Liver Lesions Research Articles

Evaluation of colorectal liver metastases using virtual monoenergetic images obtained from dual-layer spectral computed tomography.

To assess the potential of virtual monoenergetic images in assessing colorectal liver metastasis (CRLM) compared with conventional CT images. This single-center, retrospective study included 173 consecutive patients (mean age, 65.5 ± 10.6years; 106 men) who underwent dual-layer spectral CT (DLSCT) between November 2016 and April 2021. Portal venous phase images were reconstructed using hybrid iterative reconstruction (iDose) and virtual monoenergetic imaging at 50keV. Four radiologists independently and randomly reviewed the de-identified iDose and 50keV images. Lesion detection, CRLM conspicuity, and CRLM diagnosis were compared between these images using a generalized estimating equation analysis. The reference standards used were histopathology and follow-up imaging findings. The study included 797 focal liver lesions, including 463 CRLMs (median size, 18.1mm [interquartile range, 10.9-37.7mm]). Lesion detection was better with 50keV images than with iDose images (45.0% [95% confidence interval [CI]: 39-50] vs 40.0% [95% CI: 34-46], P = 0.003). CRLM conspicuity was higher in the 50keV images than in the iDose images (3.27 [95% CI: 3.09-3.46] vs 3.09 [95% CI: 2.90-3.28], P < 0.001). However, the specificity for diagnosing CRLM was lower with 50keV images than with iDose images (94.5% [95% CI: 91.6-96.4] vs 96.0% [95% CI: 93.2-98.1], P = 0.022), whereas sensitivity did not differ significantly (77.6% [95% CI: 70.3-83.5] vs 76.9% [95% CI: 70.0-82.7], P = 0.736). Indeterminate lesions were more frequently noted in 50keV images than in iDose images (13% [445/3188] vs 9% [313/3188], P = 0.005), and 56% (247/445) of the indeterminate lesions at 50keV were not CRLMs. The 50keV images obtained from DLSCT were better than the iDose images in terms of CRLM conspicuity and lesion detection. However, 50keV images did not improve CRLM diagnosis but slightly increased the reporting of indeterminate focal liver lesions associated with CRLMs.

Percutaneous Cryoablation in the Liver: A Meta-Analysis and Review of Safety with a Focus on Incidence of Cryoshock and Major Complications.

The aim of the present meta-analysis was to systematically determine the overall complication rate and incidence of cryoshock in patients undergoing cryoablation of the liver. A systematic review and meta-analysis adhering to the PRISMA guidelines and focusing on studies of cryotherapy for liver malignancies published after 2000 were conducted. PubMed, Web of Science, Embase, and Scopus were systematically searched for articles reporting incidences of adverse events associated with percutaneous cryoablation in patients with liver malignancies. Data extraction and screening were independently conducted by two reviewers, who resolved discrepancies through consensus. Statistical analysis was performed to assess heterogeneity and pooled complication rates and included a moderator analysis to explore factors influencing the occurrence of complications. The initial search yielded 4,145 articles, of which 26 met our inclusion criteria. From these 26 articles, pooled data on 4,029 patients were extracted. Variance between studies reporting cryoshock was low (I2 = 13.15%), while variance among studies reporting major complications was high (I2 = 82.52%). The pooled weighted proportion of major complications was 4.71% while that of cryoshock was as low as 0.265%. Moderator analysis identified publication year as the only moderator for major complications and no moderator for the occurrence of cryoshock. Analysis of currently available evidence indicates that cryoablation has a relative safe profile with a pooled incidence of major complications below 5%. Cryoshock occurred in less than 0.3% of procedures and was not reported for liver lesions smaller than 3cm.

A non-invasive predictive model based on multimodality ultrasonography images to differentiate malignant from benign focal liver lesions

