bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use Of Temozolomide In Parathyroid Carcinoma With Negative Mgmt Promoter Methylation
Authors: Reddy Niyoti , Dima Danai , Kuri Danica Maria Vodopivec , McAneny David , Kulke Matthew , Lee Stephanie L 
Published: May 2021

Abstract
Introduction: Parathyroid carcinoma (PC) is a rare malignancy with a high rate of recurrence and metastasis. Case: A 63-year-old man with a 13-year history of recurrent PC requiring 5 operations, including parathyroidectomies, thyroidectomy, and neck dissections presented with polyuria, polydipsia, and worsening rib pain. He had been recently treated with 6 monthly octreotide injections and maximal dose cinacalcet for gradually rising Ca/PTH levels. Tests revealed serum Ca 13.1mg/dL (8-10.5mg/dL), PTH 1750pg/mL (11-90 pg/mL), and serum Cr 3.34mg/dL (0.5-1.3mg/dL). Imaging identified tumor in the right 6th rib (3.6cm lytic lesion), and soft tissue lesions in the left thyroid bed (3 masses, the largest 1.6cm) and the suprasternal notch (1.1cm). He underwent rib resection (metastasectomy) and PTH declined from 2334pg/mL to 671pg/mL. Although metastasectomy improved the PTH level, Ca levels began to rise from the residual tumor. A multidisciplinary team deemed the risk of complications from repeat neck surgery to be prohibitively high. Temozolomide (TEM) (150-200mg/m2/d x 5d, q28d) was instituted 3 months after the rib resection. 13 months later, PTH has stably ranged from 600-800 pg/mL with a normal serum Ca of 9.8mg/dL. Recent imaging shows stable disease in the neck, without distant disease. Discussion: The mainstay of therapy for initial and recurrent/metastatic PC is surgery. Inoperable disease has a poor prognosis because of lack of effective systemic therapies. Radiation and chemotherapy have not shown much efficacy. Results of treatment with octreotide have not been encouraging. Anti-PTH immunotherapy and Lutathera are promising but require further investigation. Usually, no targetable mutation is found. Anti-angiogenic TKI’s (sorafenib, lenvatinib) have been used with varying success. An exciting therapy used in this patient is TEM, an alkylating agent used for CNS tumors, neuroendocrine tumors (NET) and aggressive pituitary tumors. A previous report described successful use of TEM in a case of metastatic PC, whose tumor harbored high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive response in CNS tumors. Promoter methylation is an epigenetic alteration that leads to low MGMT enzyme activity & enhances the cytotoxicity of TEM. Some studies in NET demonstrated tumor response irrespective of MGMT status. This leads to the question of whether the same is true in PC. Our patient has radiographic/biochemical stable disease on TEM, and a surprising retrospective discovery was that the MGMT promoter was unmethylated. This is a unique case of PC which seems to be responding to TEM despite absent promoter methylation. Further studies are warranted, as the incidence of PC is rising over the past decades. In the interim, clinicians could consider using TEM for in-operable PC irrespective of MGMT methylation status.
Well-Differentiated Malignant Neuroendocrine Cell Tumor Originating From the Jejunum With Excessive Insulin Secretion
Authors: Ahmed Haris , Vu Alan , Alam Junaid , Ogar Bonny , Lines Barbara 
Published: May 2021

