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Search for other papers by Elisa Lamback in
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Search for other papers by Luiz Eduardo Armondi Wildemberg in
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Pituitary gigantism is a rare pediatric disorder caused by excess growth hormone (GH) secretion. In almost 50% of cases, a genetic cause can be identified, with pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene being the most common. We present a case of a 11-year-old boy who exhibited progressive vision loss, associated with accelerated linear growth and weight gain. On physical examination, he had enlarged hands, right eye amaurosis, and was already above his target height. Increased GH and IGF-I concentrations confirmed the diagnosis of pituitary gigantism. A magnetic resonance imaging showed a giant sellar lesion with supra- and para-sellar extensions. He underwent two surgeries which did not achieve cure or visual improvement. Histopathological analysis revealed a sparsely granulated tumor, negative for somatostatin receptor type 2 (SST2) and immunoreactivity score of 6 for somatostatin receptor type 5 (SST5). Our published artificial intelligence prediction model predicted an 83% chance of not responding to first-generation somatostatin receptor ligands. Pasireotide was therefore prescribed and afterwards cabergoline was added on. IGF-I concentrations decreased, but did not normalize. We discovered a novel germline single nucleotide variant in the splicing donor region of intron 2 of AIP gene (NM_003977.4:c.279+1 G>A), classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines.
Search for other papers by Leo Baxendale-Smith in
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Selective internal radiation therapy (SIRT) is a novel intervention for both primary and metastatic malignant liver lesions. Adrenocortical carcinoma (ACC) is rare with limited treatment options; evidence for SIRT in ACC liver metastases consists of case reports only. Selective internal radiation therapy (SIRT) was employed to treat recurrent liver metastases in a 49-year-old gentleman with ACC, who previously underwent a left-sided hepatectomy. The patient opted for SIRT after reviewing the literature regarding mitotane chemotherapy and its toxicities. Selective internal radiation therapy (SIRT) provided several months of progression-free survival (PFS), with no toxicity and an excellent radiological response. The patient re-presented 12 years after the initial diagnosis with skeletal metastases and sadly died in September 2022. Substantial unmet need exists for effective treatments in ACC, with 75% of patients presenting with incurable disease. Developing widespread disease, SIRT offered 2 years’ PFS in our patient; this was well tolerated with minimal residual liver impairment. Its use in ACC liver-limited disease warrants investigation.
Significance statement
Adrenocortical carcinoma (ACC) is a rare and aggressive tumour with limited treatments. Once metastatic disease develops, existing standard-of-care treatments offer a dismal overall survival, alongside marked toxicities. Selective internal radiation therapy (SIRT) may represent a new intervention in the treatment paradigm for liver-limited, metastatic ACC. Here, we present the case of a patient treated with multiple rounds of SIRT for relapsed, liver-limited ACC, prolonging survival by several years. Recurrent SIRT led to maintained liver function and no toxicities. Little evidence outlines its use in ACC but further study is certainly warranted to ascertain the value of SIRT, considering the limited treatment landscape that currently exists.
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Search for other papers by Elisabeth S Lim in
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Search for other papers by Patricia A Cronin in
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Search for other papers by Chee-Chee Stucky in
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Background
The 2015 American Thyroid Association (ATA) guidelines added thyroid lobectomy (TL) as the appropriate treatment for low-risk differentiated thyroid cancer (DTC). We aimed to investigate the population-level factors that influence the utilization of TL.
Methods
The Surveillance, Epidemiology and End Results (SEER) database was queried for all DTC patients fitting low-risk criteria as defined by the ATA. Trends in total thyroidectomy (TT) and TL were identified using a Cochrane–Armitage test. Multivariable logistic regression identified patient and socioeconomic characteristics associated with TL, and difference-in-difference analysis was used to control for secular trends over time.
Results
A total of 43,526 patients with low-risk DTC were identified in the SEER database; 39,411 pre-2015 and 4115 post-2015. After 2015, TT continued to outnumber TL (76.2% vs 23.8%), although the rate of TL increased significantly (11.6% to 23.8%, P < 0.001). However, difference-in-difference analysis found that age > 55 (OR 1.11, 95% CI 1.01–1.19, P < 0.001) and rurality (OR 1.16, 95% CI 1.05–1.28, P < 0.001) were independently associated with TT. TL was associated with T1 disease (OR 1.11, 95% CI 1.04–1.19, P = 0.001).
Conclusion
Although the 2015 ATA guideline update led to an increase in TL for low-risk DTC, most patients still underwent TT. Age and neighborhood significantly impact the odds of receiving guideline-appropriate TL for low-risk DTC, especially for T2 disease.
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Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Objectives
The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT.
Materials and methods
Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression.
Results
Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid.
Conclusions
We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.