We have developed a non-invasive predictive nomogram model that combines image features from Sonazoid contrast-enhanced ultrasound (SCEUS) and Sound touch elastography (STE) with clinical features for accurate differentiation of malignant from benign focal liver lesions (FLLs). This study ultimately encompassed 262 patients with FLLs from the First Hospital of Shanxi Medical University, covering the period from March 2020 to April 2023, and divided them into training set (n = 183) and test set (n = 79). Logistic regression analysis was used to identify independent indicators and develop a predictive model based on image features from SCEUS, STE, and clinical features. The area under the receiver operating characteristic (AUC) curve was determined to estimate the diagnostic performance of the nomogram with CEUS LI-RADS, and STE values. The C-index, calibration curve, and decision curve analysis (DCA) were further used for validation. Multivariate and LASSO logistic regression analyses identified that age, ALT, arterial phase hyperenhancement (APHE), enhancement level in the Kupffer phase, and Emean by STE were valuable predictors to distinguish malignant from benign lesions. The nomogram achieved AUCs of 0.988 and 0.978 in the training and test sets, respectively, outperforming the CEUS LI-RADS (0.754 and 0.824) and STE (0.909 and 0.923) alone. The C-index and calibration curve demonstrated that the nomogram offers high diagnostic accuracy with predicted values consistent with actual values. DCA indicated that the nomogram could increase the net benefit for patients. The predictive nomogram innovatively combining SCEUS, STE, and clinical features can effectively improve the diagnostic performance for focal liver lesions, which may help with individualized diagnosis and treatment in clinical practice.

The Role of Diffusion-Weighted MRI in Correlation with Contrast-Enhanced MRI and Histopathology in the Evaluation of Focal Liver Lesions

The Role of Diffusion-Weighted MRI in Correlation with Contrast-Enhanced MRI and Histopathology in the Evaluation of Focal Liver Lesions

Mildly Increased 68 Ga-Pentixafor Uptake in Hepatic Hemangioma.

68 Ga-pentixafor uptake in hemangioma is rare. We report 68 Ga-pentixafor PET/MRI findings of a hepatic hemangioma in a 54-year-old woman. The images revealed a hyperintense lesion in the right posterior liver on T2-weighted images, with mild pentixafor uptake. The lesion was consistent with typical presentations of a hemangioma on MRI and contrast-enhanced CT.

Isolation and pathogenicity of a fowl adenovirus 8b (FAdV-8b) strain in Cherry Valley ducks

ABSTRACT Inclusion body hepatitis (IBH) is an economically important viral disease primarily affecting the poultry industry. In this study, we isolated a strain of FAdV-8b (strain SDYT) from naturally infected ducks and the hexon and fiber gene sequences were analysed by polymerase chain reaction (PCR) amplification. In order to study the pathogenicity of FAdV-8b in Cherry Valley ducks, we inoculated 10- and 20-day-old ducks with 0.3 ml of FAdV-4 virus (TCID50 of 105.5/0.1 ml) either orally or intramuscularly. Clinical signs, gross lesions and histopathological changes, cytokines, viral load and antibody levels were observed and recorded within 15 days after infection. Pathomorphological investigations revealed that ducks in the experimental group exhibited hepatitis. Histopathology showed multiple organ damage, including serious liver and kidney lesions. Furthermore, elevated levels of inflammatory cytokines and antibodies were noticed, due to the infection and innate immune response. At a later stage of infection, immunosuppression occurred, resulting in decreased levels of cytokines. Determination of viral load showed that the virus was present in several organs, with the highest viral DNA load found in the liver, followed by the kidney. Compared to birds infected orally, the intramuscular group exhibited the highest viral load. In summary, this study increases our understanding of the pathogenicity of FAdV-8b in ducks and establishes a model that will inform antiviral drug testing and vaccine evaluation for IBH, thereby preventing and reducing the spread of IBH in the poultry industry. RESEARCH HIGHLIGHTS A strain (SDYT) of fowl adenovirus 8b (FAdV-8b) was successfully isolated from ducks. Cherry Valley ducks were successfully infected with FAdV-8b. Different routes of infection can lead to duck mortality, more pronounced when birds are injected intramuscularly. FAdV-8b (SDYT) was distributed in various tissues and organs of ducks, causing different degrees of lesions.

