Abstract Background and Objective: Advanced pancreatic neuroendocrine tumors (pNETs) respond poorly to current FDA-approved therapies, emphasizing the urgent need to find new and effective treatment targets. Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD biosynthesis pathway, has emerged as a crucial therapeutic target in pNETs. Despite its importance, specific inhibitors directly targeting NAMPT for pNET treatment are currently lacking. This study aimed to evaluate the efficacy of RPT-E-037, a novel NAMPT inhibitor, in preclinical models of pNETs. Methods: Growth inhibition was determined by MTT, colony formation and apoptosis assays. We also measured growth arrest using cell cycle analysis. Expression of gene or protein was determined using quantitative PCR, and western blotting techniques. The impact of NAMPT inhibitor RPT-E-037 was evaluated in pNET in vitro cultures and in in vivo. Results: RPT-E-037 demonstrated its growth inhibitory effect in BON-1 and QGP-1 pNET cell lines at pharmacologically relevant concentrations. The inhibitory concentration-50 (IC50) were determined as 0.3 and 1.2 micromolar (µM) in BON-1 and QGP-1 cells respectively. Importantly, RPT-E-037 demonstrated selectivity, showing no adverse effects on normal islet cells (ABC-TC4286, AcceGen) at concentrations effective against tumor cells (reflected by its 40-folds higher IC50). In addition, growth inhibitory effect of RPT-E-037 significantly rescued by nicotinic acid (niacin) treatment in BON-1 cells. Niacin also diminishes its colony reduction and apoptotic ability of RPT-E-037 in this cell line. The novel NAMPT inhibitor RPT-E-037 was shown to induce “DNA synthesis (S) phase” cell cycle arrest. However, niacin treatment switches “S phase” cell cycle arrest to “G0/G1 phase” cell cycle arrest. RPT-E-037 synergized with pNETs standard of care mTOR targeted agent everolimus in both BON-1 and QGP-1 cell lines leading to superior cell deaths (CI<1). The in vivo efficacy of RPT-E-037 in BON-1 and QGP-1 cell line derived xenografts (CDxs) are under way. Conclusion: For the first time, this study reveals the therapeutic potential of RPT-E-037, a new NAMPT inhibitor, for pNETs in preclinical models. RPT-E-037 shows promise as a novel NAMPT inhibitor and deserves further clinical investigation for pNETs.Generative AI was used for improving the language of the abstract. Citation Format: Md Hafiz Uddin, Husain Yar Khan, Amro Aboukameel, Sahar F. Bannoura, Irfana Muqbil, Hugo Jimenez, Filza Khan, Rafic Beydoun, Gregory Dyson, Yang Shi, Mohammed N. Al Hallack, Nitin Vaishampayan, Ibrahim Azar, Steve Kim, Eliza W. Bael, Miguel Tobon, Khalil Choucair, Walid Sukkari, Hafsa Imtiaz, Herbert Chen, Muhammad W. Saif, Anthony Frank Shields, Ramzi M. Mohammad, Philip Philip, Bassel F. El Rayes, Min Wu, Michael Schelle, Boris Pasche, Asfar S. Azmi. Targeting NAMPT using Novel Inhibitor RPT-E-037 in Pancreatic Neuroendocrine Tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 419.

Pancreatic neuroendocrine tumors (PNETs) represent a biologically heterogeneous group of neoplasms shaped by both intrinsic genomic alterations and dynamic interactions with the tumor microenvironment (TME). Conventional analytical approaches offered limited insight into these complex mechanisms. However, the emergence of multi-omics technologies including genomics, transcriptomics, proteomics and spatial single-cell platforms dramatically expanded current understanding of tumor evolution, immune-stromal crosstalk and phenotypic plasticity. In the present review, findings from novel multi-omics studies were integrated to reframe PNET biology through the perspective of TME co-evolution. The present review highlighted how genomic instability serves as a key driver, promoting transcriptomic reprogramming and clonal evolution that subsequently remodels the TME into an immunosuppressive niche rich in cancer-associated fibroblasts and characterized by immune exclusion. The present review further emphasized the novel role of spatial multi-omics in deciphering the spatial heterogeneity of the PNET ecosystem. These insights accelerated the identification of novel biomarkers and revealed novel therapeutic susceptibilities, potentially paving the way for rational combination strategies that target both tumor-intrinsic pathways and microenvironmental constraints. Therefore, the present review proposed that multi-omics profiling provides not only a descriptive landscape but a mechanistic framework for precision oncology, enabling improved patient stratification and biomarker-driven therapeutic interventions in PNETs.

