Adenocarcinoma Research Articles

SERPINA1 promotes the invasion, metastasis, and proliferation of pancreatic ductal adenocarcinoma via the PI3K/Akt/NF-κB pathway

Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells in vitro and in vivo. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.

Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming.

Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRASMUT-dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRASMUT-dependent manner.

Mechanisms of Action of Sea Cucumber Triterpene Glycosides Cucumarioside A0-1 and Djakonovioside A Against Human Triple-Negative Breast Cancer.

Breast cancer is the most prevalent form of cancer in women worldwide. Triple-negative breast cancer is the most unfavorable for patients, but it is also the most sensitive to chemotherapy. Triterpene glycosides from sea cucumbers possess a high therapeutic potential as anticancer agents. This study aimed to identify the pathways triggered and regulated in MDA-MB-231 cells (triple-negative breast cancer cell line) by the glycosides cucumarioside A0-1 (Cuc A0-1) and djakonovioside A (Dj A), isolated from the sea cucumber Cucumaria djakonovi. Using flow cytometry, fluorescence microscopy, immunoblotting, and ELISA, the effects of micromolar concentrations of the compounds on cell cycle arrest, induction of apoptosis, the level of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), and expression of anti- and pro-apoptotic proteins were investigated. The glycosides caused cell cycle arrest, stimulated an increase in ROS production, and decreased Δψm in MDA-MB-231 cells. The depolarization of the mitochondrial membrane caused by cucumarioside A0-1 and djakonovioside A led to an increase in the levels of APAF-1 and cytochrome C. This, in turn, resulted in the activation of caspase-9 and caspase-3 and an increase in the level of their cleaved forms. Glycosides also affected the expression of Bax and Bcl-2 proteins, which are associated with mitochondria-mediated apoptosis in MDA-MB-231 cells. These results indicate that cucumarioside A0-1 and djakonovioside A activate the intrinsic apoptotic pathway in triple-negative breast cancer cells. Additionally, it was found that treatment with Cuc A0-1 resulted in in vivo inhibition of tumor growth and metastasis of murine solid Ehrlich adenocarcinoma.

Comparison of computed tomography findings between perianal tumors originating from the anal sacs and perianal glands in dogs.

Tumors originating from the anal sacs and perianal glands are common tumors of the perianal region. However, differentiation of perianal tumors based on CT findings remains challenging because perianal tumors can show overlapping CT characteristics. Therefore, this retrospective, multi-institutional study aimed to identify the CT findings that can differentiate between tumors originating from the anal sacs and perianal glands in canines. Twenty dogs were included, with nine apocrine gland anal sac adenocarcinomas (AGASACAs), six perianal gland adenomas, three perianal gland carcinomas, and two perianal gland epitheliomas. The tumor CT features included the tumor growth pattern, tumor shape, cystic changes within the tumor, contrast enhancement pattern, displacement of the anus, and identification of the anal sacs. The prevalences of suspected metastatic lymphadenopathy of the iliosacral lymph centers and lung metastases were evaluated. The tumor volumes and values normalized to body weight were also assessed. The tumor growth patterns differed significantly between AGASACAs and perianal gland tumors. AGASACAs mostly showed unilateral growth, whereas perianal gland tumors mostly exhibited bilateral growth. CT features, except for the tumor growth pattern, failed to show significant differences between tumors arising from the anal sacs and those arising from the perianal glands. Although histopathological diagnosis remains the gold standard, this study's findings suggest that CT analysis of tumor growth patterns may help differentiate AGASACAs from perianal gland tumors.

Effect of elevated CEA levels on the outcome of colorectal cancer patients with different histopathologic types: A SEER population-based study.

Limited and contradictory evidence has been reported regarding the prognostic effects of carcinoembryonic antigen (CEA) on the prognosis and metastasis of classical adenocarcinoma (CA), mucinous adenocarcinoma (MA), and signet-ring cell carcinoma (SRCC) in colorectal cancer patients. We investigated the associations between histological subtypes and preoperative serum CEA levels in determining the oncologic outcomes of colorectal cancer (CRC) patients. A total of 47,692 patients with clearly diagnosed CRC were selected from the Surveillance, Epidemiology, and End Results (SEER) database and divided into two cohorts based on serum CEA levels: CEA-normal (C0) and CEA-elevated (C1). Chi-square analysis revealed a correlation between CEA levels and histological classification. We then included a newly defined interaction variable (H&CEA) in the Cox regression analysis, which demonstrated that this variable could serve as an independent prognostic factor (P<0.001). CA, in the context of elevated serum CEA levels, differed from the other two histopathological types, showing unexpectedly higher risks for both OS (HR = 1.70, 95% CI = 1.65-1.75, P<0.001) and CSS (HR = 1.78, 95% CI = 1.72-1.85, P<0.001). Furthermore, elevated CEA levels significantly increased the proportion of liver metastases in the CA group (25.43% vs. 3.95%, P<0.001). The interaction variable H&CEA can be used as an independent prognostic factor for CRC and should be considered in the diagnosis of CRC and the development of personalized treatment plans. Additionally, in the context of elevated CEA levels, CA is associated with poor prognosis and increased liver metastases. This CRC subgroup warrants special clinical attention from oncologists.

