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JCI Insight Oct 2023Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline...
Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization showed elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone/renin ratio, and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induced tonic-clonic seizures. Neurologic abnormalities included hyperlocomotion, impaired performance in the rotarod test, impaired nest building, and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance responded to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.
Topics: Humans; Male; Female; Mice; Animals; Aldosterone; Hyperaldosteronism; Isradipine; Calcium; Autism Spectrum Disorder; Mutation; Adenoma; Seizures
PubMed: 37698934
DOI: 10.1172/jci.insight.162468 -
Nature Communications Nov 2023Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. As the available therapeutic options show a lack of efficacy, novel therapeutic...
Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. As the available therapeutic options show a lack of efficacy, novel therapeutic strategies are urgently needed. Given its T-cell infiltration, we hypothesized that MPM is a suitable target for therapeutic cancer vaccination. To date, research on mesothelioma has focused on the identification of molecular signatures to better classify and characterize the disease, and little is known about therapeutic targets that engage cytotoxic (CD8+) T cells. In this study we investigate the immunopeptidomic antigen-presented landscape of MPM in both murine (AB12 cell line) and human cell lines (H28, MSTO-211H, H2452, and JL1), as well as in patients' primary tumors. Applying state-of-the-art immuno-affinity purification methodologies, we identify MHC I-restricted peptides presented on the surface of malignant cells. We characterize in vitro the immunogenicity profile of the eluted peptides using T cells from human healthy donors and cancer patients. Furthermore, we use the most promising peptides to formulate an oncolytic virus-based precision immunotherapy (PeptiCRAd) and test its efficacy in a mouse model of mesothelioma in female mice. Overall, we demonstrate that the use of immunopeptidomic analysis in combination with oncolytic immunotherapy represents a feasible and effective strategy to tackle untreatable tumors.
Topics: Humans; Female; Animals; Mice; Mesothelioma, Malignant; Pleural Neoplasms; Mesothelioma; Immunotherapy; Peptides; Cell Line, Tumor; Lung Neoplasms
PubMed: 37923723
DOI: 10.1038/s41467-023-42668-7 -
Problemy Endokrinologii Sep 2023Hyperprolactinemia accompanies growth hormone hypersecretion in approximately 25-39% of cases. There is a recommendation to determine the level of prolactin in clinical... (Observational Study)
Observational Study
BACKGROUND
Hyperprolactinemia accompanies growth hormone hypersecretion in approximately 25-39% of cases. There is a recommendation to determine the level of prolactin in clinical guidelines for diagnosis and treatment of acromegaly. However, there is no understanding of the necessity to investigate the IGF-1 level in patients with hyperprolactinemia and a pituitary adenoma.
AIM
Determining the proportion of patients with hyperprolactinemia and pituitary adenoma, who were examined for IGF-1 levels, and identifying the proportion of patients with acromegaly among this cohort.
MATERIALS AND METHODS
Between December 2019 and December 2022 a single-center observational single-stage single-sample uncontrolled study was conducted. At the first stage of the study, the proportion of patients with pituitary adenoma and hyperprolactinemia with studied IGF-1 levels was determined, according to medical records. At the second stage of the study, patients without known indicators of IGF-1 were determined. The concentration of growth hormone was studied during the oral glucose load in the case of increased IGF-1 levels.
RESULTS
At the first stage, 105 patients were included in the study. The level of IGF-1 was determined in 41/105 (39%) cases. There were 22/41 (53.7%) cases in the subgroup with pituitary incidentalomas and 19/64 (29.7%) cases in the subgroup with hyperprolactinemia among them. At the second stage, the IGF-1 level was additionally determined in 53 patients with hyperprolactinemia and pituitary adenoma (total 94 patients). The level of IGF-1 was elevated in 11/94 patients, further acromegaly was confirmed in 3/94 patients (3.2%).
CONCLUSION
In real clinical practice the level of IGF-1 is studied only in 39% of cases in patients with pituitary adenoma and hyperprolactinemia. The disease was detected in 3 cases (3.2%) out of 94 people with hyperprolactinemia and pituitary adenoma without clinical manifestations of acromegaly. We consider the study of IGF-1 levels justified as a screening for acromegaly in patients with hyperprolactinemia and pituitary adenoma.
Topics: Humans; Hyperprolactinemia; Female; Acromegaly; Male; Pituitary Neoplasms; Adult; Insulin-Like Growth Factor I; Middle Aged; Adenoma; Human Growth Hormone
PubMed: 38796756
DOI: 10.14341/probl13344 -
The Journal of Clinical Endocrinology... Nov 2023Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I...
CONTEXT
Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control.
OBJECTIVE
As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed.
METHODS
A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal).
RESULTS
Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment.
CONCLUSION
Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs.