Introduction: Preoperative imaging is widely advocated for and often routinely ordered for patients undergoing parathyroidectomy. Yet its actual benefit in contributing to surgical safety considering high rates of nondiagnostic imaging remain debated. This study aims to evaluate if imaging before parathyroidectomy contributes to improving post operative outcomes in hyperparathyroidism. Methods: We conducted a retrospective cohort study of patients who underwent parathyroidectomy (PTx) for hyperparathyroidism between 2000 and 2023 at our institution. Patients with prior thyroid or parathyroid surgery were excluded. Data collected included demographics, clinical features, biochemical parameters, and outcomes. Localization status was determined by ultrasound, sestamibi, or 4D-CT. Patients without imaging were 1:1 propensity-matched to those with imaging by age, gender, preop calcium, and PTH. Assessed complications included transient and permanent hypocalcemia, hoarseness, and persistent hyperparathyroidism. Results: Of 2,287 eligible patients, 349 (15.3%) underwent PTx without preoperative imaging, while 1,938 (84.7%) had at least one imaging study. We matched 311 imaging-naive patients to counterparts with imaging. Among those imaged, 13.1% (n = 253) had negative localizing studies; 17.4% of these had undergone multiple imaging tests. Negative imaging was significantly associated with normocalcemic or normohormonal disease (OR 1.6, 95% CI 1.2 - 2.2, p = 0.003), double adenomas (OR 2.5, p < 0.001), and hyperplasia (OR 1.5, p = 0.06). Complication rates were similar between imaging and non-imaging groups as were cure rates based on normocalcemia at 6 months (94.5% vs 97.1%, p = 0.2). Conclusion: Preoperative imaging is not essential for successful parathyroidectomy performed by experienced surgeons as outcomes remain comparable even without localization.

The journal retracts the article “Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells” [...]

Sporadic pancreatic neuroendocrine tumors (pNETs) with wild type MEN1 represent a major yet largely ignored subset whose biology and metastatic potential remain poorly understood. Because metastasis can occur despite low histologic grade and modest mutational burden, we hypothesized that metastatic competence in MEN1-wild-type pNETs reflects quantitative reinforcement of shared oncogenic pathways rather than distinct mutational processes. We profiled 75 primary low-grade pNETs by whole-exome and RNA sequencing, including 25 percent with lymph node and/or liver metastasis, and integrated genomic and transcriptomic data to connect pathway lesions with expression state. Metastatic tumors showed a slight increase in mutation frequency but conserved base-substitution spectra relative to non-metastatic cases, and adverse clinicopathologic features were enriched in Grade 2 disease. Aggregating alterations to pathways revealed broad convergence on canonical networks, with transcriptomic analyses demonstrating cohort-wide enrichment of Calcium, WNT, and KRAS/PI3K-AKT programs in metastasis. Intersection of significantly mutated genes with differentially expressed genes identified a focused 29-gene overlap, including RYR1 and ZNF273, that marks these convergent axes and distinguishes metastatic from non-metastatic tumors. Gene set enrichment confirmed preferential activation of Calcium, WNT, and PI3K-AKT signaling in metastatic tumors, consistent with a network-intensity model of progression. Finally, upstream-regulator analysis (iPathwayGuide) and gene-centric perturbation mapping (Gene2Drug) nominated candidate targeted and repurposable agents predicted to reverse the metastatic expression phenotype and flagged drugs unlikely to provide benefit, yielding a prioritized, testable therapeutic shortlist which includes fasudil and spaglumic acid. Convergent, domain-specific mutational patterns in highly mutated genes such as ZNF273 and CLCA1 define a molecular signature that could stratify metastatic risk in low-grade pNETs. Collectively, our data reframe metastasis in MEN1-wild-type low-grade pNETs as a property of pathway state rather than mutation quantity and provide a translational blueprint for biomarker-guided therapy development focused on Calcium, WNT, and KRAS/PI3K hubs.