Predictive Factors of Canine Malignant Hepatic Diseases with Multifocal Hepatic Lesions Using Clinicopathology, Ultrasonography, and Hepatobiliary Ultrasound Scores

Multifocal hepatic lesions in dogs arise from various benign and malignant liver diseases. Diagnosing these lesions is challenging because clinical signs, hematological data, and serum biochemistry are not definitive indicators. Ultrasound is utilized as a diagnostic imaging tool to evaluate liver parenchyma and detect hepatic lesions. This study aims to investigate the predictive factors that differentiate between benign and malignant multifocal hepatic lesions by examining ultrasound characteristics, blood tests, and serum biochemistry. In total, 43 dogs with multifocal hepatic lesions were included in this study. All dogs were classified into benign hepatic diseases (n = 32) and malignant haptic diseases (n = 11). For all dogs, their liver characteristics, lesion characteristics, and hepatobiliary ultrasound score by ultrasound were evaluated and we collected individual clinicopathological data for analysis. The findings of the univariate analysis revealed significant differences in four hematological and blood chemical parameters (hematocrit, white blood cell count, aspartate transaminase (AST), and alkaline phosphatase (ALP)) and six ultrasonographic parameters (liver parenchymal echogenicity, lesion homogeneity, lesion echogenicity, maximum lesion dimension, average lesion dimension, and hepatobiliary ultrasound score). Using multivariate analysis, only two parameters, hepatobiliary ultrasound score and lesion homogeneity, showed significant differences (p-value &lt; 0.001 and p-value = 0.011, respectively). Additionally, these parameters demonstrated high accuracy in predicting malignant multifocal liver lesions, with accuracy rates of 97.67% and 93.02%, respectively. Therefore, the hepatobiliary ultrasound score and lesion homogeneity are considered effective parameters for screening malignant multifocal liver lesions in dogs.

Comparison of diagnostic accuracy of radiomics parameter maps and standard reconstruction for the detection of liver lesions in computed tomography.

The liver is a frequent location of metastatic disease in various malignant tumor entities. Computed tomography (CT) is the most frequently employed modality for initial diagnosis. However, liver metastases may only be delineated vaguely on CT. Calculating radiomics features in feature maps can unravel textures not visible to the human eye on a standard CT reconstruction (SCTR). This study aimed to investigate the comparative diagnostic accuracy of radiomics feature maps and SCTR for liver metastases. Forty-seven patients with hepatic metastatic colorectal cancer were retrospectively enrolled. Whole-liver maps of original radiomics features were generated. A representative feature was selected for each feature class based on the visualization of example lesions from five patients. These maps and the conventional CT image data were viewed and evaluated by four readers in terms of liver parenchyma, number of lesions, visual contrast of lesions and diagnostic confidence. T-tests and chi²-tests were performed with a significance cut off of p<0.05 to compare the feature maps with SCRT, and the data were visualized as boxplots. Regarding the number of lesions detected, SCTR showed superior performance compared to radiomics maps. However, the feature map for firstorder RootMeanSquared was ranked superior in terms of very high visual contrast in 57.4% of cases, compared to 41.0% in standard reconstructions (p < 0.001). All other radiomics maps ranked significantly lower in visual contrast when compared to SCTR. For diagnostic confidence, firstorder RootMeanSquared reached very high ratings in 47.9% of cases, compared to 62.8% for SCTR (p < 0.001). The conventional CT images showed superior results in all categories for the other features investigated. The application of firstorder RootMeanSquared feature maps may help visualize faintly demarcated liver lesions by increasing visual contrast. However, reading of SCTR remains necessary for diagnostic confidence.

Pictorial review of hepatic echinococcosis: Ultrasound imaging and differential diagnosis.

Echinococcosis is a zoonotic disease caused by parasites belonging to the genus Echinococcus that primarily affect the liver. The western plateau and pastoral areas of China are high-risk regions for hepatic cystic echinococcosis and hepatic alveolar echinococcosis (HAE). The high late mortality rate associated with HAE underscores the critical need for early diagnosis to improve cure rates and mitigate the disease burden in endemic areas. Currently, the World Health Organization recommends ultrasonography as the preferred initial screening method for hepatic echinococcosis. However, distinguishing between specific types of lesions, such as those of hepatic cystic echinococcosis and HAE, and other focal liver lesions is challenging. To address this issue, contrast-enhanced ultrasound is recommended as a tool to differentiate solid and cysto-solid hepatic echinococcosis from other focal liver lesions, significantly enhancing diagnostic accuracy. In this comprehensive review, we discuss the progression of hepatic echinococcosis and detail the imaging features of various types of echinococcosis using conventional, contrast-enhanced, and intraoperative ultrasound techniques. Our objective is to provide robust imaging evidence and guidance for early diagnosis, clinical decision making, and postoperative follow-up in regions with high disease prevalence.