Abstract
Background: Insulinomas are rare, well-differentiated insulin-secreting neuroendocrine tumors of the pancreas. Insulin-secreting, extra-pancreatic tumors have rarely been reported in the literature. We present a case of a well-differentiated neuroendocrine tumor with clinical, laboratory, and immunohistochemical tumor findings supportive of ectopic insulin production in a non-pancreatic neuroendocrine tumor of the small bowel.
Clinical Case: A 70 year-old female with past medical history of end stage renal disease, Type II diabetes mellitus, and hypertension presented to our facility with multiple episodes of dizziness and syncope due to hypoglycemia. She had initially managed her diabetes with metformin but stopped taking the medication due to increasingly frequent episodes of hypoglycemia. Significant labs during the hospitalization include blood glucose &lt;20 mg/dL, insulin 75.9 IU/mL (2.6-21.9 IU/mL) and C-peptide 57.7 ng/mL (1.1-4.4 ng/mL). Her symptoms persisted despite dextrose supplementation. Abdominal and Pelvic CT showed proximal small bowel obstruction and sclerosing mesenteritis with a calcified lymph node but no pancreatic mass. A diagnostic laparoscopy was performed, showing 18 inches of small bowel with malignant appearing masses that were adherent to the mesentery. A 21.0 cm segment of jejunum was resected. There were at least 30, variably sized masses throughout the bowel, involving the mucosa, submucosa, muscularis propria and subserosal fat; along with lymphatic, venous, and perineural space tumor permeation, and metastases involving multiple regional lymph nodes. The tumors ranged in size from 0.5 up to 1.5 cm. They showed well-differentiated nuclear morphology, a mitotic count of 0 per 80 high power fields, and a Ki-67 proliferation index of 1%, indicative of a G1 NET. Immunohistochemical stains confirmed neuroendocrine differentiation with positive staining for chromogranin, synaptophysin, and INSM1 (insulinoma-associated protein 1) transcription factor, while insulin staining was negative. The patient was diagnosed with a pT3N1, G1, ectopic insulin-secreting neuroendocrine tumor of small bowel origin. She was started on diazoxide with significant improvement in her hypoglycemia.
Conclusion: Insulin production by non-pancreatic tumors is extremely rare. Clinical, laboratory, and immunohistochemical tumor findings in this case support ectopic insulin production by a well-differentiated neuroendocrine tumor of small bowel origin.
Effect of Conventional Chemotherapy in Patients With Neuroendocrine Tumours: A Systematic Review
Authors: Divanovic Anida , Druce Maralyn Rose 
Published: May 2021

Abstract
Background: Neuroendocrine tumours (NETs) are a wide-ranging group of neoplasms originating from neuroendocrine cells. In 2014 NETs incidence was 7 per 100000 people annually. The purpose of this systematic review is to evaluate the safety and efficacy of various types of chemotherapeutic agents on gastroenteropancreatic NETs (GEP NETs) and to determine which type of chemotherapy is the most effective for different tumour types, with minimum adverse events. To our knowledge, this study is the first systematic review that compares several types of chemotherapy and evaluates their safety and efficacy on GEP NETs. Methods: The study followed recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on reporting systematic reviews. The literature search for this systematic review was conducted using the following databases and search engines: Cochrane library, EMBASE, Google Scholar, PubMed, and Web of Science, from 1963 to 2020. Results: The review comprised 26 observational studies, and 5 randomized controlled trials (RCTs). The total number of subjects included in this study was 1783. Our study showed that the most effective treatment for Grade 3 NETs and Grade 3 neuroendocrine carcinomas was cisplatin/etoposide. Furthermore, capecitabin/temozolomide therapy has been shown to be most effective in Grade 1 and Grade 2 NETs. Conclusion: Therapy with two chemotherapeutic agents has been shown to be more effective than monotherapy and therapy with three chemotherapeutic agents. Unfortunately, our study has limitations and we urgently need RCTs or larger observational studies that will contain all the necessary efficacy and safety tools, and thus provide answers to our clinical questions.
Effects of Growth Hormone in Human Melanoma Drug Resistance
Authors: Arora Pranay , Basu Reetobrata , Kopchick John Joseph 
Published: May 2021

Abstract
Melanoma, an extremely drug resistant form of cancer, displays elevated levels of growth hormone (GH) and growth hormone receptor (GHR) expression. We have described a GH dependent mechanism of chemoresistance in melanoma through a series of earlier studies. In GHR overexpressing human melanoma, GH action drives active drug efflux and phenotype switching by upregulating ATP-binding cassette transporters (ABC-transporters) and epithelial-to-mesenchymal transition (EMT) markers. Inhibition of GHR activation reverses these effects, increases drug retention, and sensitizes the melanoma cells to chemotherapy. GH action in melanoma also appears to drive drug sequestration in melanosomes as we present here. GH action was found to modulate the levels of melanocyte-inducing transcription factor (MITF), the master regulator of melanosome synthesis and melanoma. Additionally, MITF target gene levels and drug sequestering ABC transporter expression were also elevated by GH treatment in vitro and in vivo in mouse tumor xenografts. This was corroborated by in silico analyses of tumor databases. Furthermore, we observed a dose dependent increase in tyrosinase activity and melanogenesis in human melanoma cells with GH, in the presence of chemotherapy, which was suppressed by siRNA mediated GHR inhibition. Thus, we describe an array of molecular mechanisms by which GH drives chemoresistance in melanoma. Therefore, GHR inhibition combined with chemotherapy should lead to better tumor clearance and improve overall survival.
Effects of Growth Hormone on Pancreatic Cancer Derived Exosomes
Authors: Kulkarni Prateek , Basu Reetobrata , Kopchick John J 
Published: May 2021

