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Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.
Department of Urology IEO European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Università degli Studi di Milano, Milan, Italy
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Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy
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Department of Urology, Medical University of Graz, Graz, Austria
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Università degli Studi di Milano, Milan, Italy
Department of Urology, IRCCS Policlinico San Donato, Milan, Italy
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Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
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Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy
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Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy
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Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy
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Department of Urology, IRCCS Ospedale Galeazzi - Sant'Ambrogio, Milan, Italy
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Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy
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Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy
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We developed a novel contemporary population-based model for predicting cancer-specific survival (CSS) in adrenocortical carcinoma (ACC) patients and compared it with the established 8th edition of the American Joint Committee on Cancer staging system (AJCC). Within the Surveillance, Epidemiology, and End Results database (2004–2020), we identified 1056 ACC patients. Univariable Cox regression model addressed CSS. Harrell’s concordance index (C-index) quantified accuracy after 2000 bootstrap resamples for internal validation. The multivariable Cox regression model included the most informative, statistically significant predictors. Calibration and decision curve analyses (DCAs) tested the multivariable model as well as AJCC in head-to-head comparisons. Age at diagnosis (>60 vs ≤60 years), surgery, T, N, and M stages were included in the multivariable model. Multivariable model C-index for 3-year CSS prediction was 0.795 vs 0.757 for AJCC. Multivariable model outperformed AJCC in DCAs for the majority of possible CSS-predicted values. Both models exhibited similar calibration properties. Finally, the range of the multivariable model CSS predicted probabilities raged 0.02–75.3% versus only four single AJCC values, specifically 73.2% for stage I, 69.7% for stage II, 46.6% for stage III, and 15.5% for stage IV. The greatest benefit of the multivariable model-generated CSS probabilities applied to AJCC stage I and II patients. The multivariable model was more accurate than AJCC staging when CSS predictions represented the endpoint. Additionally, the multivariable model outperformed AJCC in DCAs. Finally, the AJCC appeared to lag behind the multivariable model when discrimination addressed AJCC stage I and II patients.
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We observed that some patients with well-differentiated neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with Lutetium-177 (177Lu) DOTATATE developed rapid disease progression with biopsy-proven histologic transformation to neuroendocrine carcinoma (NEC), an outcome that has not been previously described. Therefore, we conducted a retrospective review of all patients with well-differentiated G1-G2 NET who received at least one cycle of PRRT with (177Lu) DOTATATE at our center from January 2019 to December 2020. Among 152 patients, we identified 7 patients whose NET transformed to NEC. Median time from start of PRRT to transformation was 8.2 months (range: 2.6–14.4 months). All patients whose tumors underwent transformation had pancreatic tail as the primary site and had prior chemotherapy with temozolomide. No differences in the incidence of transformation were observed according to gender, race, original tumor grade, or number of prior therapies. Six patients received treatment with platinum and etoposide after transformation with two patients having partial response as best response. All patients with transformation died from progressive disease with median overall survival (OS) after transformation of 3.3 months (95% CI 2.1–4.4). Molecular testing of transformed NEC identified mutation(s) in TP53 and/or ATM in all cases. Transformation of NET to NEC following PRRT is associated with aggressive course and dismal prognosis. Patients with pancreatic tail as the primary site who had prior therapy with temozolomide may be at a higher risk. Further investigation is necessary to determine the best treatment sequence in this patient population.
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Weill Cornell Medical College, Cornell University, New York, New York, USA
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The chemotherapy regimen capecitabine/temozolomide (CAPTEM) is routinely used in neuroendocrine tumors (NET), with antitumor activity particularly demonstrated in pancreatic or high-grade neuroendocrine neoplasms (NEN). However, different dosing regimens are used, and the optimal schedule remains to be defined. This single-center retrospective analysis assessed the efficacy and safety of CAPTEM in patients with NEN using a schedule starting both compounds simultaneously (temozolomide on days 1–5 and capecitabine on days 1–14 of a 28-day cycle) rather than sequentially. The primary parameters of interest were response rates, progression-free survival (PFS), and toxicities following this treatment regimen, hereinafter referred to as TEMCAP. The study population comprised 40 patients, half of whom (n = 20) had pancreatic NEN, and 9 patients (22.5%) had pulmonary or thymic NETs. The most common histology was NET G3 (n = 15, 37.5%), and 8 patients (20.0%) had a neuroendocrine carcinoma (NEC). Most patients (77.5%) had at least one prior systemic therapy, and 16 patients (40.0%) prior chemotherapy. The median number of TEMCAP cycles was 6 (range 1–16). Median PFS for the highly heterogeneous population was 13.3 months, while the median overall survival was 31.9 months. In total, 14/36 patients (38.9%) exhibited a partial response, and the disease control rate was 75.0%. The safety profile of TEMCAP (at a below-target mean temozolomide dose of 118.85 mg/m2) in our cohort was remarkably good with no toxicities of grade 3 or 4. Taken together, the results of this analysis further support the use of temozolomide/capecitabine in NEN and prompt further assessment of our modified TEMCAP schedule.