8273 ACTH-Dependent Cushing's Syndrome Due To Metastatic Cervical Cancer: A Case Report

Abstract Disclosure: T.D. Bertolacini da Silva: None. V.D. Kamura: None. P.D. Buchalla: None. A.G. Simoes: None. S. Glina: None. Z.M. Campos: None. I.S. Rosa: None. P.X. Santi: None. Background: The association of dependent Cushing's ACTH Syndrome with certain types of cancer is well known, such as small cell lung cancer, enteropancreatic tumors, thymoma, thyroid cancer, however, in association with cervical cancer there are almost no cases described. Clinical Case: A 39-year women, showed about 2.5 years ago with abnormal uterine bleeding, being submitted to colposcopy with the presence of exophytic, friable and hardened lesion in the anterior region of the cervix. Biopsies revealed adenocarcinoma, endometrioid type and immunohistochemistry (IHC) positive for: Ki-67 80%, vimentin and CEA. Patient underwent initial treatment with chemotherapy and radiotherapy, losing follow-up with Oncology. After 1 year, the patient was admitted to a hospital with behavioral alteration, including suicidal ideation, muscle weakness, breast enlargement and hair growth on the face. On physical examination, there was the presence of hypertension, hyperglycemia, centripetal obesity, legs edema and hirsutism. Due to the typical symptoms, the hypothesis of Cushing's Syndrome was made and laboratory and imaging tests were requested. Initial tests: K 1.9 mmol/L (3.5-5.6 mmol/L), Na 146 mmol/L (137-145 mmol/L), TSH 0.25 uIU/mL (0.49-5.58 uIU/mL/mL), free T4 0.78 ng/dL (0.89-1.53 ng/dL), pH 7.57 (7.36-7.41), HCO3 43.1 mmol/L (23-27 mmol/L), LH 0.15 mIU/mL (1.9-12.5 mIU/mL), FSH 1.02 mIU/mL (2.5-10 mIU/mL), estradiol 84.1 pg/mL (&amp;lt; 32.2 pg/mL), ACTH 365.0 pg/mL and 98.6 pg/mL (&amp;lt; 46 pg/mL), cortisol &amp;gt; 75 ug/dL (5.27-22.5 ug/dL), urinary cortisol 3790 ug/24h (4-60 ug/24h), testosterone 333 ng/dL (12 - 59 ng/dL), free testosterone 10.12 ng/dL (0.08-1.1 ng/dL), dehydrotestosterone 1,620 pg/mL (&amp;lt; 596 pg/mL), androstenedione &amp;gt; 10 ng/mL (0.3-3.3 ng/mL). The dosages of ACTH and cortisol were performed after the dexamethasone suppression test and a pituitary MRI was normal. The MRI of the abdomen and pelvis showed multiple solid nodular lesions in liver with varying sizes compatible with metastatic disease, in addition, showed the increase in the bilateral volume of the adrenals. Liver biopsy was performed exhibiting carcinoma infiltration with IHC compatible with neuroendocrine tumor, positive for: CDX-2, SATB2, chromogranin A and synaptophysin (waiting for ACTH). Other primary sites were ruled out. The patient was initially treated with Etomidate in a continuous infusion, without tolerance and little control of hypercortisolism, after initiating Ketoconazole which was suspended due to hepatotoxicity, and then underwent bilateral adrenalectomy. Unfortunately, she died 4 days after surgery due to septic shock. Conclusion: This case report brings a very rare association of Cushing's syndrome by ectopic ACTH due to cervical cancer, with less than 10 cases reported, in which we highlight the diagnostic difficulty, the complexity of treatment and the high risk of morbidity and mortality. Presentation: 6/1/2024

