Treatment Of Neuroendocrine Tumors Research Articles

Key updates and interpretation of the ninth version of AJCC staging system for neuroendocrine tumors of the stomach

The cancer staging system of the American Joint Committee on Cancer (AJCC) is the most widely used clinical basis for tumor staging. In October 2023, AJCC released the staging system (ninth version) for the neuroendocrine tumors of stomach (NET), which has been implemented in January 2024. The ninth version of NET staging system mainly updated the histopathologic classification, diagnosis and staging methods, clinical and pathological staging, prognosis grade, tumor and non-tumor prognostic features. The update and implementation of the staging system provide a more detailed reference for the accurate diagnosis, staging and precise treatment of gastric neuroendocrine tumors. Moreover, it is convenient for clinicians to carry out clinical practice. The purpose of our article is to provide a high-level overview of the major changes in AJCC staging system (version 9) for gastric NET based on the latest evidence-based medical research.

Nuclear medicine approaches in the diagnosis and treatment of neuroendocrine neoplasms

Despite, or perhaps because of the rarity of neuroendocrine neoplasms, the diagnosis and treatment of these malignancies is of particular importance. Nuclear medicine can make an important contribution to this challenge. It offers the most sensitive and specific imaging of these tumor entities and can be helpful in treatment due to the radiotherapeutic drugs that have recently been approved. This theragnostic (fusion of therapeutic and diagnostic) concept is based on the frequent overexpression of somatostatin receptors on neuroendocrine tumor cells.Using diagnostic and therapeutic pharmaceuticals based on analogues from somatostatin, most applications from the nuclear medicine are successful, an additional therapeutic method is SIRT, also known as TARE, in which the hypervascularization of NEN-metastases is used as a therapeutic target.

Clinical application of traditional Chinese medicine in the treatment of neuroendocrine neoplasms

AbstractNeuroendocrine neoplasms (NENs) are a group of rare tumors with strong heterogeneity. Among these tumors, well‐differentiated tumors can have a relatively good survival prognosis, while some tumors can have strong malignant potential and lead to increased mortality. Traditional Chinese medicine (TCM), which has a long history of thousands of years, has been widely used to treat tumors due to its unique advantages, such as economy, efficacy and few side effects. In recent years, the role of TCM in the treatment of NENs has gradually emerged. It can not only help prevent tumor recurrence and reduce the side effects of radiotherapy and chemotherapy but also relieve symptoms and improve quality of life. Various clinical studies have indicated that TCM has achieved good curative effects at different stages of treatment. We summarized the last 10 years of research progress on the clinical application of TCM in the treatment of NENs from four points of entry, aiming to provide a reference for the treatment of NENs.

Elevated Baseline Mean Corpuscular Volume Predicts the Development of Severe Hematologic Toxicity After 177Lu-DOTATATE Therapy.

177Lu-DOTATATE is an effective second-line treatment for metastatic or nonresectable neuroendocrine tumors. This treatment can result in hematologic severe adverse reactions (SARs). Preemptive identification of patients at risk of SARs could mitigate this risk and improve treatment safety and outcomes. Methods: Demographic and oncologic history, pretreatment laboratory values, and SAR frequency were obtained for 126 sequential patients treated with 177Lu-DOTATATE. Univariable and multivariable logistic regression models identified factors correlating with SARs. Results: Relative pretreatment anemia, leukopenia, thrombocytopenia, and elevated mean corpuscular volume (MCV) were significantly correlated with SARs, with an odds ratio of 16 (95% CI, 5-65) in patients with an MCV greater than 95 fL. Conclusion: Pretreatment bone marrow dyscrasias, including an MCV greater than 95 fL, may predict patients at risk for SARs when treated with 177Lu-DOTATATE. Further study is needed to determine whether the risks of SARs outweigh the benefit in these patients.

Spleen Volume Reduction Is a Reliable and Independent Biomarker for Long-Term Risk of Leukopenia Development in Peptide Receptor Radionuclide Therapy.

177Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia. Methods: We retrospectively analyzed blood counts and imaging data of 88 patients with histologically confirmed, unresectable metastatic neuroendocrine tumors who received 177Lu-DOTATATE treatment at our institution from February 2009 to July 2021. Inclusion criterium was a tumor uptake equivalent to or greater than that in the liver on baseline receptor imaging. We excluded patients with less than 24 mo of follow-up and those patients who received fewer than 4 treatment cycles, additional therapies, or blood transfusions during follow-up. Results: Our study revealed absolute and relative white blood cell counts and relative spleen volume reduction as independent predictors of radiation-induced leukopenia at 24 mo. However, a 30% decline in spleen volume 12 mo after treatment most accurately predicted patients proceeding to leukopenia at 24 mo (receiver operating characteristic area under the curve of 0.91, sensitivity of 0.93, and specificity of 0.90), outperforming all other parameters by far. Conclusion: Automated splenic volume assessments demonstrated superior predictive capabilities for the development of leukopenia in patients undergoing 177Lu-DOTATATE treatment compared with conventional laboratory parameters. The reduction in spleen size proves to be a valuable, routinely available, and quantitative imaging-based biomarker for predicting radiation-induced leukopenia. This suggests potential clinical applications for risk assessment and management.

Treatment, Prognostic Markers, and Survival in Thymic Neuroendocrine Tumors, with Special Reference to Temozolomide-Based Chemotherapy

Background: Thymic neuroendocrine tumors (Th-NETs) are rare and aggressive, with a scarcity of research on predicting patient prognosis. Our study aimed to assess the impact of prognostic markers and temozolomide (TMZ)-based chemotherapy on survival in Th-NETs. Methods: We retrospectively reviewed the medical records of patients diagnosed with Th-NETs between 2013 and 2023 at our institution. We collected clinicopathological data, including tumor pathological grading, staging, serum concentrations of neuron-specific enolase (NSE) and pro-gastrin-releasing peptide, levels of inflammatory factors, and expression of oxygen 6-methylguanine-DNA methyltransferase (MGMT). Treatment details (such as surgery and chemotherapy) and survival outcomes were also documented. Results: A total of 32 patients were included in our study after excluding those without complete available information. The median progression-free survival (PFS) was 12.5 months (95%CI, 8–16 months) for 19 patients who received TMZ-based chemotherapy. Twenty-one patients underwent surgery as the primary treatment, demonstrating a median disease-free survival (DFS) of 51.0 months. The inflammatory factor neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic indicator of DFS in postoperative patients and PFS in TMZ-treated patients. The overall 3-, 5-, and 10-year survival rates were 86.6%, 69.5%, and 33.8%, respectively. Ki67 level exceeding 10% (p = 0.048) and absence of surgical resection (p = 0.003) were significantly associated with worse overall survival (OS). Conclusion: Surgical treatment was currently the primary method for treating Th-NETs, and postoperative adjuvant therapy was an essential consideration for specific patient cohorts. Despite widespread positive MGMT expression, TMZ-based chemotherapy showed promise. Some potential prognostic biomarkers such as NLR and NSE need more attention.

Effects of Recombinant α1-Microglobulin on Early Proteomic Response in Risk Organs after Exposure to 177Lu-Octreotate.

Recombinant α1-microglobulin (A1M) is proposed as a protector during 177Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177Lu-octreotate and/or A1M administration. Mice were injected with 177Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 h or 7 d. The differential protein expression was analyzed with tandem mass spectrometry. The dosimetric estimation was based on 177Lu activity in the kidney. PHLDA3 was the most prominent radiation-responsive protein in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177Lu-octreotate+A1M group. Altogether, a tissue-dependent proteomic response followed exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not inhibit the radiation-induced protein expression early after exposure, and late effects should be further studied.

Biochemical Markers for Neuroendocrine Tumors: Traditional Circulating Markers and Recent Development—A Comprehensive Review

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain.

РЕЗУЛЬТАТЫ ПОСЛЕДОВАТЕЛЬНОГО ХИРУРГИЧЕСКОГО ВМЕШАТЕЛЬСТВА И ТЕРАПИИ ИНТЕРФЕРОНАМИ МЕТАСТАЗОВ НЕЙРОЭНДОКРИННОГО РАКА ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ У ПАЦИЕНТКИ С БОЛЕЗНЬЮ ФОН ГИППЕЛЯ-ЛИНДАУ