BACKGROUND:Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that contributes disproportionately to thyroid cancer-related mortality. Historically, systemic treatment options for advanced MTC were limited due to poor responsiveness to radioactive iodine and conventional chemotherapy. The development of targeted therapies has significantly transformed disease management. METHODS:This narrative review summarizes current evidence on targeted therapies for advanced MTC, including multikinase inhibitors (MKIs), selective RET inhibitors, and emerging treatment strategies. Literature on efficacy, safety, resistance mechanisms, and novel therapeutic approaches was evaluated. RESULTS:First-generation MKIs, including vandetanib and cabozantinib, demonstrated clinical benefit by targeting RET and angiogenic pathways, though off-target toxicities limited tolerability. More recently, selective RET inhibitors, such as selpercatinib and pralsetinib, have shown high response rates and improved safety profiles, establishing them as preferred first-line therapies for RET-mutant MTC. However, pralsetinib's recent market withdrawal due to regulatory challenges highlights the need for additional options. Emerging therapies, including BOS172738, SY-5007, and peptide receptor radionuclide therapy, show promising early results. Resistance mechanisms, including gatekeeper and solvent front mutations, remain a challenge. Advances in clinical biomarkers and novel approaches, such as CAR-T cell therapy, may further support personalized treatment. CONCLUSION:Targeted therapies have reshaped the management of advanced MTC, with selective RET inhibitors offering improved efficacy and tolerability. Continued research is essential to overcome resistance, expand therapeutic options, and improve patient outcomes.

BACKGROUND:Tertiary hyperparathyroidism is a common complication in kidney transplant (KT) recipients, often persisting despite successful graft function. However, the optimal treatment for improving long-term graft survival remains unclear. Parathyroidectomy (PTX) offers a definitive approach to restoring calcium homeostasis. This study aims to assess the effect of PTX on graft failure, the need for dialysis, and renal osteodystrophy in the 2 groups. STUDY DESIGN:A retrospective analysis of electronic medical records from a multi-institutional database (TriNetX) was completed. Patients diagnosed with tertiary hyperparathyroidism after KT were divided into 2 groups based on the type of intervention: cinacalcet or PTX. Patients were followed for up to 5 years, starting from the day after initiating cinacalcet or PTX. Propensity score matching was used to balance demographics, comorbidities, creatinine levels before intervention, and vitamin D deficiency. Cox regression analysis was performed to determine measures of association. RESULTS:A total of 811 patients were included in each treatment group after propensity score matching. During the study period, 42.8% of patients (n = 347 of 811) receiving cinacalcet became dialysis-dependent, compared with 30.9% (n = 251 of 811) of those who underwent surgery (p < 0.01). Regarding renal osteodystrophy, 10.8% of patients (n = 74 of 684) on cinacalcet developed the condition, whereas only 5.1% (n = 32 of 628) in the PTX group experienced it (p < 0.01). Additionally, 17.2% of those on cinacalcet experienced graft failure, compared with 12.6% in the PTX group (p < 0.04). CONCLUSIONS:Patients who underwent PTX experienced lower rates of KT failure and dialysis, outperforming those treated with cinacalcet; however, this finding should be cautiously interpreted regarding its clinical relevance. Improved electrolyte balance and parathyroid hormone levels may be associated with a lower rate of renal osteodystrophy.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by high metabolic demand and dependency on NAD salvage pathways. NAMPT, the rate-limiting enzyme in NAD biosynthesis, is upregulated in PDAC and supports tumor survival under therapeutic stress. We investigated the preclinical activity of a novel hyperbolic NAMPT inhibitor (NAMPTi) in combination with standard-of-care (SOC) chemotherapy regimens including gemcitabine, paclitaxel, 5-FU, oxaliplatin, hydroxychloroquine, and paricalcitol to determine whether NAMPT blockade enhances cytotoxic and immunomodulatory responses. Methods: Human and murine PDAC cell lines (PANC-1, MIA PaCa-2, KPC-Luc, and patient-derived 2838c) were treated with NAMPTi (5 μM) alone or with SOC agents at clinically relevant doses. Synergy was assessed in 2D viability and 3D spheroid assays. Olaparib combinations were also tested in BRCA-related models. In vivo, KPC allografts received NAMPTi (20 mg/kg, 5×/week) with gemcitabine, paclitaxel, hydroxychloroquine, 5-FU, oxaliplatin, or paricalcitol for three weeks. Immune infiltrates (CD45+, CD8+, CD4+ subsets), functional markers (GZMB, CD107a, IFNγ, TNFα), and fibroblast subtypes (apCAF, myCAF, iCAF) were quantified by flow cytometry. Results: Across all PDAC models, NAMPTi alone produced modest growth inhibition, while combination treatment consistently outperformed monotherapies. NAMPTi synergized with gemcitabine-paclitaxel-hydroxychloroquine and gemcitabine-paclitaxel regimens, significantly reducing cell viability in both human and KPC-derived lines. In vivo, NAMPTi combinations markedly suppressed KPC tumor growth compared to SOC alone and reduced metastatic burden to liver and lung (e.g., GPH+NAMPTi: 60% metastasis-negative vs. 20-40% in monotherapy groups). Dual treatment increased CD8+ T-cell infiltration and effector phenotypes, enhanced cytotoxic function (GZMB+, CD107a+), and elevated IFNγ and TNFα production. NAMPTi also shifted fibroblast composition, with significant reductions in myCAFs and apCAFs, suggesting stromal remodeling. In FO and GPH regimens, combining NAMPTi produced superior tumor control, decreased immunosuppressive cell populations, and improved effector memory T-cell signatures. Conclusions: NAMPT inhibition robustly enhances SOC chemotherapy efficacy in PDAC by simultaneously amplifying cytotoxic responses, remodeling the tumor immune microenvironment, and reducing metastatic spread. These findings support NAMPTi-based combinations as a promising therapeutic strategy and justify further translational development, including biomarker-driven clinical evaluation in PDAC. "Generative AI was used for improving the language of the abstract". Citation Format: Purnachandra Nagaraju Ganji, Sujith Sarvesh, Dhana Sekhar Reddy Bandi, Husain Yar Khan, Irfana Muqbil, Amro Aboukameel, Sahar Bannoura, Khalil Choucair, Walid Sukkari, Sunil Jaiman, Rafic Beydoun, Gergory Dyson, Yang Shi, N Vaishampayan, Eliza W. Bael, Miguel Tobon, Steve Kim, Herbert Chen, Muhammad W. Saif, Anthony Frank Shields, Philip A. Philip, Min Wu, Michael Schelle, Boris Pasche, Asfar S. Azmi, Bassel F. El-Rayes. NAMPT inhibition enhances the efficacy of standard chemotherapies and immunomodulation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2936.