The Great Mimicker: Goblet Cell Adenocarcinoma of the Appendix Mimicking Mammary Carcinoma in a Patient with a History of Metastatic Breast Cancer

Abstract Introduction/Objective Goblet cell adenocarcinoma of the appendix is a rare and aggressive malignancy with high- grade histological patterns that pose diagnostic challenges due to their resemblance to other tumors. Previous reports have indicated that high-grade goblet cell adenocarcinoma may exhibit similarities to well-differentiated neuroendocrine tumors, and metastatic high-grade goblet cell adenocarcinoma can manifest diverse histologic growth patterns within a single section. Methods/Case Report We present a case of an 82-year-old female with a known history of breast cancer with sacral metastasis, presenting with a left upper quadrant “pinching” sensation. Histopathological examination following colectomy showed features of metastatic mammary carcinoma with mixed lobular (pleomorphic and partial signet ring cell type) and ductal features (Figure 1); Notably, different histologic patterns were observed in two tumor deposits, highlighting the complexity of the diagnosis (Figure 2). However, further investigation of the tip of the appendix revealed goblet-like mucinous cells arranged in a tubular growth pattern (Figure 3). Immunohistochemical stains were performed with adequate controls, revealing positive staining for CK20, SATB2, and CDX2, while showing negativity for BRST2, SATB2, GATA3, CK7, PR, ER, and HER2 (Figure 4). These findings corroborate the diagnosis of goblet cell adenocarcinoma. Results (if a Case Study enter NA) NA Conclusion In our case, we observed morphological features of goblet cell adenocarcinoma that overlapped with those of established mammary carcinomas. This scenario underscores the diagnostic challenges posed by rare tumors and emphasizes the significance of identifying the low-grade component of goblet cell adenocarcinoma, particularly in patients with a history of metastatic breast cancer.

First reported advanced pancreatic cancer with hyperprogression treated with PD-1 blockade combined with chemotherapy: a case report and literature review.

Pancreatic cancer is among the most immune-resistant tumor types due to its unique tumor microenvironment and low cancer immunogenicity. Single-agent immune modulators have thus far proven clinically ineffective. However, a growing body of evidence suggests that combination of these modulators with other strategies could unlock the potential of immunotherapy in pancreatic cancer. Herein, we describe the case of a 59-year-old male with metastatic pancreatic ductal adenocarcinoma, referred to our center to receive immunotherapy (serplulimab, a novel anti-PD-1 antibody) combined with chemotherapy (gemcitabine/nab-paclitaxel). During the initial three treatment cycles, the patient was assessed as having stable disease (SD) according to RECIST 1.1 criteria. However, following two additional cycles of combination therapy, the primary tumor mass increased from 4.9cm to 13.2cm, accompanied by the development of new lung lesions, ascites, and pelvic metastases. He succumbed to respiratory failure one month later. Retrospective analysis revealed that the patient had MDM4 amplification, identified as a high-risk factor for hyperprogressive disease (HPD). To our knowledge, this is the first reported case of HPD in pancreatic cancer with multiple metastases treated using combination therapy. We investigated the potential mechanisms and reviewed the latest literature on predictive factors for HPD. These findings suggest that while chemotherapy combined with immunotherapy may hold promise for treating pancreatic cancer, it is imperative to identify and closely monitor patients with high-risk factors for HPD when using immunotherapy.

Surgical Treatment and Clinical Evaluation of Calvarial Metastases.