Abstract. Introduction. The article provides a literature review on the epidemiology, diagnosis, and treatment of neuroendocrine tumors. The morpho-functional classification by WHO 2022 is presented with the division of neuroendocrine tumors into three groups. Justifications are given for the choice of instrumental methods of topical diagnostics and the need for determining universal and specific biochemical markers in blood serum or plasma. The principles are indicated for choosing the advanced methods of treating neuroendocrine tumors. Aim. To review the scientific literature on neuroendocrine tumors, providing our own clinical observations. Materials and Methods. Russian- and English-language literature sources on this disease were searched for in the databases, such as PubMed, Medscape, Cochrane Library, and eLibrary. Clinical case of our female patient V., 36 years old, with von Hippel-Lindau disease (heterozygous mutation R167W of the VHL gene). Results and Discussion. As an example, we describe a clinical case of surgical treatment followed by long-term use of interferons in a female patient with neuroendocrine pancreatic cancer with metastases to the liver and retroperitoneal lymph nodes. Histological examination of the surgical material revealed highly differentiated neuroendocrine cancer with low malignant potential. A screening examination of the genetic syndrome components revealed a heterozygous mutation R167W of the VHL gene. Her survival under treatment exceeded 9.5 years, including more than 4.5 years from the start of interferon therapy. This pathology occurred in a young woman with one of the rare genetic multiorgan hereditary forms of neuroendocrine tumors, Von Hippel-Lindau disease that manifested itself as a combination of benign (retinal angiomatosis of both eyes and adenomas of both adrenal glands) and malignant diseases (pancreatic cancer). Conclusions. The given clinical example demonstrates that in a patient with highly differentiated metastatic pancreatic cancer, after distal subtotal resection of the pancreas, splenectomy, retroperitoneal lymphadenectomy, followed by treatment with interferons, life expectancy was more than 9.5 years, including more than 4.5 years from the start of therapy with interferons only. Despite the numerous side effects of interferons described in the literature, the patient tolerated the treatment well. At the same time, a connection between the hypothyroidism detected in the patient and treatment with interferons cannot be ruled out, since dysfunction of the thyroid gland is one of its side effects.

Staged Surgical Treatment of the Giant Pituitary Neuroendocrine Tumors

To investigate the long-term clinical outcomes of staged surgical resection in giant Pituitary Neuroendocrine Tumors(pitNET).Method We performed a retrospective analysis of the clinical data of 16 patients who underwent surgery. The patients were diagnosed and underwent surgery at the Department of Neurosurgery of Shiyan Taihe Hospital from January 2013 to March 2021. Among the cases, 12 patients underwent primarily transsphenoidal surgery followed by secondary transcranial surgery, while 4 patients underwent primarily transsphenoidal surgery followed by secondary transsphenoidal surgery. Before the surgery, all patients underwent a pituitary MRI scan, pituitary hormone level examination, visual acuity, and visual field examination. A pituitary MRI was rechecked within 1 week after the operation. A tumor resection rate of 100% on MRI was considered as a total resection, between 90% to 100% as a subtotal resection, and lower than 90% as a partial resection. After the surgery, regular clinical visits and telephone or internet platform follow-ups were conducted. Outcome In our clinical investigation, after staged surgery 10 patients had a total resection, 5 had a subtotal resection, and 1 had a partial resection depending on the tumor size and invasion. The clinical outcomes showed that 1 case suffered from postoperative intracranial infection, 1 case had decreased visual acuity, and 6 cases experienced decreased pituitary function after surgery.Postoperative complications were cured after symptomatic treatment, except for 1 patient who experienced decreased vision and 1 patient sufferred hypopituitarism required long-term oral levothyroxine tablet treatment. No cases of intracranial hemorrhage or death were caused by intentionally staged resection surgery. Conclusion Staged surgery for giant pitNET is a safe and effective clinical surgery strategy.

Prolonged Response to Dabrafenib/Trametinib in Grade 3 Metastatic Pancreatic Neuroendocrine Tumor (NET G3) with BRAF V600E Mutation.

Treatment of metastatic pancreatic neuroendocrine tumors (pancNETs), particularly grade 2 (G2) and grade 3 (G3), often presents a dilemma in choosing from multiple similarly efficacious therapies. Data on targeted therapies for these tumor types is limited, and this report presents BRAF-targeted therapy as a therapeutic option for metastatic pancNET G3. This is a case report of a patient with G3 pancNET metastatic to the liver, lung, lymph node, and scalp (soft tissue) treated with dabrafenib/trametinib (D/T) in the presence of a BRAF V600E mutation detected in tumor tissue. This patient has demonstrated an ongoing partial response to therapy at all involved sites for nearly 15months with minimal side effects attributable to D/T. Dabrafenib/trametinib therapy for BRAF-mutated metastatic pancNETs provides a novel treatment option and, especially in the G3 setting, should be considered a first-line option. Tumor testing for actionable mutations should be undertaken at the time of diagnosis and/or progression to identify novel therapeutic avenues in these rare tumors.

