Neuroendocrine Tumors Research Articles

The tumor immune microenvironment of SCLC is not associated with its molecular subtypes

IntroductionSmall-cell lung carcinoma (SCLC) is a high-grade neuroendocrine carcinoma of poor prognosis. Although immune checkpoint blockers have shown promising results in advanced SCLC, the tumor immune microenvironment (TME) remains poorly understood, with no validated prognostic or predictive biomarkers of efficacy. MethodsThis retrospective study included surgically samples from 48 SCLC patients between 2009 and 2018. We assessed the TME using two quantitative 7-plex immunofluorescence panels focusing on T and B cells, and compared it to NSCLC (N = 10). Molecular subtypes were determined by assessing the expression of ASCL1, NEUROD1 and YAP1 using immunohistochemistry. ResultsImmune-hot SCLC were defined as those exhibiting the highest immune cell and immune-related marker densities. They were associated with longer overall survival, significantly more frequently detected at early stages, and exhibited high PD-L1 expression in immune cells, but were not associated with molecular subtypes. Compared to NSCLC, SCLC had significantly lower densities of CD20 + cells and higher density of PD1 + cells, with no significant differences in CD4 + , CD8 + and plasma cell densities. In univariate analysis, the highest OS was significantly associated with early stage (p < 0.001), low expression of NEUROD1 (p = 0.047), high PD1 + cell density (p < 0.001) and high PD-L1 immune cell expression (p = 0.04). Only stage and PD1 + cell density emerged as independent prognostic markers. ConclusionSCLC TME is highly heterogeneous. Immune-hot tumors were associated with OS but not with molecular classification. PD1 expression and PD-L1 expression by immune cells may thus serve as a prognostic marker.

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.

A Frozen Tale of Two Tumors in the Pancreas: An Intraoperative Diagnostic Challenge of Clear Cell Pancreatic Neuroendocrine Tumor Mimicking Metastatic Clear Cell Renal Cell Carcinoma

Abstract Introduction/Objective Clear cell pancreatic neuroendocrine tumor (PanNET) is rare, with very few cases reported in the literature, and is often found in patients with von Hippel-Lindau (VHL) disease. The differential for this entity includes ectopic adrenal tissue and metastatic clear cell neoplasms. These challenges during intraoperative consultation add to the complexity of diagnosing this condition. Distinguishing it from other pancreatic lesions requires careful examination and further ancillary testing. Methods/Case Report We report a case of clear cell PanNET mimicking metastatic clear cell renal cell carcinoma (RCC) in a 56-year-old woman with recently diagnosed VHL. She presented with renal masses and a pancreatic lesion with previous biopsy showing conventional NET. Intraoperative consultation during her pancreaticoduodenectomy identified a 1.3 cm well-circumscribed, golden-yellow solid mass. Further characterization was deferred to permanent sections given the diagnostic challenge of distinguishing between a PanNET and metastatic clear cell RCC. Permanent sections showed nests of clear cells with prominent nucleoli. The neoplastic cells were immunohistochemically positive for neuroendocrine markers synaptophysin, chromogranin and insulinoma- associated protein 1(INSM1), as well as pankeratin and PAX8, with a Ki-67% proliferation index &amp;lt;1%, consistent with low-grade clear cell PanNET. Clear cell RCC marker, CA-IX, as well as adrenocortical marker SF1, were negative. The combination of immunohistochemical stains is key for making the diagnosis. The previously biopsied conventional PanNET was also identified, which was positive for neuroendocrine markers and had a Ki-67 proliferation index &amp;lt;1%. Results (if a Case Study enter NA) NA Conclusion Given the rarity of this entity and its strong association with VHL, clear cell PanNET should be considered in the intraoperative consultation to inform clinical management. Furthermore, literature review indicates that metastatic RCC in the pancreas is exceptionally rare in VHL patients and typically of low nuclear grade, suggesting low metastatic potential. Thus, this case emphasizes the diagnostic challenges and the necessity of deferring to permanent sections with immunohistochemical work-up during intraoperative consultation or when assessing small biopsies.

Variable anatomical features of acromegaly in the nasal cavity and paranasal sinuses: implications for endoscopic endonasal transsphenoidal surgery.

Growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs) are the most common cause of acromegaly. The endoscopic endonasal transsphenoidal approach (EEA) is commonly employed to remove them. Although morphological differences in the nasal cavity exist between acromegaly patients and those with other types of PitNET, few quantitative studies have been performed. This study aimed to evaluate the anatomical features of the nasal cavity and paranasal sinuses in patients with acromegaly. Preoperative computed tomography images of the nasal cavity and paranasal sinuses were compared between 20 patients with a GH-secreting PitNET (acromegaly group) and 22 with a non-functioning PitNET (control group). In the acromegaly group, the relationships between preoperative GH and/or insulin-like growth factor 1 (IGF-1) levels and anatomical characteristics were assessed. In the acromegaly group, the distance between the nostril and dorsum sellae was significantly longer and the distance between the parasellar internal carotid arteries was significantly shorter (p = 0.0022 and 0.0092, respectively). Pneumatization volume in the nasal cavity did not differ between the groups. Nasal mucosa and bony hypertrophy were observed in the acromegaly group. Preoperative GH level was correlated with the width of the piriform aperture (p = 0.0171). The nasal and paranasal changes associated with acromegaly can make EEA challenging to perform. Widening the surgical corridor anterior to the sphenoid sinus is important in these patients.

Advancing Treatment Options for Merkel Cell Carcinoma: A Review of Tumor-Targeted Therapies.

Although rare, Merkel cell carcinoma (MCC) is a highly aggressive and increasingly prevalent neuroendocrine cancer of the skin. While current interventions, including surgical resection, radiation, and immunotherapy have been employed in treating many patients, those who remain unresponsive to treatment are met with sparse alternatives and a grim prognosis. For this reason, it is of interest to expand the repertoire of available therapies for MCC patients who remain resistant to current primary interventions. Recently, our improved mechanistic understanding of aberrant cell signaling observed in both MCPyV-positive and -negative MCC has facilitated exploration into several small molecules and inhibitors, among them receptor tyrosine kinase inhibitors (TKIs) and somatostatin analogs (SSAs), both of which have positively improved response rates and reduced tumor volumes upon application to treatment of MCC. The introduction of such targeted therapies into treatment protocols holds promise for more personalized care tailored towards patients of diverse subtypes, thereby improving outcomes and mitigating tumor burden, especially for treatment-resistant individuals. In this review, we characterize recent findings surrounding targeted treatments that have been applied to MCC and provide an overview of emerging perspectives on translatable options that can be further developed to offer additional therapeutic avenues for patients with the disease.

Liver metastases in high-grade neuroendocrine neoplasms: A comparative study of hepatic tumor volume and biochemical findings in NET G3 versus NEC.

Abnormal liver blood tests and liver tumor burden are known prognostic factors in neuroendocrine neoplasms (NEN). However, the relationship between biochemical liver parameters and hepatic tumor load is largely unknown in NEN and in high-grade NEN (G3) specifically. The primary objective of this study was to correlate the biochemical parameters and liver tumor volume of patients with neuroendocrine tumors grade 3 (NET G3) or neuroendocrine carcinomas (NEC). We wanted to investigate whether patients with NET G3 with extensive liver involvement had less severely elevated laboratory liver parameters than NEC patients. In total, 46 patients with NEN were included, 31 had NEC and 15 NET G3. All patients had distant metastatic disease, with liver metastases being the most common (n = 39). Both laboratory results and semiautomatic volumetric measurements of liver tumor burden were obtainable for 34 patients at baseline and 26 patients at follow-up. Alkaline phosphatase (AP), gamma-GT (gGT), and lactate dehydrogenase (LDH) increased significantly between the two time periods (p < .01). In a regression model, liver tumor burden significantly affected several blood parameters, for example, increasing AP, gGT, LDH, and aspartate aminotransferase (ASAT) by a factor of 1.02-1.04 per unit increase (1% tumor burden; all p < .001). AP, gGT, and LDH were significantly lower in NET G3 (factor of 0.43-0.68) than in NEC. Here, we found that liver chemistries changed over the NEN disease course, correlated with hepatic tumor burden, and differed by histologic subtype. The current data can potentially guide treatment decisions, for example, with regard to integration of liver-directed therapies.

68Ga-DOTATATE and 18F-FDG PET/CT in a Rapidly Progressing Lymphoma.

68Ga-DOTATATE PET/CT targeting somatostatin receptors is commonly utilized in the imaging of neuroendocrine tumors. However, other malignancies such as lymphomas (both Hodgkin and non-Hodgkin) also have expression of somatostatin receptors, albeit to a lesser degree compared with the neuroendocrine tumors, and thus can be positive on a 68Ga-DOTATATE PET/CT. We describe an atypical presentation of an aggressive large B-cell lymphoma mimicking a metastatic neuroendocrine tumor at initial presentation with high somatostatin receptor expression demonstrated on the 68Ga-DOTATATE PET/CT and a rapidly progressing course on the subsequent 18F-FDG PET/CT.