Abstract
In 2020, the National Cancer Institute (NCI) estimates 57,600 new cases and 47,050 deaths in the US due to pancreatic ductal adenocarcinoma (PDAC). A dismal 10% five-year overall survival rate in PDAC is attributed to late diagnosis, limited treatment options, a remarkably high metastasis rate, and resistance of this cancer to available therapies. Therefore, a better understanding of the mechanisms of how PDAC tumors acquire drug resistance and spread to distal parts of the body are necessary for developing novel therapeutic approaches. Exosomes, microscopic vesicles released from most cells (both tumor and non-tumor) have been recently established to play a significant role in cell to cell communication. Exosomes modulate their target cell responses systematically depending on the nature of exosomal cargoes (nucleic acids, proteins, and lipids). PDAC derived exosomes have been implicated to promote metastasis via forming a pre-metastatic niche of cells as well as enhancing drug resistance. Growth hormone (GH) secreted primarily by the pituitary gland promotes metastasis and drug resistance as shown by plethora of studies. No study has directly assessed the effect of GH on exosomal cargoes in terms of promoting metastases and drug resistance. In this report, we show that GH modulates various pancreatic cancer cell exosomal cargoes which in turn potentially amplifies tumor invasion and metastases. Our data shows that GH treatment on human and mouse PDAC cells increases the exosomal protein levels of TGFβ - a critical inducer of epithelial-to-mesenchymal transition (EMT, a process leading to metastasis). In addition, GH treatment also increases extracellular matrix-degrading enzymes, MMP2 and 9, as well as multi-drug efflux pump ABCC1, ABCB1, and ABCG2 in PDAC cells. These results strongly implicate GH action in driving EMT and chemoresistance via exosomes in pancreatic cancer. Exosomes have a crucial impact especially in the areas of diagnostics and therapeutics. This report is the first to show that GH modulates the effects of exosomes secreted by pancreatic cancer cells. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.
High Expression of Nucleobindin-2 Is Associated With Poor Prognosis in Gastric Cancer
Authors: Okada Junichi , Yamada Eijiro , Saito Tsugumichi , Nakajima Yasuyo , Ozawa Atsushi , Okada Kazuya , Pessin Jeffrey E , Okada Shuichi , Yamada Masanobu 
Published: May 2021

Abstract
Nucleobindin-2 (NUCB2) is a 396-amino acid protein, cleaved into the N-terminal nesfatin-11-82, nesfatin-285-163 and the C-terminal nesfatin-3166-396. NUCB2 contains a signal peptide, a leucine zipper structure, two Ca2+ binding EF-hand domains, and has a wide variety of basic cellular functions. NUCB2 is also a precursor protein of nesfatin-1, which was originally identified in hypothalamic nuclei, and which is a regulatory factor involved in the central control of food intake and energy balance. There are several reports indicating that NUCB2 is also expressed in various human peripheral tissues. Moreover, recent studies have reported that high levels of NUCB2 mRNA and protein are a potent prognostic factor for prostate cancer, endometrial carcinoma, and breast cancer. NUCB2 was also identified as a potential tumor antigen eliciting autoantibody responses in 5.4% of gastric cancer patients but not in the healthy individuals. However, theclinicopathological significance of NUCB2 expression in gastric cancer has still not been elucidated. Therefore, we examined NUCB2 expression in a large number of gastric cancer patients, using immunohistochemistry, to explore its clinicopathological significance. To explore this, we aimed to investigate the NUCB2 expression in gastric cancer tissues and adjacent non-tumor tissues and its potential relevance to clinicopathological factors and prognosis using immunohistochemistry analysis. In our study, NUCB2 level in gastric cancer tissues was higher than in non-tumor tissues. A high expression of NUCB2 is significantly associated with tumor depth, lymph node metastasis, lymphatic invasion, venous invasion and clinical stage. Furthermore, the expression level of NUCB2 protein was independent predictor of progression-free survival. In summary, NUCB2 might play a crucial role in gastric cancer development and could serve as an independent predictor of prognosis of gastric cancer patients.
Leptin Mediates Obesity-Induced DNA Damage in BRCA1 Breast Epithelial Cells
Authors: Bhardwaj Priya , Bareja Rohan , Oshchepkova Sofya , Iyengar Neil , Elemento Olivier , Morrow Monica , Spector Jason , Brown Kristy A 
Published: May 2021