7040 Embolization Of Hepatic Metastases Is Effective For Palliative Management Of Severe Cushing Syndrome

Abstract Disclosure: S. Zhang: None. C. Musonza: None. A. Pillai: None. M. Ramos-Roman: None. J. Abramowitz: None. S. Mirfakhraee: None. P. Polanco: None. A.P. Dackiw: None. S. Al Mutar: None. A. Mallik: None. L. Jia: None. O. Hamidi: None. Background: Cushing syndrome (CS) due to metastatic endocrine neoplasms poses substantial treatment challenges. Arterial embolization and Yttrium-90 (Y-90) radioembolization for hepatic metastases are effective in the management of metastases due to neuroendocrine tumors (NETs). However, data are scarce on the role of embolization of liver metastases in patients with CS. Here, we report two cases of severe CS due to bulky hepatic metastases treated with embolization techniques. Case 1 A 49-year-old woman presented with severe ectopic CS and a 15-cm hepatic metastatic conglomerate. Liver biopsy showed NET of unknown primary. Treatment with subcutaneous octreotide and metyrapone (total daily dose 3000mg) resulted in modest improvement of serum cortisol from 89.8 to 45.8 mcg/dL. She was not a candidate for bilateral adrenalectomy or hepatectomy due to bulky hepatic metastases and subsequently underwent bland embolization to the hepatic conglomerate. Cortisol decreased from 63.9 mcg/dL to 13.8 mcg/dL after the initial procedure, but then rebounded to 35.8 mcg/dL. Serum cortisol decreased to 19.4 mcg/dL following additional embolization, and she was discharged on metyrapone 500mg three times daily. CS remained controlled 12 weeks after the procedure. Interval imaging showed a decrease in size of the dominant hepatic mass (9.7 cm). The patient is currently undergoing chemotherapy with carboplatin and etoposide. Case 2: A 40-year-old man presented to an outside institution with CS due to a 6.9 cm right adrenal mass and underwent adrenalectomy. Pathology showed oncocytic neoplasm of uncertain malignant potential. A year later, he presented to our hospital with recurrent CS and was found to have a 10.2 cm liver lesion, confirming stage IV adrenocortical carcinoma. FDG PET/CT did not show additional lesions. He was treated with osilodrostat and mitotane but his hypercortisolism remained uncontrolled. Mitotane was discontinued after a few doses due to side effects. Metastasectomy was attempted but halted due to extensive peritoneal carcinomatosis noted in the operating room. He was subsequently treated with Y-90 radioembolization to the liver metastasis. Afterwards, osilodrostat was held and serum cortisol decreased from 49.6 to 6.9 mcg/dL on day 14 post-procedure. Hydrocortisone was initiated for treatment of adrenal insufficiency. He received cisplatin, doxorubicin, and etoposide, but stopped after the first cycle due to side effects. Recent imaging showed a decrease in the hepatic lesion to 6.5 cm. Presently, the patient continues to have persistent adrenal insufficiency confirming remission of CS. Conclusion: These cases illustrate the potential efficacy of bland embolization and Y-90 radioembolization for palliative treatment of severe CS in patients with hepatic metastases. Presentation: 6/2/2024

6799 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

7044 It Is Back, Three Decades Later! When To Stop Glucagonoma surveillance?

Abstract Disclosure: A.T. Wahba: None. J.S. Dillon: Advisory Board Member; Self; Crinetics Pharmaceuticals, CA. A 76-year-old woman presented to the Neuroendocrine Tumor (NET) Clinic for evaluation of sore mouth, perianal area and itchy ankles. She had a medical history notable for glucagonoma, status post distal pancreatectomy and splenectomy in 1988, 32 years prior to her current presentation. She recalled that she had CT imaging post operatively for a few years, but no more recent imaging. She was diagnosed with diabetes mellitus in approximately 2002, with highly variable glucose control. She developed a left leg DVT with pulmonary emboli one year prior to presentation. Shortly after her thromboembolic events, she noted her current presenting complaints. A CT abdomen scan with contrast was reported as normal. Three months later, an abdomen ultrasound for evaluation of right upper quadrant pain and intractable vomiting, showed a liver mass. MRI revealed a contrast enhancing 3.1x2.1x1.8 cm lesion in liver segment 6 and 7. Her plasma Glucagon concentration, which had been undetectable when last checked in 2007, was 382 (N: &amp;lt; 80 pg/ml). CT-guided needle biopsy of the liver lesion confirmed a well differentiated neuroendocrine tumor, immunohistochemically positive for somatostatin receptor 2 (SSTR2A), Islet-1 and PAX6, with low mitotic count and Ki-67 proliferation index of 0.45%. Gallium-68 DOTATATE-PET scan showed a single avid hepatic metastasis, with no other evidence of somatostatin receptor expressing tumor. She was initially started on a combination of short-acting Octreotide 100 mcg TID and monthly 20 mg Sandostatin LAR injections for symptomatic relief. Zinc copper 100 mg capsules were prescribed with significant improvement of skin rash and glossitis within 2-4 months. Repeat MRI abdomen at 3 months and 6 months showed a stable single liver lesion without evidence of additional metastasis. She has continued annual clinic visits and abdomen MRI follow up with stable imaging findings at 3 years. Percutaneous ablation, trans hepatic arterial embolization and surgical resection were discussed, but the patient preferred a more conservative approach of monthly octreotide LAR, which she tolerated well, and which resolved her symptoms. Glucagonoma syndrome presents classically with 5D’s: Dermatitis (Necrolytic Migratory Erythema), DVTs, Diabetes mellitus, Depression, Diarrhea. The National Comprehensive Cancer Network guidelines recommend monitoring glucagonoma patients post-resection for up to 10 years with clinical evaluation, glucagon levels every 6-12 months and imaging studies as clinically indicated. Our case illustrates that recurrence can occur after 30 years from initial resection and that longer surveillance should be considered. Presentation: 6/3/2024