Radiologically guided interventional therapies for the treatment of neuroendocrine tumors

The majority of patients with neuroendocrine tumors (NET) develop liver metastases during the course of the disease, significantly impacting prognosis and quality of life. Radiologically guided interventional therapies, such as thermal ablation, transarterial embolization (TAE)/chemoembolization (TACE), and selective internal radiotherapy (TARE), can play acrucial role in the treatment of metastatic NET. Due to the rarity of the disease, the majority of evidence is based on retrospective studies. For thermal ablation, the complete response rates ranging from 31.6to 95.3% depending on the study. No significant differences in outcomes were found between TAE, TACE, and TARE. In several studies, all intra-arterial procedures led to areduction of tumor-related symptoms and achieved disease control. Thermal ablation can be used as acurative therapy in oligometastatic patients with nonresectable liver metastases from NETs. In cases of disseminated liver metastases, intra-arterial therapy using TAE, TACE, or TARE can be employed.

Endoscopic submucosal dissection for rectal neuroendocrine tumours: A multicentric retrospective study

IntroductionEndoscopic Submucosal Dissection (ESD) has been reported as a feasible and effective treatment for Rectal Neuroendocrine Tumours (R-NETs). However, most of the experience on the topic comes from retrospective tertiary centre from Eastern Asia. Data on ESD for R-NETs in Western centres are lacking. Materials and MethodsThis is a retrospective study, including patients who underwent endoscopic resection of R-NETS by ESD between 2015 and 2020 in Western Centres. Important clinical variables such as demographic, size of R-NETs, histological type, presence of lymphovascular invasion or distant metastasis, completeness of the endoscopic resection, recurrence, and procedure related complications were recorded. Results40 ESD procedure on R-NETs from 39 patients from 8 centres were included. Mean R-NETs size was 10.3 mm (SD 4.01). Endoscopic en-bloc resection was achieved in 39/40 ESD (97.5 %), R0 margin resection was obtained in 87.5 % (35/40) of the procedures, one patient was referred to surgery for lymphovascular invasion, two procedures (5 %) reported significant episodes of bleeding, whereas a perforation occurred in one case (1/40, 2.5 %) managed endoscopically. Recurrence occurred in 1 patient (2.5 %). ConclusionESD is an effective and safe treatment for R-NETs in western centres.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P=0.032) as the only significant independent favorable predictive factor. The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.

Current developments in the treatment of neuroendocrine tumors

Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent on various factors. With currently available systemic therapies, the prognosis is often favorable. This article aims to provide an overview of current treatment strategies for NET, addressing the most important NET locations. The current European guidelines and further relevant literature on the treatment of NET were reviewed for this purpose. The therapeutic spectrum for NET is extremely broad: For NET of the stomach/duodenum, appendix, and rectum, endoscopic or surgical resection is often sufficient, and metastatic tumors are rare. NET of the pancreas, small intestine and lung should also undergo potentially curative resection in the early stages. In the metastatic stage, locoregional treatments such as surgery and liver tumor embolization play arole. Major advances have been made in drug therapy, with somatostatin analogs (octreotide and lanreotide), an mTOR inhibitor (everolimus), and atyrosine kinase inhibitor (sunitinib) being widely used. Peptide receptor radionuclide therapy (PRRT) is also an invaluable option. In some cases, classic chemotherapy is indicated. Many effective therapies are now available for NET. It is important to select the right therapy at the right time for each patient through interdisciplinary management.

Carcinoid syndrome with right-sided valve involvement - a case report and review of the literature.

The survival of patients with neuroendocrine tumors has substantially improved with modern treatment options. Although the associated carcinoid syndrome can be diagnosed early and controlled effectively, cardiologists still encounter patients with cardiac manifestations, particularly among individuals with persistently high levels of vasoactive mediators. Treatment options have been limited to surgical valve replacement in fully manifested disease. Since surgery is not always feasible, transcatheter valve implantation is becoming an interesting alternative. A case of a 50-year-old woman with carcinoid syndrome and right-sided valvular heart disease is presented. Moderate pulmonary valve stenosis and severe tricuspid valve regurgitation were diagnosed during the evaluation and treatment of neuroendocrine tumor. The possibility of rare valve involvement and the need for interdisciplinary cooperation in the diagnosis, monitoring and treatment of patients with neuroendocrine tumors producing vasoactive substances must be emphasized. The patient had a typically presenting carcinoid syndrome with a rare cardiac manifestation. Although monitoring and treatment were carried out in accordance with recommendations and appropriate to the clinical condition, rapid progression of the metastatic disease ultimately precluded invasive cardiac intervention.