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Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA
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Radiotherapy is one of the major options currently for cancer treatment. Radiotherapy causes cellular damage inducing cell death, which is expected to be selective for tumor cells. However, side effects that alter the surrounding normal tissue are often hard to be avoided. When radiation involves the hypothalamic–pituitary axis, growth hormone deficiency (GHD) is frequently induced, causing developmental and metabolic-related diseases in childhood cancer survivors. Growth hormone (GH) replacement therapy has been used for these patients and has been shown to be safe in general. However, there are some debating for its long-term safety due to the known roles of GH in inducing cell growth, which could be related to cancer recurrence. In addition, studies have shown that GH is involved in the development of resistance to chemotherapy and radiotherapy through various mechanisms. In this review, we will first discuss the effects of GHD induced after radiotherapy and the safety of the GH replacement treatment. Then, we will discuss the role of the GH–IGF-1 axis in radioresistance via a mechanism of improving DNA repair.
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The activation of Treg cell subsets is critical for the prognosis of tumor patients; however, their heterogeneity and disease association in papillary thyroid carcinoma (PTC) need further investigation. We performed high-dimensional flow cytometry for immunophenotyping on thyroid tissues and matched peripheral blood samples from patients with multinodular goiters or PTC. We analyzed CD4+ T cell and Treg cell phenotypes and compared the recurrence-free survival of PTC patients with different Treg cell subset characteristics using TCGA. Furthermore, PTC recurrent and non-recurrent group were compared by multiplex immunohistochemistry. High-dimensional flow cytometry and bioinformatics analysis revealed an enrichment of Tregs in tumors compared with multinodular goiters and peripheral blood specimens. Moreover, effector Tregs (e-Tregs) as well as FOXP3+ non-Tregs were enriched in tumor samples, and the expression of CD39, PD-1, and CD103 increased on tumor Tregs. TCGA data analysis showed that individuals with CD39hi PD-1loCD103loe-Treghi and CD39loPD-1loCD103hie-Treghi expression patterns had a high recurrence rate. According to the multiplex immunohistochemistry and analysis, compared with non-recurrent group, the proportion of high recurrence rate effector Treg clusters (CD39+PD-1−CD103− plus CD39−PD-1−CD103+) was increased in recurrent patients. Overall, our results highlight the potential of e-Treg subsets as future immunotherapy targets for PTC recurrence.
Department of Clinical Research, University of Basel, Basel, Switzerland
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Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
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Department of Clinical Research, University of Basel, Basel, Switzerland
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Department of Clinical Research, University of Basel, Basel, Switzerland
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Sex differences affect the management of several diseases in both male and female patients. However, the influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from July 2014 to September 2022. The analysis included 1985 patients (46% female and 54% male). No significant difference in tumor grading was found between male and female patients. However, male patients presented with higher staging at time of diagnosis and with more lymph node and bone metastases. Surgery was performed more often in female compared to male patients (73.4% vs 68.7%, P = 0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, P = 0.003). The median overall survival was significantly shorter for male compared to female patients (male: 18 years, female: not reached, P < 0.001, hazard ratio (HR) 1.55 (1.19–2.01), P = 0.001). Multivariable analyses revealed advanced age (HR 1.02 (1.01–1.04)), cancer of unknown origin (HR 2.01 (1.09–3.70)), higher grading (G3: HR 6.74 (4.22–10.76)), having metastases at the time of diagnosis (HR 2.11 (1.47–3.02)), and surgical treatment (HR 0.67 (0.48–0.93)) as independent predictors for overall survival. In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.
Department of Urology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China
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Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Guangzhou, Guangdong
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Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
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Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.
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Department of General, Visceral and Transplantation Surgery, Division of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany
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Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1–40 mm (node metastasis and biochemical cure) and 10.1–40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27–41% (overall 24.0%) point difference, followed by biochemical cure with a −15–35% (overall −20.3%) point difference and extrathyroid extension with a 17–24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.