6799 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

8604 Ectopic Cushing’s Syndrome Associated with a Metastatic Pancreatic Mixed Neuroendocrine Non-neuroendocrine Neoplasm (MiNEN) with Amphicrine Features

Abstract Disclosure: A. DeMarsilis: None. C. Jiang: None. O. Lavrynenko: None. D. Motavalli: None. C. Musurakis: None. Z.H. Taxin: None. E.D. Rosen: Advisory Board Member; Self; Source Bio, Inc.. Consulting Fee; Self; Novartis Pharmaceuticals, Gensaic. M.S. Irwig: None. Background: Ectopic Cushing’s Syndrome (CS) makes up 9-18% of ACTH-dependent CS cases, of which fewer than 15% are attributed to pancreatic neuroendocrine tumors (1). Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare, aggressive carcinomas, often driven by high-grade neuroendocrine components, with a poor prognosis (2). Amphicrine neoplasms contain neuroendocrine and exocrine components in the same cell. Clinical Case: A 34 year-old woman with asthma, hypertension, and depression presented with new onset lower extremity edema, facial hirsutism, mood changes, polyuria and polydipsia. She had an elevated morning serum cortisol of 52 ug/dL (normal &amp;lt; 20) with plasma ACTH 42 pg/mL (normal &amp;lt; 50), 24-hour urine free cortisol of 1003 mcg (normal &amp;lt; 50), K+ of 2.6 mEq/L, and fasting glucose 164 mg/dL. CT showed multiple hepatic lesions, pulmonary nodules, a pancreatic tail lesion, and lymphadenopathy concerning for metastatic disease. Her adrenal glands were thickened bilaterally without nodules. A pituitary MRI was normal. These findings were concerning for ectopic CS. She was admitted due to rapidly developing symptoms. Potassium, insulin, sitagliptin, and prophylactic anticoagulation were started. Spironolactone and ketoconazole were initiated while awaiting biopsy results of liver and pancreas lesions. Osilodrostat was not available and a trial of metyrapone was poorly tolerated. The liver and pancreatic tail lesion biopsy revealed metastatic MiNEN with amphicrine features, of pancreatic origin, with Ki67 proliferation index of 70%. Section staining of pancreas and liver biopsies were negative for ACTH. A Ga-68 Dotatate scan showed minimal uptake, so octreotide was not prescribed. Palliative chemotherapy was planned. Although ketoconazole was titrated to 1600 mg/day, urine free cortisol levels and serum free cortisol levels did not reach target. Cushing disease was considered but not suspected, as ACTH levels remained modest despite a relative decrease in cortisol level. Given significant morbidity from uncontrolled hypercortisolism, and plans for urgent initiation of systemic chemotherapy, after multidisciplinary discussion the patient was treated with a surgical bilateral adrenalectomy. Post-operative morning serum cortisol measured 8.3 ug/dL. After one week, palliative chemotherapy with FOLFIRINOX (oxaliplatin, leucovorin, fluorouracil, and irinotecan) was initiated. She was discharged home on stress dose steroids with plan for taper. Conclusion: Ectopic ACTH secretion is a rare phenomenon, particularly when presenting with a rare case of metastatic pancreatic MiNEN with amphicrine features, associated with significant morbidity. To improve tolerance and survival of further treatment, early surgical bilateral adrenalectomy should be considered.