Molecular Basis of Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (NETs) are rare well-differentiated neoplasms with limited therapeutic options and unknown cells of origin. The current classification of pancreatic neuroendocrine tumors is based on proliferative grading, and guides therapeutic strategies, however, tumors within grades exhibit profound heterogeneity in clinical manifestation and outcome. Manifold studies have highlighted intra-patient differences in tumors at the genetic and transcriptomic levels. Molecular classification might become an alternative or complementary basis for treatment decisions and reflect tumor biology, actionable cellular processes. Here, we provide a comprehensive review of genomic, transcriptomic, proteomic and epigenomic studies of pancreatic NETs to elucidate patterns shared between proposed subtypes that could form a foundation for new classification. We denote four NET subtypes with distinct molecular features, which were consistently reproduced using various omics technologies.

Preoperative risk factors for ileostomy-associated kidney injury in colorectal tumor surgery following ileostomy formation

PurposeDiverting ileostomy is related to postoperative high-output stoma (HOS) leading to kidney injury. The purpose of our study was to clarify the risk factors for ileostomy-associated kidney injury, which is kidney injury starting after the first operation to ileostomy closure after colorectal tumor surgery with diverting ileostomy.MethodsBetween January 2013 and December 2020, 442 patients who underwent colorectal tumor surgery (cancer, neuroendocrine tumor, and leiomyosarcoma) following diverting ileostomy formation were included. We used the KDIGO (Kidney Disease Improving Global Outcomes) guidelines, which defines the acute kidney injury (AKI) to classify patients with ileostomy-associated kidney injury. The definition of AKI was (i) serum creatinine (sCr) ≥ 0.3 mg/dL or (ii) sCr ≥1.5-fold the preoperative level. Multivariate analyses were performed to identify the independent risk factors for kidney injury.ResultsKidney injury developed in 99/442 eligible patients (22.4%). Patients in the kidney injury group were older age, male sex, high American Society of Anesthesiologists Physical Status Classification System (ASA-PS) score, hypertension, cardiovascular diseases, diabetes. The preoperative hemoglobin, albumin, prognostic nutritional index (PNI), and creatinine clearance (CCr) were lower, and the maximum wound length was more extended than the non-kidney injury group. The median highest daily stoma output was significantly higher in the kidney injury group. The postoperative white blood cell (WBC) and C-reactive protein (CRP) levels were also high in the kidney injury group. The univariate analysis showed older age, male sex, high ASA-PS score, hypertension, cardiovascular diseases, and diabetes were the risk factors for kidney injury. The multivariate analysis revealed that age 70 or older, ASA-PS III/IV, hypertension, and HOS ≥2000 ml/day were independent risk factors for kidney injury.ConclusionsSurgeons should consider diverting colostomy creation for patients with risk factors such as age 70 or older, ASA-PS III/IV, and hypertension.

Gastroenteropancreatic Neuroendocrine Tumor with Peritoneal Metastasis: A Review of Current Management.

Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival-particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed.

Intraoperative intermittently scanned continuous glucose monitoring in the management of patients with pancreatic insulinoma.

Insulinomas represent the most common functional pancreatic neuroendocrine tumors. Following preoperative localization, surgical excision is the curative treatment. It may be difficult to confirm a complete resection of insulinoma. We used intermittently scanned continuous glucose monitoring (isCGM) to record the fluctuation of interstitial glucose throughout surgery to help verify the tumor's complete surgical excision. In five individuals with insulinoma undergoing laparoscopic surgery we used the isCGM system (Freestyle Libre 2 Abbott) during tumor removal in order for the surgeon to understand "in real-time" the extent of tumor removal. Two patients received no preoperative treatment, while three patients received medical treatment with either lanreotide (2 patients) or diazoxide (1 patient). In the non-treated patients, following tumor resection, there was a rapid interstitial glucose increase along with stabilized glucose levels thoroughly documented by intraoperative isCGM. Lanreotide treatment, on the other hand, resulted in only a minor increase in interstitial glucose. Finally, diazoxide-treated patients had a response that was intermediate between lanreotide-treated and non-treated patients. Our findings suggest that isCGM is a useful tool to monitor the outcome of surgery during pancreatic insulinoma excision, assisting the surgical team in successfully removing the tumor. Despite the limited sample size, the results are promising, and, if validated in larger studies, they make us believe that the use of CGM systems has a definite benefit for becoming a standard in the surgical treatment of insulinomas.