Topics: Humans; Acromegaly; Insulin-Like Growth Factor I; Glycated Hemoglobin; Retrospective Studies; Quality of Life; Treatment Outcome; Human Growth Hormone; Growth Hormone; Glucose; Adenoma
PubMed: 37357993
DOI: 10.1210/clinem/dgad378 -
Clinical and Translational... Aug 2023Patients with serrated polyposis syndrome (SPS) have an increased risk to develop colorectal cancer (CRC). Due to an abundance of serrated polyps, these CRCs are assumed...
INTRODUCTION
Patients with serrated polyposis syndrome (SPS) have an increased risk to develop colorectal cancer (CRC). Due to an abundance of serrated polyps, these CRCs are assumed to arise mainly through the serrated neoplasia pathway rather than through the classical adenoma-carcinoma pathway. We aimed to evaluate the pathogenetic routes of CRCs in patients with SPS.
METHODS
We collected endoscopy and pathology data on CRCs and polyps of patients with SPS under treatment in our center. Our primary end point was the proportion of BRAFV600E mutated CRCs, indicating serrated pathway CRCs (sCRCs). CRCs lacking BRAFV600E most likely inferred a classical adenoma-carcinoma origin (aCRCs). We assessed patient, polyp, and CRC characteristics and stratified for BRAFV600E mutation status.
RESULTS
Thirty-five patients with SPS harbored a total of 43 CRCs. Twenty-one CRCs (48.8%) carried a BRAFV600E mutation, 10 of which lacked MLH1 staining and 17 (81%) were located in the proximal colon. Twenty-two CRCs (51.1%) did not carry a BRAFV600E mutation and were MLH1 proficient. Of these 22 putatively aCRCs, 17 (77.3%) were located distally and one-third (36.4%) harbored a pathogenic KRAS or NRAS mutation. In patients with BRAFwt -CRCs, a higher ratio of the median number of conventional adenomas versus serrated polyps was found (4 vs 13) than patients with BRAFV600E -CRCs (1 vs 14).
DISCUSSION
Our study indicates that in patients with SPS, the ratio of sCRCs:aCRCs on average is 50:50. This elevated sCRC:aCRC ratio in patients with SPS, when compared with non-SPS patients, correlates well with the differences in the ratios of the numbers of sessile serrated lesions and conventional adenomas in patients with SPS and non-SPS patients, respectively.
Topics: Humans; Colonic Polyps; Colorectal Neoplasms; Adenomatous Polyposis Coli; Adenoma; Carcinoma
PubMed: 37352472
DOI: 10.14309/ctg.0000000000000611 -
Problemy Endokrinologii Feb 2024Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence... (Review)
Review
RELEVANCE
Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence of NET especially insulinoma.
AIM
Summarizing and analyzing current data on various approaches to the treatment of insulinoma. Our review includes a comprehensive assessment of the advantages and disadvantages of currently available insulinoma treatment methods in comparison with past experience, as well as a review of promising methods that are not currently widely used.
MATERIALS AND METHODS
Analysis of literature from such databases as scientific electronic library elibrary.ru, Pubmed, Google Scholar, MedLine, Scopus and Web of Science.
RESULTS
The most common treatment for insulinoma is surgery. For patients with high operative risk, alternative methods such as alcohol ablation, radiofrequency ablation, and tumor embolization may be used. Medications include the use of somatostatin analogues, diazoxide. The literature describes the potential benefit of the use of beta-blockers, phenytoin, glucagon, however, in clinical trials, these drugs have not demonstrated a significant effect. For the treatment of malignant and metastatically advanced insulinoma, targeted therapy (primarily Everolimus), chemotherapy, as well as embolization (including chemoembolization, radioembolization), radiofrequency ablation (RFA), microwave ablation and cryoablation, ultrasound ablation (HIFU), laser ablation, brachytherapy, irreversible electroporation are used.
CONCLUSION
The study of new drugs is an important task for scientists, among medications the most promising are new generations of somatostatin analogues, targeted drugs and chemotherapy drugs. The rare frequency of insulinoma makes it difficult to conduct randomized controlled trials and prospective studies. That is why physicians and scientists need to maintain close contacts with each other and take into account the experience of treating each patient with such disease, which will help develop effective treatment algorithms in the future.
Topics: Humans; Insulinoma; Prospective Studies; Neuroendocrine Tumors; Apudoma; Pancreatic Neoplasms; Somatostatin
PubMed: 38433541
DOI: 10.14341/probl13281 -
Journal of Thoracic Oncology : Official... Sep 2023Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely... (Review)
Review
Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely been explored. However, the recent introduction of next-generation sequencing-based tumor molecular profiling in the real-word setting enabled us to deeply characterize the genomic background of patients with lung cancer with or without smoking-related history, increasing the likelihood of detecting germline mutations with potential prevention and treatment implications. Pathogenic germline variants have been detected in 2% to 3% of patients with NSCLC undergoing next-generation sequencing analysis, whereas the proportion of germline mutations associated with the development of pleural mesothelioma widely varies across different studies, ranging between 5% and 10%. This review provides an updated summary of emerging evidence about germline mutations in thoracic malignancies, focusing on pathogenetic mechanisms, clinical features, therapeutic implications, and screening recommendations for high-risk individuals.