Introduction Sex-based differences in the presentation of primary hyperparathyroidism (PHPT) remain poorly understood. A comprehensive understanding of how PHPT manifests and progresses in male versus female patients in the U.S. is still lacking. This study aims to evaluate sex-based differences in the preoperative presentation and postoperative outcomes of patients undergoing parathyroidectomy (PTX). Methods A multi-institutional research network, comprising data from 58 U S. institutions, was retrospectively queried for patients presenting with PHPT (ICD-10 E21.0) and PTX (CPT 60500). The follow-up period was 3 ± 2 years. Cox regression analysis was employed to assess differences in pre-operative presentations and post-operative outcomes. Results This study included 39,216 females and 11,101 males. Females presented with PHPT at an older age (62 ± 13 vs. 60 ± 14, p < 0.01). Males presented with higher levels of pre-operative calcium (10.8 ± 0.9 vs. 10.7 ± 0.8, p < 0.001) and parathyroid hormone (136 ± 151 vs. 125 ± 139, p < 0.001). Females were more likely to present with osteoporosis (26% vs. 11%, p < 0.001), fatigue (16% vs. 12%, p < 0.01), and vitamin D deficiency (29% vs. 24%, p < 0.001). In comparison, males were more likely to present preoperatively with chronic kidney disease (11% vs. 8%, p < 0.001) and nephrolithiasis (21% vs. 13%, p < 0.001). No significant differences were observed in re-operation rates or recurrent laryngeal nerve injury. Conclusions Females make up most cases of PHPT and are more likely to experience musculoskeletal disorders and fatigue, while males are more prone to renal complications. These sex-based differences in clinical presentation underscore the importance of timely surgical intervention.

Introduction The incidence and prevalence of primary hyperparathyroidism (PHPT) are known to be increasing, yet few studies have explored these trends on a global scale. This study aims to examine worldwide trends in PHPT incidence, prevalence, and parathyroidectomy rates, while identifying potential factors contributing to the observed rise in PHPT cases. Methods A retrospective analysis of the TriNetX Global database was conducted from 1998 to 2023 to assess the incidence and prevalence of PHPT. Patients with renal hyperparathyroidism or other secondary causes of hypercalcemia were excluded. Patients were classified into PHPT subtypes based on serum calcium and parathyroid hormone (PTH) levels. Classic PHPT (cPHPT) was defined as calcium ≥10.5 mg/dL and PTH ≥66 pg/mL, ncPHPT as calcium levels between 8.8 and 10.4 mg/dL with PTH ≥66 pg/mL, and nhPHPT as calcium ≥10.5 mg/dL with PTH between 21 and 65 pg/mL. Demographic variables, including age, sex, and race/ethnicity, as well as parathyroidectomy status were collected. Annual incidence and prevalence rates per 100,000 population were calculated for each PHPT subtype to examine temporal and demographic trends. Results From 1998 to 2023, the global incidence of primary hyperparathyroidism (PHPT) increased more than seven-fold, from 3.5 to 26.9 per 100,000, while prevalence rose from 4.2 to 245 per 100,000. The greatest growth occurred in normocalcemic PHPT (ncPHPT), with incidence rising from less than 1 to 16.2 per 100,000, now representing the dominant global phenotype. Females accounted for the majority of cases, and White patients consistently showed the highest rates, though rates among Black and Asian populations grew disproportionately after 2015. Parathyroidectomy utilization remained low, with surgery performed in approximately 38% of cPHPT, 14% of ncPHPT, and 16% of nhPHPT patients despite increasing disease burden. Conclusion Global PHPT burden is increasing, driven primarily by ncPHPT, while parathyroidectomy rates remain low, further work is needed to clarify how much of this gap reflects guideline-eligible patients not undergoing surgery versus appropriate non-operative management.