Incidence and Prognostic Implications of Lymphovascular Invasion in Node-Negative Pancreatic Neuroendocrine Tumors: Results From the US Neuroendocrine Study Group.

Despite the well-known prognostic role of lymph node metastasis (LNM) in pNETs, less is known about the importance of lymphovascular invasion (LVI) among patients with these tumors. Patients undergoing pancreatectomy for pNET between 2002 and 2020 were identified in the US Neuroendocrine Tumor Study Group database. Cox regression analysis was utilized to identify the impact of LVI on recurrence-free survival (RFS) among patients with node-negative pNET. Among 853 patients who underwent resection for pNET, 214 patients (25.1%) had LNM, while 116 (13.6%) and 523 individuals (61.3%) were LVI + N0 and LVI - N0, respectively. The overall incidence of LVI among patients with N0 pNET was 18.1%; the incidence of LVI increased with increasing tumor size and Ki-67 levels (size < 2 cm and Ki-67 < 3%: 5.5%; size < 2 cm and Ki-67 ≥ 3%: 17.2%; size ≥ 2 cm and Ki-67 < 3%: 22.2%; size ≥ 2 cm and Ki-67 ≥ 3%: 43.1%, p < 0.001). Five-year RFS was highest among patients with LVI - N0 disease followed by individuals with LVI + N0 and N+ pNETs (92.8% vs. 61.6% vs. 58.3%, p < 0.001). On multivariable analysis, the presence of LVI on pathology remained independently associated with almost 2.5 times higher hazards of recurrence (HR 2.47, 05% CI 1.44-4.24) among individuals with N0 pNETs. The incidence of LVI varied according to tumor size and Ki-67. LVI was associated with a higher likelihood of recurrence among individuals who underwent formal pancreatic resection for N0 pNETs. LVI is an important prognostic indicator among patients with node-negative pNETs.

Radioligand therapy in the therapeutic strategy for patients with gastro-entero-pancreatic neuroendocrine tumors: a consensus statement from the Italian Association for Neuroendocrine Tumors (Itanet), Italian Association of Nuclear Medicine (AIMN), Italian Society of Endocrinology (SIE), Italian Association of Medical Oncology (AIOM).

This paper outlines the consensus of the Italian Association for Neuroendocrine Tumors(Itanet), the Italian Association of Nuclear Medicine (AIMN), the Italian Society of Endocrinology (SIE), and the Italian Association of Medical Oncology (AIOM) on treating neuroendocrine neoplasms (NENs)with radioligand therapy (RLT). A list of 10 questions regarding using RLT ingastroenteropancreatic neuroendocrine tumors (GEP-NETs) was addressed after a careful review of theavailable literature. compiling information from the MEDLINE database, augmented with expert opinionsand recommendations, aligns with the latest scientific research and the author's extensive knowledge.The recommendations are evaluated using the GRADE system, showcasing the level of evidence andthe strength of the recommendations. Specifically, this paper focuses on thesubcategories of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) thatexpress somatostatin receptors and are considered suitable for RLT, according to internationalguidelines.

Searching for New Biomarkers of Neuroendocrine Tumors: A Comparative Analysis of Chromogranin A and Inflammatory Cytokines in Patients with Neuroendocrine Tumors.

Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications.

Nutritional aspects in neuroendocrine neoplasms. bridging the gap between dietary interventions and cancer care strategies: a scoping review.

Neuroendocrine neoplasms (NENs) represent heterogeneous tumors arising from neuroendocrine cells in different organs. Despite growing interest in the nutritional aspects of NEN management, research in this area is limited. Aim of this review is to summarize the current state of knowledge, highlight research gaps, and underscore the significance of nutrition in the comprehensive care of NEN patients. We conducted an extensive bibliographic search focusing on studies (including retrospective and prospective studies, systematic reviews, case series, and guidelines) exploring the relationship between nutritional assessments, dietary interventions, micronutrient deficiencies, and their impact on NEN outcomes. Significant gaps exist in current research, particularly in understanding the specific nutritional needs of NEN patients and how tailored nutritional interventions can improve clinical outcomes. Evidence suggests that a high-fat Western diet may promote the growth of NEN, while a Mediterranean diet may help lower insulin levels and strengthen the immune system, potentially preventing tumor development. The ketogenic diet and intermittent fasting may also have positive impacts. Addressing common micronutrient deficiencies, such as vitamin D and niacin, is crucial to mitigate disease progression. There's a crucial need for future studies to include a comprehensive nutritional assessment incorporating patient-reported outcomes, to fully capture the impact of nutritional strategies. Nutritional management, an important but under-researched facet of NEN treatment, significantly improves patients' quality of life and survival. Integrating nutrition into personalized cancer care is essential, highlighting the role of nutritional strategies in optimizing patient outcomes.