Abstract
Background: Obesity is a risk factor for breast cancer development in women who carry a mutation in the DNA repair enzymes BRCA1 or BRCA2. Previously, we found that obesity was positively associated with DNA damage in breast epithelium from BRCA mutation carriers. Furthermore, factors secreted by obese breast adipose tissue stimulated DNA damage in BRCA mutant breast epithelial cells, suggesting a cross-talk between breast epithelial cells and the adipose tissue that surrounds them. We hypothesized that leptin, a hormone secreted in abundance by obese adipose tissue, may be a driver of DNA damage and/or decrease capacity for DNA repair in breast epithelial cells. If true, this would provide a molecular target for intervention to reduce the risk of tumor formation in this high-risk population of women. Methods: RNA-seq followed by Ingenuity Pathway Analysis (IPA) was conducted on primary breast epithelial organoids isolated from lean and obese BRCA mutation carriers. Breast adipose tissue obtained from lean and obese women were cultured as explants for 24 hours to produce lean and obese conditioned media (CM). The effect of leptin on DNA damage was assessed in a non-cancerous breast epithelial cell line (MCF10A) carrying a heterozygous BRCA1 mutation. Immunofluorescence staining of the DNA damage marker ƴH2AX was carried out after treatment with leptin (100ng-800ng), CM, or CM+leptin antibody, used to neutralize leptin. To test whether leptin affects DNA repair capacity, BRCA1+/- MCF10A cells were treated with leptin or vehicle and then irradiated (1Gy) to induce DNA damage. Resolution of damage was quantified at 0, 0.5, 4, 12, and 24 hrs post-irradiation. Results: IPA analysis identified leptin signaling as significantly upregulated in breast epithelial organoids from obese women compared with lean women. Both obese CM and leptin treatment induced DNA damage in BRCA1+/- MCF10A cells while lean CM did not have this effect. Neutralizing leptin in obese CM was sufficient to inhibit obese CM-mediated induction of DNA damage. No significant difference was observed between leptin or vehicle treatments on DNA repair capacity after irradiation of BRCA+/- MCF10A cells. Conclusions: These data identify leptin, an adipose-derived hormone, as a novel driver of DNA damage in breast epithelial cells. To date, no studies have elucidated the molecular mechanisms that explain the increased penetrance of breast cancer in obese BRCA mutation carriers compared to lean BRCA mutation carriers. This work suggests that leptin may be a mediator of the link between obesity and breast cancer development in this population. Further studies are warranted to determine if targeting the leptin signaling axis will be an effective risk reduction strategy in BRCA mutation carriers who have excess adiposity.
Long Intergenic Non Coding RNA and MicroRNA Profiles of Pheochromocytoma and Paraganglioma as Prognostic Biomarkers
Authors: Ghosal Suman 
Published: May 2021