6590 Androgen Derived Hepatocellular Adenoma And Reinitiation Of Gender Affirming Hormone Therapy

Abstract Disclosure: A.L. McKenna: None. Y. Huang: None. L. Yang: None. N. Loo: None. C. Ritchie: None. A. Metcalfe: None. R. Nakhleh: None. M. Krishna: None. S. Thota-Kammili: None. J. Eleazer: None. A.Y. Chang: None. Hepatocellular adenomas (HCA) are uncommon, benign epithelial tumors of the liver. Risk factors include exogenous estrogen or androgen use, and genetic and metabolic syndromes. Management of HCA is delineated by sex assigned at birth; Observation is recommended in an HCA less than 5 cm in an individual assigned female at birth, while resection of an HCA in an individual assigned male at birth is recommended no matter the size due to risk of malignant transformation. What is not known is whether risk is different for individuals with gender incongruence on gender affirming hormone therapy (GAHT). There is limited data on the risk of HCA in this population. One case report of a transgender man who continued GAHT after diagnosis of an HCA though no follow-up information was available. We present follow-up on a transgender man assigned female at birth with multiple hemorrhagic HCA that was re-initiated on GAHT after stabilization of adenomas off GAHT. Unlike prior cases, the molecular profile showed ß-catenin negative, estrogen and androgen receptors positive. This is the first case report to our knowledge reporting detailed follow-up after restarting masculinizing GAHT after diagnosis of HCA. A 24-year-old transgender man presented to the emergency department with right upper quadrant pain. Initial labs were notable for ALT of 239 units per liter (U/L) and AST 165 U/L. Magnetic resonance imaging (MRI) of the abdomen and liver elastogram revealed multiple bilobar hepatic masses, the largest measuring 9.9 cm concerning for hemorrhagic HCA which was subsequently confirmed on liver biopsy. Immunostains were positive for estrogen and androgen receptors. The patient had no history of alcohol or illicit drug use, tattoos, or family history of liver disease. The patient had been treated with 100 mg of intramuscular testosterone cypionate weekly for the past six years for gender incongruence locally. No testosterone concentrations were available from prior to or during acute presentation. Discontinuation of hormone therapy was recommended along with conservative management with frequent MRI. Over the next 19 months, monitoring revealed improvement/resolution of the auto infarcting adenomas with the last MRI noting two stable HCA measuring 2.1 cm and 0.8 cm without new or enlarging liver lesions. Due to gender dysphoria off GAHT, reinitiation of hormone therapy with low dose AndroGel 1.62% topically was prescribed at 18 months after presentation. The patient has been monitored with labs monthly and plans to obtain MRI abdomen every three months. To date, the patient has tolerated reinitiation of therapy. This case demonstrates that patients on masculinizing GAHT who develop HCA can be conservatively managed and monitored based on pathology and that testosterone does not necessarily explain sex differences in the presentation/malignant transformation of HCA cisgender men as opposed to cisgender women. Presentation: 6/3/2024

12325 Adrenocortical Carcinoma Masquerading As Pheochromocytoma In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: E.M. Niedzialkowska: None. A.A. Banka: None. Introduction: The development of adrenocortical carcinoma (ACC) in patients with congenital adrenal hyperplasia (CAH) is rare. The patients with CAH are at increased risk of adrenal tumors which is attributed to ACTH stimulation of adrenal gland if the disease is not appropriately treated. ACC cases mistaken for pheochromocytomas have been reported in the literature and are attributed to the variety of immunohistochemical markers expressed by the tumors. Case description:59 y.o female with salt-wasting CAH diagnosed at the age of 2 (21-hydroxylase deficiency) on hydrocortisone supplementation reported to the hospital due to episodes of sweating, tachycardia and hypertension. Work up revealed mildly elevated plasma normetanephrine 1 nmol/l (N &amp;lt;0.9), urine normetanephrine 1762 mcg (N&amp;lt;899), VMA 11.2 mcg/24hr (N 3.3-7.2). MRI of the abdomen revealed 2 left adrenal masses of 3.7 and 2.4 cm, right adrenal gland hyperplasia and low T1 and T2 enhancement. I-123 MIBG revealed increased activity and thickness of the right adrenal gland and no significant uptake on the left with nodular masses. The patient underwent left adrenalectomy with pathological report consistent with pheochromocytoma due to positive chromogranin and synaptophysin staining and moderate Ki activity. A year later follow up imaging showed an enhancing mass up to 7 cm at the suprarenal fossa invading the left kidney that was positive for nodular adrenocortical hyperplasia per pathology report. The patient continued to have elevated 17-OH- progesterone (2740 ng/l, N &amp;lt;51) despite compliance with her steroid therapy and suppressed ACTH. She underwent mass resection along with nephrectomy, splenectomy, partial colectomy and partial pancreatectomy. Pathology report was positive for adrenocortical carcinoma (positive chromogranin, synaptophysin, CAM 5.2, polycystic cytokeratin, Ki positive in greater than 10% of the tumor cells) with renal and regional lymph node invasion and colonic metastases. The patient was started on mitotane therapy but a year later PET scan was positive for liver and omental metastases and was subsequently started on carboplatin/etoposide followed by streptozocin/adriamycin with initial good response, however repeat PET a year afterwards showed progression of the liver lesions, metastases to omentum and metastatic lesion to calvarium and the patient expired soon afterwards. Discussion: CAH predisposes patients to adrenal tumors which is attributed to increased ACTH stimulation of the adrenal gland but ACC in this population is extremely rare. In very rare cases ACC can present clinically as pheochromocytoma with elevated catecholamine levels and positive synaptophysin and chromogranin staining which poses a clinical challenge. Both CAH and ACC can lead to increased androgen levels and ACTH levels can help to differentiate the origin of the hyperandrogenemia. Presentation: 6/2/2024