Topics: Humans; Germ-Line Mutation; Lung Neoplasms; Mesothelioma, Malignant; Mesothelioma; Carcinoma, Non-Small-Cell Lung; Genetic Predisposition to Disease
PubMed: 37331604
DOI: 10.1016/j.jtho.2023.05.028 -
BMC Gastroenterology Dec 2023Colorectal cancer (CRC) screening has been implemented in Tianjin, China since 2012. The objective was to estimate the neoplasia detection rate in a high-risk population...
PURPOSE
Colorectal cancer (CRC) screening has been implemented in Tianjin, China since 2012. The objective was to estimate the neoplasia detection rate in a high-risk population by age and sex and to investigate the potential factors associated with colorectal neoplasia.
PATIENTS AND METHODS
This study is based on data of the Tianjin CRC screening program from 2012 to 2020. Residents with a positive high-risk factors questionnaire (HRFQ) or a positive faecal immunochemical test (FIT) were identified as high-risk participants and were subsequently recommended for a free colonoscopy.
RESULTS
A total of 4,117,897 eligible participants aged 40-74 years completed both a HRFQ and FIT, and 217,164 (5.3%) of them were identified as high-risk participants. Positive rates of preliminary screening increased with age and were higher in females than in males. For 57,971 participants undertaking colonoscopy, the detection rates of nonadvanced adenoma, advanced adenoma and CRC were 37.8%, 5.7% and 1.6%, respectively. Detection rates of advanced neoplasia increased from the age of 50 and were higher in males. For nonadvanced neoplasia, a strong increase was observed in males from the age of 40 and in females from the age of 50. Male sex had a greater impact on individuals aged 40-49 than on older individuals. Several factors including current smoking, drinking, and higher body mass index (BMI) were significantly associated with the presence of neoplasia, whereas, these associations were mainly restricted to individuals aged above 50 but not those aged 40-49 years.
CONCLUSIONS
These findings support that age-specific risk stratification and sex-specific initiating ages for CRC screening should be recommended to improve the accuracy and effectiveness of current screening strategy.
Topics: Female; Humans; Male; Early Detection of Cancer; Risk Factors; Colorectal Neoplasms; Colonoscopy; Occult Blood; Adenoma; Mass Screening
PubMed: 38087194
DOI: 10.1186/s12876-023-03060-3 -
International Journal of Molecular... Nov 2023Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their...
Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER∝, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, < 0.01) and postoperative PRL levels (rho = 0.58, < 0.001). In our study, the ER∝ intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade ( = 0.02); CAM 5.2 pattern (densely/sparsely granulated/mixed densely and sparsely granulated) was correlated with postoperative PRL level ( = 0.002), and with ki-67 ( < 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter ( = 0.63, < 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER∝ can be used as a prognostic marker and loss of ER∝ expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.
Topics: Humans; Female; Adenoma; Retrospective Studies; Ki-67 Antigen; Pituitary Neoplasms; Prolactinoma; Prolactin; Neuroendocrine Tumors
PubMed: 38003353
DOI: 10.3390/ijms242216162 -
Clinical and Translational... Oct 2023Colorectal cancer screening plays a vital role in early detection and removal of precancerous adenomas, contributing to decreased mortality rates. Most polyps found... (Review)
Review
Colorectal cancer screening plays a vital role in early detection and removal of precancerous adenomas, contributing to decreased mortality rates. Most polyps found during colonoscopies are small and unlikely to harbor advanced neoplasia or invasive cancer, leading to the development of "leave-in-situ" and "resect-and-discard" approaches. These strategies could lead to significant cost savings and efficiencies, but their implementation has been hampered by concerns around financial incentives, medical-legal risks, and local rules for tissue handling. This article reviews the potential of artificial intelligence to enhance the accuracy of polyp diagnosis through computer-aided diagnosis (CADx). While the adoption of CADx in optical biopsy has shown mixed results, it has the potential to significantly improve the management of colorectal polyps. Several studies reviewed in this article highlight the varied results of CADx in optical biopsy for colorectal polyps. Although artificial intelligence does not consistently outperform expert endoscopists, it has the potential to serve as a beneficial secondary reader, aiding in accurate optical diagnosis and increasing the confidence of the endoscopist. These studies indicate that although CADx holds great potential, it is yet to fully meet the performance thresholds necessary for clinical implementation.
Topics: Humans; Colonic Polyps; Artificial Intelligence; Colonoscopy; Adenoma; Narrow Band Imaging
PubMed: 37747097
DOI: 10.14309/ctg.0000000000000640