Abstract
microRNAs (miRNAs) and long intergenic noncoding RNAs (lincRNAs) have been reported as important markers for many cancers. In search of new markers for the metastatic or aggressive phenotypes in the neuroendocrine tumor pheochromocytomas and paragangliomas (PCPG), we analyzed the non-coding transcriptome from patient gene expression data in The Cancer Genome Atlas. We used differential expression analysis and an elastic-net machine-learning model to identify miRNA and lincRNA transcriptomic signature specific to PCPG molecular subtypes. Similarly, miRNAs and lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis were performed for identifying factors associated with metastasis-free survival. Upregulation of 13 lincRNAs and 4 miRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation in tumor samples from PCPG patients confirmed the overexpression of 4 miRNAs and 4 lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified 3 miRNAs and 5 lincRNAs as prognostic markers for metastasis-free survival of patients in PCPGs. In a multivariate Cox regression analysis combining these miRNA and lincRNA expression signatures with the previously identified clinically relevant parameters like SDHB germline mutation, ATRX somatic mutation, tumor location and hormone secretion phenotypes, we identified the miRNA miR-182 and lincRNA HIF1A-AS2 as independent predictors of poor metastasis-free survival. We formulated a risk-score model using multivariate analysis of lincRNA and miRNA expression profiles, presence of SDHB and ATRX mutations, tumor location, and hormone secretion phenotypes. Stratification of PCPG patients with this risk-score showed significant differences in metastasis-free survival.
Molecular Genetics in a Cohort of Patients With Concurrent PTC and Melanoma
Authors: Joshi Tripti , Gupta Ruta , Olaya A Luisa Fernanda , Yu Bing , McLennan Susan , Chua Elizabeth Lian 
Published: May 2021

Abstract
PTC and melanoma are known to harbour common mutations, but this has not been extensively investigated. Targeted therapies for BRAF and PD-L1 have been used for melanoma and there are ongoing clinical trials for use of PD-L1 inhibitors in PTC but its utility is uncertain. Additionally, many of these patients have multiple cancers, so, whether they have a tumour predisposition syndrome is also unclear. Both germline and somatic mutations in BRCA1-associated protein 1 (BAP1) are associated with a wide spectrum of tumours. We hypothesized that a common genetic link may be present in our cohort of patients who have both PTC and melanoma.
The aim of this study was to elucidate molecular genetics, specifically BRAF, NRAS, KRAS, KIT using OncoFocus Mass Array System as well as expression of PD-L1 and BAP1, using a standard antibody (SP263) and C-4 respectively, in an Australian cohort with concurrent PTC and melanoma.
In our cohort of 21 patients (43% females, all Caucasian), melanoma was diagnosed about 8 years prior to PTC (50.3 ± 18.3 vs. 58.6 ± 12.8 years). The most common mutation was BRAFV600E seen in 88% of PTC, followed by NRAS mutation in 12% of PTC. Majority of the PTC (68%) stained negative for PD-L1. There was no significant association between PD-L1 tumour status and clinicopathologic outcomes. Interestingly, majority of multifocal, bilateral and both bilateral and multifocal PTC were PD-L1 negative (85%,69% and 69% respectively, P&lt;0.05); only extrathyroidal extension was found to be associated with positive (≥1%) PD-L1 staining (83.3 vs.30.8; p=0.057). Regarding melanoma, clinicopathologic and mutation data were obtained for 15/21 patients and 8/15 patients respectively. Superficial spreading type of melanoma was present in 50% patients. The BRAFV600E and NRAS mutation were present in 3/8 patients each, and 2/8 patients had no mutations. PD-L1 staining was negative in 7/12 (58%) of melanoma tissues. Of the 5 cases that stained positive for PD-L1, 4 were at &gt;25%, a much higher degree of staining compared to PTC group. Among 7 patients where data were available for both tissues, concordant mutations were found in only 2 patients (both BRAFV600E). In addition, 11 of the 21 patients had at least one other cancer apart from PTC and melanoma. Nine of the 11 patients who had more than one cancer were BRAF positive. BAP1 staining was retained in the majority of PTCs and melanoma tissues, indicating no loss of BAP1 protein.
PTC and melanoma both share molecular markers including BRAF, NRAS, PD-L1 as shown in our cohort. This is the largest study describing the mutation status of both PTC and melanoma. It is also the only study describing the PD-L1 and BAP1 expression in PTC and melanoma. BRAFV600E was the most common mutation. Majority of the PTC and melanoma stained negative for PD-L1. BAP1 expression was retained in both either PTC and melanoma tissues thus making presence of BAP1 tumour predisposition syndrome unlikely.