7213 Severe IGF-2 Mediated Hypoglycemia In A Patient With Adrenocortical Carcinoma: A Case Report

Abstract Disclosure: M. Camelo Pereira: None. P. Itersky: None. S. Sternlieb: None. N. Manuel: None. J. Dendy: None. Background: Hypoglycemia has been rarely described as a complication of adrenocortical carcinoma (ACC). Tumor cells produce insulin-like growth factor II, causing a paraneoplastic syndrome with severe refractory hypoglycemia. We report the unusual case of a patient with known ACC presented with seizures and severe IGF-2 mediated hypoglycemia. Clinical case: A 21-year-old man presented to a regional hospital due to new onset seizures in September 2023. He had been diagnosed with ACC in July 2022, when he presented to the hospital with frank Cushing’s syndrome. CT scan of his chest and abdomen at that time revealed a large left suprarenal mass and multiple lung and liver masses; a biopsy from the liver lesion confirmed the diagnosis of ACC and he was started on treatment with mitotane, levoketoconazole and hydrocortisone. Oncology attempted treatment with 3 cycles of cisplatin and etoposide, with no significant response; subsequently, treatment with Keytruda initially decreased tumor size, but ultimately his CT scan showed progression of disease and mitotane was stopped in August 2023. When brought to the hospital in September 2023 due to seizures and altered mental status, the patient’s blood glucose (BG) was 25 mg/dL (70-110 mg/dL) on point of care testing, so he was started on IV 10% dextrose with improvement in BG and mental status. He underwent endotracheal intubation and was taken to the intensive care unit, showed improvement and was eventually transferred to the general medical floor, where the dextrose infusion was discontinued. However, the following day, he had another hypoglycemic episode complicated with a seizure and had to be reintubated, returning to intensive care. The patient was subsequently transferred to a large tertiary hospital. Evaluation showed undetectable point-of-care BG (&amp;lt; 5 mg/dL) as well as hypokalemia. Fasting labs showed undetectable BHB, undetectable insulin, C-peptide of 0.32 ng/mL (0.78 - 5.19 ng/mL), and negative insulin antibodies. IGF-2/IGF-1 ratio was elevated at 15.6, suggesting IGF-2 mediated hypoglycemia. He was started on IV glucose 20% and glucagon infusions. Mitotane was restarted aiming to decrease tumor burden and consequently IGF-2 levels. Given his hypokalemia, his levoketoconazole dose had to be increased; he was also treated with stress dose steroids. His BG levels improved, and he had partial neurologic recovery, however ultimately curative treatment was not possible given the extent of his disease, so he was transitioned to comfort-focused care. Conclusion: This case illustrates the importance of appropriate workup of IGF-2 mediated hypoglycemia, allowing for the best possible therapeutic approach. In our case, reducing tumor burden was not feasible since the patient had widely metastatic disease, leading to a poor outcome. Presentation: 6/3/2024