The aim of this study is to explore surgical treatment techniques and clinical attributes associated with calvarial metastases, while providing a comprehensive review of the treatment experiences relevant to this particular type of tumor. This study involves a retrospective analysis of clinical data from 12 patients diagnosed with calvarial metastatic tumors who underwent surgical intervention. Among these patients, 5 had a history of previous malignant tumor resections, while 7 presented with calvarial metastatic tumors as their initial symptom. In all cases, the surgical approach consisted of calvarial tumor resection followed by titanium mesh repair. Following the surgical intervention, all patients underwent a comprehensive course of treatment, encompassing both local radiotherapy and systemic chemotherapy. In 1 instance, a patient presented with multiple tumors located in the central area of the frontal bone and the right temporal bone. The larger tumor situated in the middle of the frontal bone was surgically excised, while the tumor in the right temporal bone was treated using radiotherapy. In 2 cases characterized by multiple metastases within the skull, a comprehensive excision of all tumors was accomplished in a single surgical procedure. In the remaining cases featuring a solitary metastatic growth, the respective tumors were surgically removed. There were 10 instances of dura mater invasion and 3 cases involving the invasion of brain tissue. Pathologic examinations revealed 1 case of metastatic lung adenocarcinoma, 1 case of metastatic paraganglioma, 1 case of metastatic hepatocellular carcinoma, 2 cases of metastatic thyroid carcinoma, and 7 cases of metastatic clear cell renal cell carcinoma. Throughout the follow-up period, spanning from 14 to 90 months, various outcomes were noted. These included three occurrences of in situ recurrence. In addition, 1 patient required 3 distinct surgical interventions, while 2 other patients underwent 2 separate surgical procedures each. Notably, 1 of these cases involved the exposure of the titanium mesh on the scalp, necessitating the removal of the titanium mesh. Regrettably, there have been 9 recorded fatalities among the patients, while 3 individuals have survived. Solitary metastasis of calvarium region is rare, and surgical resection is effective. However, it is necessary to extend the resection range and combine with local radiotherapy to avoid local recurrence. Surgical intervention can significantly enhance the quality of life for affected patients. The prognosis of the patients mainly depends on the treatment of the primary disease and the situation of important organ dissemination and treatment.

Clinicopathological correlation of three cases of metastatic carcinoma to uterine cervix: An institutional experience

Abstract Introduction/Objective Metastasis to the female genital tract presents a rare occurrence and poses significant diagnostic hurdles. The uterine cervix, although less frequently implicated, presents additional challenges for metastatic spread owing to its diminutive dimensions, limited vascular perfusion, and abundance of fibrous tissue. Clinical manifestations often include abnormal vaginal bleeding in 62–75% of cases, frequently accompanied by involvement in other anatomical sites. Accurate identification of cervical tumor activity and its primary origin holds paramount importance for precise diagnosis, therapeutic stratagem, and prognostic assessment. Methods/Case Report Here we are reporting three cases that were encountered in our institution over a 5-year period. The first patient, a 63-year-old female with a history of breast cancer, six years later exhibited metastatic breast cancer in a cervical polyp, confirmed by positivity for AE1/AE3, GATA3, ER, and negativity for TTF-1, chromogranin, synaptophysin, PAX8, inhibin, calretinin, CDX-2, CD10, desmin, smooth muscle actin, S100, and HMB-45. The second patient, diagnosed with pancreatic adenocarcinoma, two years later manifested cervical metastasis confirmed via positive staining for CK7, CDX2, and focal p63, and did not express PAX8, vimentin, ER, p16, synaptophysin, and chromogranin. The third patient, diagnosed with lung adenocarcinoma, one year later presented with a cervical mass, histologically confirmed as metastatic lung adenocarcinoma via positivity for CK7, Napsin A, and TTF1, and negativity for PAX8, p16, p40, p53, GATA3, and ER. Results (if a Case Study enter NA) N/A Conclusion Given the challenges of identifying metastasis to the cervix, thorough diagnostic evaluation should be undertaken to differentiate primary versus metastatic disease in women with a history of non-cervical malignancy.

Pancancer analysis of NDUFA4L2 with focused role in tumor progression and metastasis of colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with a high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although NDUFA4L2 has high expressions in various tumors and affects tumor progression, its role in COAD remains unclear. The role of NDUFA4L2 in COAD was analyzed utilizing datasets available from public databases including The Cancer Genome Atlas, The Genotype-Tissue Expression (GTEx), Gene Expression Omnibus, Alabama Cancer Database (UALCAN), and The Human Protein Atlas databases. The prognostic value of NDUFA4L2 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NDUFA4L2 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NDUFA4L2 expression and immune cell infiltration levels was examined through single-sample gene set enrichment analysis (ssGSEA). The NDUFA4L2 expression levels in COAD patients and cell lines were validated through immunohistochemistry, immunofluorescence, qRT-PCR, and Western blot. Wound healing assay was also performed to evaluate the effect of NDUFA4L2 on COAD metastasis. Furthermore, the NDUFA4L2 mediated competing endogenous RNA (ceRNA) regulatory network was predicted and constructed through a variety of databases. The comprehensive pan-cancer analysis showed that NDUFA4L2 possesses diagnostic and prognostic value in many cancers, especially in COAD. GO-KEGG and GSEA analyses indicated that NDUFA4L2 was associated with multiple biological functions including epithelial-mesenchymal transition and adaptation to hypoxia. The ssGSEA analysis showed that NDUFA4L2 expression was associated with immune infiltration. In vitro experiments confirmed upregulation of NDUFA4L2 in COAD tissues and cell lines, and NDUFA4L2 overexpression significantly promoted migration of COAD cells. In addition, the C9orf139 /miR-194-3p axis was speculated as the possible upstream regulators of NDUFA4L2 in COAD. This study demonstrated that NDUFA4L2 upregulation was correlated with tumor progression, relapsed prognosis and aggressive migration of COAD, suggesting that NDUFA4L2 can act as an effective prognostic biomarker and a promising therapeutic target for COAD treatment.