ESOMA-DM1, a Maytansinoid-Based Theranostic Small-Molecule Drug Conjugate for Neuroendocrine Tumors.

Background: The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N3-Py-DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. Methods: Synthesis of the DM1 moiety (4) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [111In]InCl3 gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eSOMA-DM1 exhibited an IC50 value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [111In]In-eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [111In]In-DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [111In]In-eSOMA-DM1 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. Conclusion: eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [111In]In-eSOMA-DM1 suggest the need for adjustments to optimize its distribution.

Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma.

Immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy. However, given the limited number of current targets, the identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potent in vitro activity among established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti-tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy is overall limited in ACC due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 is extremely potent and induces complete responses in DLK1 + ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation. Single cell RNA-seq of ACC metastatic tumors reveals significantly decreased adrenocortical differentiation in DLK low or negative cells compared to DLK1 positive cells. This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial ( NCT06041516 ).

Tarlatamab-dlle: A New Hope for Patients with Extensive-Stage Small-Cell Lung Cancer.

Lung cancer is expected to contribute to about 0.234 million new cases and about 0.125 million mortalities in the United States in the year 2024. Small cell lung cancer (SCLC), a neuroendocrine carcinoma, has lesser prevalence but is more aggressive at an extensive stage where the tumor is not only confined to hemithorax, mediastinum, and supraclavicular region but spread beyond the supraclavicular region. The prognosis of SCLC, irrespective of the limited or extensive stage, is very poor. Only a 5-10% overall survival rate in five years is expected and with extensive-stage SCLC, long-term disease-free survival is rare. In May 2024, the USFDA approved Tarlatamab-dlle, a DLL3 targeted bi-specific T-cell engager, for treating extensive-stage SCLC in adult patients, on or after platinum-based chemotherapy or on progression. Before the approval of Tarlatamab-dlle, only a few drugs, such as Atezolizumab and Durvalumab, received FDA approval for treating extensive-stage SCLC. It might be possible that Tarlatamab-dlle received accelerated FDA approval for extensive-stage SCLC, leaving some questions unanswered at this stage. This manuscript is focused on clinical, pre-clinical, and other pharmacological aspects of Tarlatamab-dlle for extensive-stage SCLC.

Podoplanin Expression in Early-Stage Colorectal Cancer-Associated Fibroblasts and Its Utility as a Diagnostic Marker for Colorectal Lesions.

(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma is often encountered, suggesting PDPN-positive CAFs have emerged. However, PDPN-positive CAFs in early CRC have not been studied well. (Methods) On immunohistochemistry, PDPN expression in the lamina propria or stroma of adenomas, early CRCs, and neuroendocrine tumors, their normal neighbors, and non-neoplastic colorectal lesions were compared. Single-cell RNA sequencing (scRNA-seq) of CRC was used to explore PDPNhigh CAFs' cell origins. (Results) Reticular cells or pericryptal fibroblasts in the lamina propria of adenomas and early CRCs showed higher PDPN expression than did normal mucosae and non-neoplastic lesions (p < 0.01). Pericryptal PDPN expression was a diagnostic feature of adenomas and early CRCs. scRNA-seq of CRCs highlighted that PDPNhigh CAFs had distinctly higher COL4A1, COL4A2, and WNT5A expression, unlike well-known CAFs characterized by high FAP, POSTN, or ACTA2 expression. (Conclusions) We demonstrated that pericryptal fibroblasts and reticular cells in the lamina propria are origins of early-stage CRC CAFs and thus have potential as a diagnostic marker for distinguishing colorectal non-neoplastic from neoplastic lesions.

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.

Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1+ cells arise from KRT8+ luminal cells, progressing into transcriptionally heterogeneous ASCL1+;KRT8- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.