Abstract LB222: Elucidating the cellular responses and mechanism of action of 177Lu-based radioligand therapy

Abstract Radioligand therapy (RLT) is emerging as a safe and effective targeted approach for treating several types of cancers. Lutathera® (177Lu-Dotatate) and Pluvicto® (177Lu-PSMA-617) are two examples of FDA-approved 177Lu-based RLT drugs for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), respectively. Despite the clinical success of 177Lu-RLT, there are still patients lacking complete, durable responses. Arguably, elucidating the cellular responses to 177Lu-RLT and its mechanism of action could reveal potential opportunities for the improvement of therapy and outcome for patients. We have investigated the phenotypes and responses of multiple 177Lu- RLT-treated cell lines and observed that 177Lu-RLT induces a plethora of DNA Damage Response (DDR) markers, especially those indicative of double-strand break (DSB) repair by either non-homologous end-joining (NHEJ) or homologous recombination (HR). Furthermore, 177Lu-RLT leads to cell-cycle alterations, accumulation of micronuclei and cell death. In agreement with published reports, we have observed that either the knock-out or inhibition of NHEJ core factors such as the catalytic subunit of DNA-PK (PRKDC) renders cells sensitive to 177Lu-RLT and the combination of both the 177Lu-RLT and DNA-PK inhibitor provides a beneficial tumor growth inhibition in vivo. To further unravel the mechanism of action of 177Lu-RLT, we have conducted ‘DDR-ome’ targeted genetic screens, which also suggest that DSBs are the most cytotoxic form of 177Lu-RLT-induced DNA damage. In addition to DNA-PK, we have identified novel DDR targets that could sensitize to 177Lu-RLT. We are currently testing whether inhibiting these targets in combination with certain 177Lu-RLT could, in addition to potentially achieving greater antitumor response, allow for lower dosing to reduce radiation exposure. Taken together, our work provides better understanding of the cellular responses to 177Lu-based RLT and pinpoints NHEJ as a critical pathway promoting survival to this treatment, which could set the basis for novel combination therapies. Citation Format: Marco Ranzani, Sravanth Hindupur, Alessandro Cicconi, Guillermo Sastre-Moreno, Alexander Kristian, Barbara Schacher Engstler, Benika Pinch, Charlene Hartnagel, Delphine Gorses, Elise Simon, Emeline Mandon, Emilien Schramm, Fanny Schaeffer, Josefine Reber, Louise Barys, Luisa Deberle, Milene Walter, Ralph Bessey, Riccardo Destefani, Xavier Miot, Elias Elinati, Nan Shao, Marie Boursier, Joseph Barlow, Asmita Thapa, Alessandro Galbiati, Diego Grande, Eeson Rajendra, Niall Martin, Graeme Smith, Tobias Schmelzle, Markus Reschke, Helen Robinson, Marta Cortes-Cros. Elucidating the cellular responses and mechanism of action of 177Lu-based radioligand therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB222.

Surgical treatment of pituitary neuroendocrine tumors with coexisting intracranial lesions: A case series and review of the literature.

Pituitary neuroendocrine tumors (PitNETs) are a diverse group of benign neoplasms that account for a significant proportion of intracranial tumors (13%). The coexistence of PitNET with other intracranial lesions, such as meningiomas and intracranial aneurysms, has been constantly reported in the literature; yet, the pathophysiological mechanisms remain unknown, and the appropriate management is controversial. This study aims to describe the clinical characteristics, surgical treatment, and outcomes of patients with PitNET with coexisting intracranial lesions in a single healthcare center. A retrospective analysis was conducted on 12 patients who underwent surgical treatment for PitNET and another intracranial lesion at our single tertiary referral center over 15 years from January 2008 to May 2023. Among these coexisting lesions, aneurysms were the most commonly found (41.67%), followed by meningiomas (33.33%). Surgical intervention for both lesions was performed in a single-stage procedure for most cases (75%), employing transcranial, endoscopic endonasal, and combined approaches. We found low preoperative Karnofsky Performance Scale scores in three patients, with significant differences in functional outcomes. These findings contribute to the limited knowledge about PitNET coexisting with other intracranial lesions and emphasize the importance of patient-tailored, multidisciplinary management in these unusual scenarios.