Adaptive stereotactic radiosurgery for cerebral metastases of non-small cell lung cancer: a retrospective study

INTRODUCTION: Non-small cell lung cancer (NSCLC) is a common cause of brain metastases (BM). Adaptive stereotactic radiosurgery (ASRS) may be a useful option in the treatment of patients with large unresectable brain metastases (BM), but to date there are only a limited number of studies evaluating the effectiveness of this method.OBJECTIVE: To analyze the effectiveness of ASRS in patients with large BM NSCLC not subject to surgical resection.MATERIAL AND METHODS: We retrospectively analyzed data from 37 patients suffering from NSCLC with 45 large (&gt;2 cm in diameter, volume &gt;4 cm3) unresectable BM treated with the Gamma Knife Perfexion model using two- and three-fraction ASRS. Of these, 14 foci (31.1%) were metastases of squamous cell lung cancer, 31 (68.9%) were metastases of adenocarcinoma. The median volume of lesions treated with ASRS was 9.8 (range 4.6–30.6 cm3). The dynamics of volume changes between fractions and the cumulative incidence of local relapses (CILR) were studied, and ROC analysis was performed for the tumor volume parameter. Intracranial progression-free survival (iPFS) and overall survival (OS) were assessed. Statistics: To establish statistical significance of differences for related variables, the Wilcoxon test for pairwise comparisons and the Friedman test for three or more groups were used. The Kaplan-Meier method was used to calculate local control, PFS, and OS rates. The log-rank test was used to compare survival data in two groups.RESULTS: The median follow-up period was 19.4 months. With two-fraction ASRS, the median volume of metastasis decreased by 28.6% by the second session, with three-fraction — by 40.0% by the third session. The 1-year and 2-year CILR rates were 8.6±6.1%, respectively; 26.1±12.3%. In ROC analysis, the area under the curve (AUC) for tumor volume was 0.80 (95% CI 0.6– 1.0) with an optimal cutoff of 18.5 cm3. The differences in CILR between the groups with metastasis volume &lt;18.5 cm3 and ≥18.5 cm3 were statistically significant (p&lt;0.001). Median iPFS was 8.3 (95% CI 5.9–10.7) months, 1-year iPFS was 33.5±8.1%;2-year — 7.8±5.2%. Median OS was 13.2 (95% CI 9.0–17.4) months; 1-year OS — 52.9±8.7%, 2-year — 22.4±8.8%.DISCUSSION: Using two- and three-fraction ASRS, we delivered doses to large BM sufficient for a high level of local control with an acceptable risk of neurotoxicity: 1-year local control was 91.4%; 2-year — 73.9%; the incidence of radionecrosis is 8.5%. A statistically significant effect of lesion volume ≥18.5 cm3 on the risk of local recurrence was found. The iPFS and OS indicators after ASRS can be considered satisfactory for this group of patients.CONCLUSION: ASRS is an effective and perhaps optimal strategy for the treatment of large unresectable BM in patients with NSCLC, but comparison with other modern radiotherapy modalities such as stereotactic hypofractionated radiotherapy and WBRT with simultaneous integrated boost is needed.

Identification of novel diagnostic biomarkers associated with liver metastasis in colon adenocarcinoma by machine learning

