdomyosarcoma Study Group (IRSG), with only parameningeal disease being considered as high risk. We seek to identify other higher risk phenotypes in this population. Methods: To study the demographic, molecular and IHC characteristics, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 101 cases of HNERS. Kaplan-Meier survival curves, Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: 101 patients with confirmed HNERS were identified: median age of 6.5 years, male predominance with M:F ratio of 1.7. While R0 was achieved in 44%, surgical R1 and R2 were feasible in 13% and 44% of the cases. HNERS involved the following anatomic sites: Parameningeal (49%), Skull (40%), Maxilla (39%), Nasopharynx (34%), Ears (25%), Oropharynx (17%), Nervous system (16%), Larynx (14%), Mandible (12%), Internal Jugular (7%), Orbit and Carotids (6% each), Tongue (3%), and thyroid (2%). Lymph nodes, and bone marrow were involved in 11% and 2%, respectively. Metastases occurred in 4%. The stage distribution consisted of stage I (41%), stage II (34%), stage III (19%), and stage IV (6%). Clinical groups comprised: IA(23%), IB(4%), IIA(8%), IIB(3%), IIIA(45%), IIIB(12%), and IVA(4%). Risk groups consisted of low (53%), intermediate (41%), and high (6%). The cohort’s median DFS was 240 months whereas the median OS was not reached. OS was negatively affected by parameningeal (p = 0.01), nasopharyngeal (p = 0.02), ear (p = 0.02), nerve (p = 0.0001), bone (p = 0.002), and LN (p = 0.0004) involvement. The presence of metastases was associated with worse OS (p = 0.0001). The IRSG staging system (p &lt; 0.0001), the risk groupings (p = 0.0001), and the clinical groupings (p = 0.06) correlated with OS, though the latter did not reach statistical significance. Compared to no treatment, localized therapies such as surgery and radiation therapy, and combination chemotherapy had statistically significant improvement in OS (p = 0.027). Achieving CR was associated with superior OS (p &lt; 0.0001). OS wasn't impacted by age, sex, extent of surgery, IHC, BM involvement or other head and neck anatomic site involvement. Conclusions: Embryonal Rhabdomyosarcoma of the Head and Neck is a distinct clinical subtype of ERS not fully defined by IRSG clinical groups when compared to other types of embryonal rhabdomyosarcoma. Parameningeal, nasopharyngeal, ear involvement had poor OS and should be considered as a clinical grouping. This study presents updated data from a pooled cohort of patients with HNERS.

Implementation of a knowledge-based mechanistic model of EGFR-mutant lung adenocarcinoma that considers tumor heterogeneity and metastases to reproduce disease progression upon EGFR-TKI administration.

e21190 Background: 16,4% of lung adenocarcinomas (LUAD) are presenting a mutation in the epidermal growth factor receptor (EGFR), resulting in its constitutive activation and leading to uncontrolled cell proliferation [1]. Tyrosine kinase inhibitors (TKI) have been developed to inhibit EGFR activity but the presence of metastases and resistance mutations explain the lack of durable response to the treatment [2]. Knowledge-based mechanistic models reproducing existing clinical trials, based on population characteristics, can be used to help the design of future clinical trials. In particular, they can inform on the best responders to given treatments. Methods: We developed a physiologically based pharmacokinetic model of osimertinib, a 3rd generation TKI, to account for the distribution of the drug in the primary tumor and metastases after oral administration. This model was then combined to a pathophysiological mechanistic model of EGFR-mutant LUAD to represent the impact of osimertinib on the signals arising from EGFR activation. The combined model outputs the evolution of the primary tumor and each metastasis to allow the evaluation of the patient progression according to the RECIST criteria. Furthermore, each tumor in the model is composed of several subclones each possessing their own set of mutations and therefore responding differently to the treatment. Data from the clinical trials FLAURA and AURA3, in which osimertinib was given respectively as first and second line, were used to calibrate the model. Visual predictive checks as well as statistical tests were performed to ensure the proper behavior of the model. Results: The model successfully reproduced the time to progression in an EGFR mutant LUAD population treated with osimertinib as first line or as second line. In addition, the model reproduced the causes of progression according to the RECIST criteria and the sites of apparition of new metastases (in lung, brain, liver and bone). Conclusions: Reproduction of real world data brings credibility to the model. This is essential to use the model as an investigational tool to provide relevant insights, potentially on the best responders to osimertinib. After validation with additional clinical patient level data, the model could be used to create synthetic control arms in upcoming clinical trials. This would grant an improved analysis of covariate relationships with the comparison of an investigational treatment to the standard of care osimertinib administered as first or second line. It would also reduce the number of patients needed in the trial.

Metastatic Dissemination: Role of Tumor-Derived Extracellular Vesicles and Their Use as Clinical Biomarkers.

Cancer is a major cause of mortality in humans; often, rather than the primary tumor, it is the presence of metastases that are the cause of death. Extracellular vesicles (EVs) are small structures released by both normal and cancer cells; regarding the latter, they have been demonstrated to modulate almost all cancer-related processes, such as invasion, angiogenesis induction, drug resistance, and immune evasion. In the last years, it has become clear how EVs are widely involved in metastatic dissemination as well as in pre-metastatic niche (PMN) formation. Indeed, in order to achieve a successful metastatic process, i.e., penetration by cancer cells into distant tissues, the shaping of a favorable environment into those distant tissue, i.e., PMN formation, is mandatory. This process consists of an alteration that takes place in a distant organ and paves the way for the engraftment and growth of circulating tumor cells derived from the tumor primary site. This review focuses on the role of EVs in pre-metastatic niche formation and metastatic dissemination, also reporting the last studies suggesting the EVs role as biomarkers of metastatic diseases, possibly in a liquid biopsy approach.