Background Surgical management is recommended in patients with secondary hyperparathyroidism (SHPT) when parathyroid hormone (PTH) levels exceed 9 times the normal, and medical management has failed to control PTH levels or associated complications. We aimed to examine the impact of the timing of parathyroidectomy on clinical outcomes in patients with SHPT and PTH exceeding 9x normal. Methods In this retrospective cohort study using TriNetX database, we included adults with a PTH ≥600 pg/mL and concurrent CKD stage 5 or eGFR ≤15 mL/min/1.73 m2 who underwent parathyroidectomy. Patients with prior kidney transplants were excluded. Parathyroidectomy timing was classified as early (≤2 years) or delayed (>2 years) from the index PTH elevation. Cohorts were propensity score matched based on demographics, Charlson comorbidities, BMI, laboratory values, dialysis dependence, and medication use. A secondary matched analysis compared outcomes in kidney transplant recipients undergoing parathyroidectomy before versus after transplantation. Outcomes measured were fatigue, hypercalcemia, osteoporosis and cardiovascular complications after index event. Results 1,413 patients underwent parathyroidectomy without prior kidney transplant. 916 (64.8%) underwent early, while 497 (35.2%) underwent delayed parathyroidectomy. Kidney transplant occurred in 15.8% of early and 35.8% of delayed patients at median intervals of 1.8 and 3.9 years. After matching at the index PTH elevation (n=730), the mean age was 44, with 50% female and 43% Black. Delayed parathyroidectomy was associated with a higher risk of malaise and fatigue (HR=1.5, p=0.02), osteoporosis (HR= 1.63, p=0.04) and hypercalcemia (HR=1.42, p=0.01). Cardiovascular complications were significantly more frequent in the delayed group. In a secondary analysis of kidney transplant recipients (n=1,054), parathyroidectomy performed after transplantation was associated with a 2.6-fold increased hazard of graft failure. Conclusions In patients with SHPT undergoing parathyroidectomy, early surgery performed at a PTH of 9x normal may mitigate the risk of complications.

CONTEXT:Secondary hyperparathyroidism is a common complication of chronic kidney disease that accelerates bone loss and increases fracture risk. While parathyroidectomy (PTx) is the definitive treatment for medically refractory cases, its impact on bone mineral density (BMD) has not been comprehensively evaluated. EVIDENCE ACQUISITION:A systematic search of PubMed, Embase, and Scopus was conducted from inception through January 2026. Studies were included if they reported dual-energy X-ray absorptiometry-measured BMD before and after PTx in adults with secondary hyperparathyroidism due to chronic kidney disease. Two reviewers independently screened and selected studies using the PICOS framework, and additional articles were identified through reference searching. EVIDENCE SYNTHESIS:Across 11 studies encompassing 452 patients with paired measurements, all demonstrated significant improvement in BMD following a site-specific hierarchy favoring cancellous bone. The lumbar spine (+7-50% g/cm2) and femoral neck (+8-23% g/cm2) showed the most consistent gains, while the distal radius showed minimal change. Higher preoperative parathyroid hormone levels, elevated alkaline phosphatase, and lower baseline BMD were associated with greater skeletal recovery. The only available randomized trial confirmed the superiority of PTx over cinacalcet for bone density improvement. CONCLUSIONS:PTx consistently improves BMD in patients with refractory secondary hyperparathyroidism, with the greatest gains at cancellous-rich skeletal sites. Clinicians should consider the skeletal benefits of PTx when counseling patients with medically refractory disease, particularly those with low baseline bone density and markedly elevated parathyroid hormone levels.