BackgroundLiver metastasis is one of the primary causes of poor prognosis in colon adenocarcinoma (COAD) patients, but there are few studies on its biomarkers.MethodsThe Cancer Genome Atlas (TCGA)-COAD, GSE41258, and GSE49355 datasets were acquired from the public database. Differentially expressed genes (DEGs) between liver metastasis and primary tumor samples in COAD were identified by limma, and functional enrichment analysis were performed. MuTect2 and maftools were used to measure somatic mutation rates, while ADTEx was used to measure copy number variations (CNVs). The intersection of three machine learning methods, support vector machine (SVM), Random Forest, and least absolute shrinkage and selection operator (LASSO), is utilized to screen biomarkers, and their diagnostic performance is subsequently validated. The correlation between biomarkers and immune cells infiltration was analyzed by Spearman method.Results47 DEGs between liver metastasis and primary tumor samples in COAD were obtained, which were mainly enriched in the complement and coagulation, extracellular matrix (ECM), and peptidase regulator activity, etc. 38 out of 47 DEGs had mutations and exhibited a high frequency of CNV amplification or deletion. Furthermore, 3 biomarkers (MMP3, MAB21L2, and COLEC11) were screened, which showed good diagnostic performance. The proportion of multiple immune cells, such as B cells naive, T cells CD4 naive, Monocytes, and Dendritic cells resting, was higher in liver metastasis samples than that in primary tumor samples. Meanwhile, MMP3, MAB21L2, and COLEC11 exhibited an outstanding correlation with immune cells infiltration.ConclusionIn short, 3 biomarkers with good diagnostic efficacy were identified, providing a new perspective of therapeutic targets for liver metastasis in COAD.

Circulating tumor DNA predicts recurrence and survival in patients with resectable gastric and gastroesophageal junction cancer.

Gastric and gastroesophageal junction (GEJ) cancer represents a significant global health challenge, with high recurrence rates and poor survival outcomes. This study investigates circulating tumor DNA (ctDNA) as a biomarker for assessing recurrence risk in patients with resectable gastric and GEJ adenocarcinomas (AC). Patients with resectable gastric and GEJ AC, undergoing perioperative chemotherapy and surgery, were prospectively enrolled. Serial plasma samples were collected at baseline, after one cycle of chemotherapy, after preoperative chemotherapy, and after surgery. ctDNA was assessed by a ddPCR test (TriMeth), which targets the gastrointestinal cancer-specific methylation patterns of the genes C9orf50, KCNQ5, and CLIP4. ctDNA analysis was performed on 229 plasma samples from 86 patients. At baseline, ctDNA was detected in 56% of patients, which decreased to 37% following one cycle of chemotherapy, 25% after preoperative chemotherapy and 15% after surgical resection. The presence of ctDNA after one cycle of chemotherapy was associated with reduced recurrence-free survival (RFS) (HR = 2.54, 95% confidence interval (CI) 1.33-4.85, p = 0.005) and overall survival (OS) (HR = 2.23, 95% CI 1.07-4.62, p = 0.032). Similarly, ctDNA after surgery was associated with significantly shorter RFS (HR = 6.22, 95% CI 2.39-16.2, p < 0.001) and OS (HR = 6.37, 95% CI 2.10-19.3, p = 0.001). Multivariable regression analysis confirmed ctDNA after surgery as an independent prognostic factor (p < 0.001). ctDNA analysis has the potential to identify patients at elevated risk of recurrence, thus providing personalized treatment strategies for patients with resectable gastric and GEJ cancer. Further validation in larger cohorts and ctDNA-guided interventions are needed for future clinical use.

6857 Adrenal Incidentaloma In A Patient With Surgically Treated Lung Adenocarcinoma A Decade After Complete Remission

Abstract Disclosure: L. Kaur: None. R. Kaur: None. F. Haider: None. A. Iqbal: None. N. Patel: None. Adrenal incidentaloma is an adrenal mass &amp;gt;1 cm in size commonly discovered incidentally in up to 5-7% of patients on imaging performed for reasons other than adrenal causes. Metastasis to the adrenal glands is common due to their rich blood supply, with lung cancer being the most common primary site, followed by the stomach, esophagus and the liver. Bilateral adrenal metastasis is common, however isolated metachronous or synchronous adrenal metastasis is rare, with an incidence of 1-6%. We present a case of incidentally discovered isolated right adrenal mass ten years after curative surgical resection of right lung adenocarcinoma. A 74 year old male with history significant for adenocarcinoma of the right upper lung lobe stage 1A , negative for metastasis status post lobectomy and no adjuvant chemotherapy or radiation 10 years ago presented to the hospital for his routine follow up evaluation. His vitals were within normal limits and physical examination was unremarkable. The follow up diagnostic CT imaging was done which showed an incidental 2.1 x 1.6 x 1.2 cm right adrenal mass without any pathological lesion or lymphadenopathy. A review of CT scan done one year ago revealed no prior adrenal mass or other suspicious findings. The patient was referred to endocrinology for evaluation of the adrenal mass. He denied abdominal or right flank pain, headaches, palpitations, elevated blood pressure, sweating, muscle weakness, weight gain/loss and was healthy appearing. Lab work up including biochemical studies for hormonal over production, including aldosterone-renin ratio, adrenocorticotropic hormone, plasma catecholamines with urine metanephrines and urine cortisol were within physiological ranges. CT scan was repeated after 2 months which revealed right adrenal mass of 3.2 x 1.8 x 1.7 cm in size with heterogeneity and high pre contrast density. Given the patient's history of lung cancer, imaging characteristics and rapid interval increase in size, there was high suspicion for metastatic disease. Other differentials considered due to fast growth rate included adrenocortical carcinoma and less likely adrenal adenoma. A decision was made to proceed with right adrenalectomy for definitive resection and histological diagnosis secondary to quickly growing adrenal mass with no lymphadenopathy. The patient underwent laparoscopic adrenalectomy and the final pathological report was consistent with metastatic lung adenocarcinoma. Postoperatively the patient recovered well. At 2 week and 3 month follow up he reported no concerns. Isolated adrenal metastasis is unusual and rare but may occur in lung cancer patients years after curative resection of the primary tumor and hence long term annual follow up imaging and monitoring is recommended for prompt diagnosis and timely treatment. Presentation: 6/2/2024