Abstract 7614: Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy

Abstract Background: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTATATE is an effective treatment for metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs). However, it remains unknown why some patients (pts) respond more favorably than others. Pre-clinical data suggests that mutations in the MEN1, DAXX, and/or ATRX genes influence DNA repair capabilities and increase radiation effect in cancer cells. We therefore thought to evaluate the association between response to PRRT and the presence of MEN1, DAXX, and/or ATRX mutations in patients with GEP-NETs. Methods: We retrospectively analyzed CLIA certified tissue-based Next Generation Sequencing (NGS) assay results and clinicopathological data from 28 pts with GEP-NETs treated with PRRT at our center from 2017 to 2023. Genetic findings were correlated with progression-free survival (PFS) using Kaplan-Meier estimators and Cox proportional hazards regression modeling. Objective response was assessed per RECIST v1.1 by investigator review. Results: Pts with mutations in MEN1, DAXX, or ATRX (n = 13, 46.42%) had a longer PFS [mPFS, 26.47 months (95% CI, 17.97 - NA) vs. 12.13 months (95% CI, 9.17 - NA); HR, 0.19; 95% CI, 0.06 - 0.68; p = 0.01] than wildtype (n = 15, 53.58%) pts, when adjusted for surgery prior to PRRT and tumor grade. Pts with mutations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended towards better PFS compared to patients without concurrent mutations [only MEN1mt or DAXXmt/ATRXmt, but not both; mPFS, 31.53 months (95% CI, 28.43 - NA) vs. 17.97 months (95% CI, 11.17 - NA); HR, 0.25; 95% CI, 0.05 - 1.29; p = 0.09]. Among evaluable pts, objective response rate was higher in pts with a mt in MEN1, DAXX, or ATRX compared to wild-type pts (41.67% vs. 15.38%; p = 0.09). In the pancreatic NET (PNET) subset, mutations in either MEN1, DAXX, or ATRX were found in 11/16 pts (68.75%) and were also associated with a better PFS compared to wild type patients [mPFS, 28.43 months (95% CI, 11.50 - NA) vs. 9.83 months (95% CI, 7.83 - NA); HR, 0.21; 95% CI, 0.05 - 0.95; p = 0.04). Conclusions: Mutations in MEN1/DAXX/ATRX correlate with improved PFS in patients with GEP-NETs receiving PRRT. Concurrent mutations in MEN1 and DAXX/ATRX may have additive effects on response to PRRT. If validated in larger studies, these findings may represent a novel biomarker to predict PRRT response. Limitations: Limited sample size precludes generalization of results and might overestimate effect sizes. Citation Format: Rushabh Gujarathi, Sara Abou Azar, Joseph Tobias, Xavier Keutgen, Chih-Yi Liao. Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7614.

Efficacy and Safety of 225 Ac-DOTATATE in the Treatment of Neuroendocrine Neoplasms With High SSTR Expression.

We aimed to evaluate the efficacy and safety of 225 Ac-DOTATATE targeted α therapy (TAT) in various neuroendocrine neoplasms (NENs) with high somatostatin receptor (SSTR) expression. This single-center prospective study included 10 patients with histologically diagnosed NENs that exhibited increased SSTR expression on 68 Ga-DOTATATE PET/CT imaging. All patients received 225 Ac-DOTATATE TAT. The primary end points were molecular imaging-based response and disease control rate (DCR), measured using the slightly modified Positron Emission Tomography Response Criteria in Solid Tumors 1.0. The secondary end points were adverse event profiles and clinical responses. The adverse event profile was determined according to the Common Terminology Criteria for Adverse Events version 5.0. Clinical response was assessed using the EORTC QLQ-C30 v3.0 (European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire version 3.0). A molecular imaging-based partial response was observed in 40% of all patients, SD in 40%, PD in 20%, and DCR in 80%. The DCR was 83.3% (5/6) in patients who were previously treated with 177 Lu-DOTATATE. According to the EORTC QLQ-C30 v3.0 score, most symptoms improved after 225 Ac-DOTATATE treatment, with only diarrhea showing no improvement. Grade III/IV hematological, kidney, and liver toxicities were not observed. The median follow-up time was 14 months (7-22 months), and no deaths were reported. This initial study suggests that 225 Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.