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Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
Department of Pathology, Tohoku University Hospital, Sendai, Japan
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Elucidating the mechanisms of action of steroid hormones will contribute to the development of therapeutic strategies for hormone-dependent tumors. Recent advances in genetic engineering have revealed the complex and diverse mechanisms of steroid hormone signaling; however, these techniques are limited to in vitro or animal experiments. It is believed that verifying hormone signals elucidated using human pathological tissue specimens will directly aid in treatment and diagnosis. However, pathological tissue specimens are generally formalin-fixed paraffin-embedded (FFPE), and protein/gene analyses of FFPE tissues are limited. Protein detection using immunohistochemistry with specific antibodies in FFPE tissues is a classical technique essential for diagnosis and treatment decisions in various types of cancer. In steroid hormone signaling, the expression and localization of receptors, hormone-related enzymes, and proteins encoded by response genes can be clarified using immunohistochemistry. Although protein-protein interactions such as receptor dimers and DNA-binding proteins are mainly detected in vitro, they can be examined in FFPE tissues using in situ proximity ligation assays and southwestern histochemistry, respectively. Using these detection methods, including immunohistochemistry, it is possible to analyze each hormone signaling pathway in hormone-related tumors histopathologically. Although FFPE tissues still suffer from gene and protein denaturation, their advantages include the ability to retrospectively study target factors/signals and obtain spatial information through microscopy. This review describes a visualization method for elucidating steroid hormone signaling in hormone-dependent tumors using FFPE tissues.
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The field of nuclear theranostic clinical trials is continuously expanding as an increasing number of novel agents and treatment combinations are explored for treating advanced and metastatic cancers. Moving from ‘bench-to-bedside’ is oftentimes a complex and lengthy process. The objective of this overview is to explore the basic elements involved in designing clinical trials with a special focus on theranostics in nuclear medicine. The 'bench-to-bedside' journey involves translating basic scientific research into patient-effective treatments. Preclinical studies, a crucial initial step, are a complex process encompassing in vitro experiments, in vivo studies, and animal models to explore hypotheses in humans. Clinical trials follow, with predefined phases assessing safety, effectiveness, and comparisons to existing treatments. This process demands investments in data management, statistics, good clinical practice (GCP) accreditations, and collaborative efforts for funding and sustainable pricing. Theranostics, merging diagnostics and personalized treatment, is at the forefront. Continuous efforts to enhance existing agents involve reducing adverse effects, exploring new indications, and incorporating advanced imaging modalities. Radionuclide therapy, unique with non-uniform distribution and complex radiobiology, plays a distinct role. This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine, emphasizing meticulous trial design, dosimetry optimization, and the necessity of collaborative stakeholder efforts for successful implementation.
Center for Translational Immunology, Columbia University, New York, New York, USA
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Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts, USA
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Search for other papers by Lirim Shemshedini in
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Androgen receptor (AR) and its constitutively active splice variant, AR Variant 7 (AR-V7), regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by the ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrate that the interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to a reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.
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Background
Mönckeberg sclerosis is a form of calcification of the tunica media of small and medium size arteries. It occurs more often in the peripheral arteries of the lower limbs and it has been associated with diabetes and renal disease. Although there are a few reports of Mönckeberg sclerosis in thyroid vessels, there are no data regarding its significance in thyroid disease.
Objective
The aim was to investigate the possible prognostic value of Mönckeberg sclerosis in thyroid vessels of patients with diagnosed thyroid cancer.
Methods
We retrospectively studied patients with papillary thyroid cancer treated at the Theagenio Hospital of Thessaloniki from 2005 to 2021. The patients were divided into two groups based on the presence, or absence, of histopathological findings of Mönckeberg sclerosis in the thyroid vessels along with papillary thyroid cancer. Patient characteristics, histopathological details, personal history of thyroid disease, and metabolic parameters were compared between the two groups.
Results
Thirty-three patients with papillary thyroid carcinoma and Mönckeberg sclerosis were identified and matched to 33 controls with papillary thyroid cancer, without evidence of Mönckeberg sclerosis. The metabolic profile of patients with Mönckeberg sclerosis was not significantly different from those who did not have Mönckeberg sclerosis. Moreover, the comparison between the two groups did not reveal any remarkable differences in terms of the aggressiveness of the disease.
Conclusion
The presence of Mönckeberg sclerosis does not seem to impact on histological characteristics of patients with papillary thyroid cancer.
Search for other papers by Catherine M Skefos in
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This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.
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There is interest in optimizing peptide receptor radionuclide therapy (PRRT) for the management of metastatic neuroendocrine neoplasms (NEN). The addition of stereotactic body radiation therapy (SBRT) may provide synergistic benefits by targeting specific sites of disease that may represent areas of tumor heterogeneity. Little is known about the efficacy or potential toxicity of this approach; understanding the outcomes of patients treated with these two modalities in a sequential fashion will provide insights into the appropriateness of embarking on a combined therapy strategy. An institutional retrospective review of 21 patients with NEN treated with sequential PRRT and SBRT (64 targets) was performed. Median overall survival and progression-free survival were 19.6 months and 12.8 months, respectively. Median time to local recurrence at the SBRT site was not reached, with rates at 12 and 24 months of 1.8% and 5.9%, respectively. The toxicity profile remains favorable. Given the safety and efficacy of sequential SBRT and PRRT, further trials evaluating a concurrent treatment approach may be warranted.