8104 Rare Case Of Ectopic Cushing’s Syndrome Secondary To Metastatic Parotid Pleomorphic Adenocarcinoma

Abstract Disclosure: B.S. Neutel: None. P. Manroa: None. Background: Pleomorphic adenocarcinoma of the parotid gland is a rare malignancy and ectopic ACTH secretion from these tumors is very rarely described. We report a case of ectopic Cushing’s syndrome (CS) in such a patient and describe the clinical course. Clinical Case: A 69-year-old female with left parotid pleomorphic adenocarcinoma status post surgery and adjuvant radiotherapy presented to her local hospital approximately 7 months after initial treatment with proximal muscle weakness and near-syncope. Workup revealed profound hypokalemia at 1.6 mmol/L (n 3.5-5.3 mmol/L) along with new-onset hypertension (BP 175/110 mm Hg) and hyperglycemia with a HbA1c 6.5 % (n &amp;lt;5.7%), as well as metabolic alkalosis with a bicarbonate level of &amp;gt;40 mmol/L (n 22-32 mmol/L). A CT scan showed multiple liver metastases and a biopsy confirmed metastatic parotid pleomorphic adenocarcinoma. She was then transferred to our comprehensive cancer center for further management. She reported muscle weakness, easy bruising, and facial edema. She denied acne, hirsutism, or abdominal striae. Endocrine workup revealed a random cortisol of 56 mcg/dL (n 3-18 mcg/dL) and ACTH of 378 pg/mL (n 7.2-63.3 pg/mL). Her AM cortisol level remained unsuppressed at 79.2 and 59.4 mcg/dL (n&amp;lt; 1.8 mcg/dL) after 1 mg and 8 mg overnight dexamethasone suppression tests respectively. Late-night salivary cortisol was 7.9 mcg/dL (n &amp;lt;0.112 mcg/dL). An MRI of the sella was negative for any pituitary lesions. After stabilizing her clinical condition and correcting electrolyte abnormalities, she was started on chemotherapy with paclitaxel and carboplatin by the oncologist. Based on clinical suspicion of ectopic CS, ketoconazole was started and titrated upwards with rapid improvement of blood pressure, hypokalemia, and hyperglycemia. She was discharged home and antihypertensives were tapered off. ACTH staining on the liver biopsy was unable to be performed due to paucity of the specimen. A Ga-68-DOTATATE PET CT revealed increased radiotracer uptake in the liver lesion suggestive of SSTR 2 receptor positivity. Despite initial clinical improvement, her disease progressed with widespread liver, lymph node, and osseous metastases within 3 months necessitating escalating doses of ketoconazole, spironolactone, and potassium supplementation. The patient elected to pursue hospice care due to intolerance to chemotherapy and passed away shortly afterward. Conclusion: Although ectopic CS caused by parotid pleomorphic adenocarcinoma is rare, prompt recognition and treatment is necessary because ectopic ACTH production is associated with poor prognosis in these patients. Presentation: 6/3/2024

9316 Modulation Of Intracellular Lipid Access By ATGL Determines Ferroptosis Sensitivity In Castration-resistant Prostate Cancer

Abstract Disclosure: P. Cao: None. D. Awad: None. J. Han: None. D.E. Frigo: Grant Recipient; Self; GTx, Inc.. Other; Self; Familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics. Ferroptosis induction has recently been recognized as a novel therapeutic approach to alter the outcomes of drug-resistant cancer. Ferroptosis is cell death that is caused by the intracellular accumulation of toxic lipid hydroperoxides. Due to their elevated metabolism, castration-resistant prostate cancer (CRPCs) are highly prone to ferroptosis; yet, many of them manage to avert this cellular fate. We have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders CRPCs with the ability to resist ferroptosis. Our data has shown that ATGL deletion by CRISPR-Cas9 knockout method sensitized human CRPC cell lines such as C4-2, C4-2BLT, and PC3 cells to the ferroptosis inducer RSL3. In all cases, RSL3-mediated cell death could be blocked by the antioxidant Ferrostatin-1, confirming ferroptosis as the mechanism of cell death. Knocking out ATGL also augmented the ferroptosis inducer-mediated increase in lipid peroxides as indicated by the increased ratio of oxidized to non-oxidized C11-BODIPY 581/591. With regards to the mechanism for the sensitivity of ATGL KO to ferroptosis induction, previous research has established that the enzyme long-chain acyl-CoA synthetase 4 (ACSL4) is universally essential to facilitate ferroptosis. More specifically, ATGL(PNPLA2) was found to inversely correlate with ACSL4 in the Taylor et al., the TCGA PanCancer Atlas, and Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team) datasets in both primary and metastatic tumors. qPCR and western blot analysis of ACSL4 levels further showed that ACSL4 expression is closely tied to the lipase activity of ATGL. Addition of arachidonic acid significantly induced ferroptosis when combined with RSL3 in a dose-dependent manner only in ATGL KO cells. This indicates that PUFAs can render ATGL KO cells even more sensitive to RSL3-induced ferroptosis while cells with functional ATGL remain highly resistant, further reinforcing that ATGL is an essential safeguard of CRPC against ferroptosis. ATGL KO cells also demonstrated sensitivity to the antiandrogen Enzalutamide. The combination of Enzalutamide and RSL3 substantially decreased cell viability in ATGL KO cells as compared to control cells, indicating a strong synergy effect particularly seen in ATGL KO cells. In summary, this work demonstrates that ATGL is an important and novel regulator of ferroptosis in CRPC and supports the use of ferroptosis inducer as a new therapeutic approach in CRPC. Presentation: 6/2/2024

6463 A Case of Tumour-Induced Osteomalacia Which Remitted After Treatment of Metastatic Prostate Cancer

Abstract Disclosure: J. Chua: None. M. Chuah: None. A case Tumour-induced osteomalacia (TIO) which remitted after treatment of metastatic prostate cancer. Dr Chua Jia Min, Dr Matthew Chuah Bingfeng Abstract Case report: A 69-year-old gentleman with a known history of bladder cancer presented to the emergency department with fatigue, lower back pain and bilateral lower limb weakness worsening over the past one month. MRI and bone scan revealed extensive osteoblastic bone metastases across the skeletal system. This gentleman was referred to the Endocrinology service for the evaluation of high PTH. His corrected calcium was normal at 2.17mmol/L (2.09-2.46mmol/L) and iPTH was raised at 8.74pmol/L (1.60-6.90pmol/L). He was noted to have severe hypophosphatemia 0.34mmol/L (0.94-1.50mmol/L). Bicarbonate levels were normal, there was no glycosuria or proteinuria. There was no history of IV ferrous carboxymaltose use. Further investigations were consistent with urinary phosphate loss - TRP was 0.398 and TMP-GFR was 0.199. ALP was elevated at 282ug/L (39-99ug/L). 25-hydroxyvitamin D was low at 12 ug/L, which accounted for the high PTH levels (secondary hyperparathyroidism). FGF-23 levels returned high at 1293 RU/ml (&amp;lt;180 RU/ml). BMD showed osteoporosis with T-score of -2.6 at the left femoral neck. He was subsequently diagnosed with metastatic prostate adenocarcinoma, based on histology from a bone biopsy of an affected vertebrae. PSA was markedly raised at 606ug/L. A diagnosis of TIO secondary to metastatic prostate cancer was made. The patient was started on PO sodium-phosphate solution 4ml TDS (approximately 3mmol/kg/day of elemental phosphorus), calcitriol 0.25mcg BD and vitamin D was replaced. After phosphate was replete, the patient's weakness and fatigue improved. He was subsequently started on androgen deprivation therapy with leuprorelin acetate injection once every 3 months and apalutamide daily. SC denosumab 60mg Q6monthly was also commenced in view of extensive bone metastases. Repeat imaging showed response to treatment with decrease in the size of the prostate and bone lesions. His PSA levels are now undetectable and TMP-GFR has normalised. His oral phosphate and calcitriol doses were gradually reduced and subsequently stopped. His calcium and phosphate levels remain within normal limits on no supplementation, suggesting remission of his TIO. PTH levels normalised after vitamin D repletion. Learning points TIO is a rare paraneoplastic syndrome usually associated with mesenchymal tumours, and treatment involves resection of the causative tumour. Cases of TIO secondary to prostate cancer (an epithelial cancer) are exceedingly rare. Despite metastatic disease, this patient responded exceedingly well to his cancer therapy. Suppression of the tumour cells with androgen deprivation therapy resulted in the lack of phosphotonin production and remission of his TIO. Presentation: 6/1/2024

Development and external validation of a nomogram for predicting lymph node metastasis in 1-3cm lung adenocarcinoma.

Aim: This study aimed to investigate the risk factors for lymph node metastasis in 1-3cm adenocarcinoma and develop a new nomogram to predict the probability of lymph node metastasis.Materials & methods: This study collected clinical data from 1656 patients for risk factor analysis and an additional 500 patients for external validation. The logistic regression analyses were employed for risk factor analysis. The least absolute shrinkage and selection operator regression was used to select variables, and important variables were used to construct the nomogram and an online calculator.Results: The nomogram for predicting lymph node metastasis comprises six variables: tumor size (mediastinal window), consolidation tumor ratio, tumor location, lymphadenopathy, preoperative serum carcinoembryonic antigen level and pathological grade. According to the predicted results, the risk of lymph node metastasis was divided into low-risk group and high-risk group. We confirmed the exceptional clinical efficacy of the model through multiple evaluation methods.Conclusion: The importance of intraoperative frozen section is increasing. We discussed the risk factors for lymph node metastasis and developed a nomogram to predict the probability of lymph node metastasis in 1-3cm adenocarcinomas, which can guide lymph node resection strategies during surgery.

Transcriptomic analysis reveals Streptococcus agalactiae activation of oncogenic pathways in cervical adenocarcinoma.

Cervical adenocarcinoma (AC), a subtype of uterine cervical cancer (CC), poses a challenge due to its resistance to therapy and poor prognosis compared with squamous cervical carcinoma. Streptococcus agalactiae [group B Streptococcus (GBS)], a Gram-positive coccus, has been associated with cervical intraepithelial neoplasia in CC. However, the underlying mechanism interaction between GBS and CC, particularly AC, remains elusive. Leveraging The Cancer Genome Atlas public data and time-series transcriptomic data, the present study investigated the interaction between GBS and AC, revealing activation of two pivotal pathways: 'MAPK signaling pathway' and 'mTORC1 signaling'. Western blotting, reverse transcription-quantitative PCR and cell viability assays were performed to validate the activation of these pathways and their role in promoting cancer cell proliferation. Subsequently, the present study evaluated the efficacy of two anticancer drugs targeting these pathways (binimetinib and ridaforolimus) in AC cell treatment. Binimetinib demonstrated a cytostatic effect, while ridaforolimus had a modest impact on HeLa cells after 48 h of treatment, as observed in both cell viability and cytotoxicity assays. The combination of binimetinib and ridaforolimus resulted in a significantly greater cytotoxic effect compared to binimetinib or ridaforolimus monotherapy, although the synergy score indicated an additive effect. In general, the MAPK and mTORC1 signaling pathways were identified as the main pathways associated with GBS and AC cells. The combination of binimetinib and ridaforolimus could be a potential AC treatment.

Survival analysis of the metastatic cohort of Italian Association of Medical Oncology (AIOM) GARIBALDI survey

This analysis from the GARIBALDI study was aimed to address the role of center self-declared expertise, type and commitment on the overall survival (OS) of patients with metastatic Pancreatic Ductal Adenocarcinoma (mPDAC).Treatment-naïve patients ≥18-year with pathological diagnosis of mPDAC were enrolled. OS was defined as the time from chemotherapy start to death from any cause. The impact of clinical-demographic and centers characteristics on OS was evaluated using Cox models.Between July 2017 and October 2019, 473 patients enrolled in 43 centers were eligible for this analysis. Median age was 69.3 (first-third quartile 61.2–74.5); 46.1 % females; 90.8 % ECOG PS 0–1; 67.4 % had liver metastases; median CA19.9700.5 UI/mL (first-third quartile 77.5-6629.5). For 37.1 % of patients chemotherapy started <4 weeks from diagnosis; 69.9 % of patients received nab-paclitaxel + gemcitabine; 16.9 % gemcitabine alone; 7.6 % FOLFIRINOX. The median follow-up was 51.8 months and 428 patients died. No statistically significant role of the type of institution was observed. Additionally, no statistically significant role of neither the self-declared expertise nor the accrual rate was observed.The GARIBALDI study suggests that the self-declared center expertise and the academic brand are not associated to OS in patients with mPDAC, while center commitment warrants further exploration.