Search

Purpose: Patients submitted to curative surgery for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) exhibit a variable risk of disease relapse. Aims of this meta-analysis were to estimate the rate of disease recurrence and to investigate the risk factors for disease relapse in patients submitted to curative surgery for NF-PanNENs., Methods: Medline/Pubmed and Web of Science databases were searched for relevant studies. A meta-regression analysis was performed to investigate the source of recurrence rate heterogeneity. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CI) were used to assess the effect of each possible prognostic factor on disease-free survival., Results: Fifteen studies, involving 2754 patients submitted to curative surgery for NF-PanNENs, were included. The pooled rate of disease recurrence was 21% (95% CI 15-26%). Study quality (Odds ratio, OR 0.94, P = 0.016) and G3-PanNENs rate (OR 2.18, P = 0.040) independently predicted the recurrence rate variability. Nodal metastases (HR 1.63, P < 0.001), tumor grade G2-G3 (G1 versus G2: HR 1.72, P < 0.001, G1 versus G3 HR 2.57, P < 0.001), microvascular (HR 1.25, P = 0.046) and perineural (HR 1.29, P = 0.019) invasion were identified as significant prognostic factors. T stage (T1-T2 versus T3-T4, P = 0.253) and status of resection margins (R0 versus R1, P = 0.173) did not show any significant relationship with NF-PanNENs recurrence., Conclusion: Disease relapse occurs in approximately one out of five patients submitted to curative surgery for NF-PanNENs. Nodal involvement, tumor grade, microvascular and perineural invasion are relevant prognostic factors, that should be taken into account for follow-up and for possible trials investigating adjuvant or neoadjuvant treatments., (© 2021. Italian Society of Endocrinology (SIE).)

Background: Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS., Methods: Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS., Results: The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%-44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675-0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%., Conclusions: We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients., Competing Interests: Declaration of Competing Interest Outside the submitted work, Dr. Abu-Rustum reports grants from Stryker/Novadaq and GRAIL (paid to the institution). The remaining authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Spinal metastases (SpMs) from thyroid cancers (TC) significantly reduce quality of life by causing pain, neurological deficits in addition to increasing mortality. Moreover, prognosis factors including surgery remain debated., Methods: Data were stored in a prospective French national multicenter database of patients treated for SpM between January 2014 and 2017. Fifty-one consecutive patients affected by TC with 173 secondary SpM were included., Results: Mean overall survival (OS) time for all patients from the diagnosis of a thyroid SpM event was 9.1 years (SD 8.7 months). The 1-year, 5-year and 10-year survival estimates were 94% (SD 3.3), 83.8.0% (SD 5.2), and 74.5% (SD 9.9). The median period of time between primary thyroid tumor diagnosis and the SpM event was 31.4 months (SD 71.6). In univariate analysis, good ECOG-PS (status 0 and 1) (p < 0.0001), ambulatory status (Frankel score) (p < 0.0001) and no epidural involvement (p = 0.01), were associated with longer survival, whereas cancer subtype (p = 0.436) and spine surgery showed no association (p = 0.937). Cox multivariate proportional hazard model only identified good ECOG-PS: 0 [HR: 0.3, 95% CI 0.1-0.941; p < 0.0001], 1 [HR: 0.8, 95% CI 0.04-2.124; p = 0.001] and ambulatory neurological status: Frankel E [HR: 0.262, 95% CI 0.048-1.443; p = 0.02] to be independent predictors of better survival., Conclusion: For cases presenting SpM from TC, we highlighted that the only prognostic factors were the progression of the cancer (ECOG-PS) and the clinical neurological impact of the SpM (Frankel status). Surgery should be discussed mainly for stabilization and neurological decompression., Competing Interests: Declaration of competing interest The authors declare that they have no personal conflicts of interest and no institutional financial interest in any drugs, materials, or devices described in this manuscript. The authors have no financial disclosures to report. In addition, all patients gave their informed consent for any medical and scientific investigations. This paper has not been published previously, is not under consideration for publication elsewhere. All authors are responsible for reported research., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Introduction: Medullary thyroid carcinoma (MTC) is an aggressive form of thyroid cancer. Early detection is essential because only complete resection of the thyroid tumor and any local metastases can cure MTC. Calcitonin (CT) is a marker used for diagnosis of MTC. In controversial cases of slightly elevated CT levels, stimulation tests have shown their utility, but their safety should also be taken into account., Objective: Our aim is to present our own experience regarding the safety of CT stimulating tests., Materials and Methods: We applied a specific protocol of calcium stimulation test in 176 patients after informed consent (115 women with a median age of 46 years, range 21-79; 61 men with a median age of 54 years, range 22-78). We recorded the side effects and a further analysis was performed., Results: The most frequent side effects noted were hot flashes in 159 out of 176 patients (90.34%), followed by dysgeusia (32/176) and bradycardia (10/176). Severe bradycardia was reported in only one patient (0.568%), which was rapidly reversible. There was no correlation between patients' age, weight, height, body mass index, basal CT or peak stimulated CT, and grade of severity, but men were more likely to develop cardiovascular side effects than women, namely, bradycardia, tachycardia, ventricular or atrial extrasystoles, hypertension, hypotension, or angina (p = 0.024), with an odds ratio of 2.94 (CI: 1.11-7.76). We recommend thyroid surgery in all women with sCT above 285 pg/ml., Conclusion: The calcium stimulation test is well tolerated, with few adverse reactions. The test should be performed with appropriate precautions (i.e., ECG monitoring during and after the test) to minimize the possibility of a serious event., (© 2021. Hellenic Endocrine Society.)

To the best of our knowledge, we report a case of MEN2A complicated by moyamoya syndrome. A 52-year-old woman presented with vertigo. Magnetic resonance angiography (MRA) revealed bilateral supraclinoid stenosis of the internal carotid artery and abnormal moyamoya-like vessels around the basal ganglia. She had a heterozygous variant of RNF213 , which is the susceptibility gene for moyamoya disease. She had also previously received diagnoses of medullary thyroid carcinoma (MTC) at age 23 and left-sided pheochromocytoma (PHEO) at age 41. Genetic testing revealed heterozygosity for a mutation at codon 634 in exon 11 (TGC-TTC mutation; p.Cys634Phe) of the Ret gene. Intracranial vascular stenosis may have been caused by a genetic mutation of RNF213 and hypersecretion of catecholamines by MEN2A. Physicians should recognize that MEN2A can be present with moyamoya syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Matano, Murai, Watanabe, Shirokane, Igarashi, Shimizu, Shimada and Morita.)

A 70-year-old woman was referred to our department due to a solitary mediastinal tumor which gradually grew near the site of anastomosis for 8 years after radical surgery of esophageal squamous cell carcinoma. It was difficult to distinguish the lymph node recurrence of esophageal cancer from another tumor of unknown primary origin. Endoscopic ultrasound-guided fine-needle aspiration was performed, and the tumor was diagnosed to be neuroendocrine carcinoma. She received concurrent chemoradiotherapy with etoposide plus cisplatin. After the completion of chemoradiotherapy, the tumor disappeared. A solitary growing tumor which develops after radical resection of cancer would be better to be examined histologically in order to make an accurate diagnosis and select the most appropriate treatment.

Objective: Symptoms of depression and anxiety are common in neuroendocrine tumor (NET), yet controversy exists over whether serotonin-mediated antidepressants (SAs) are safe in this population. We sought to address this knowledge gap., Method: Following PRISMA guidelines, we conducted a systematic review to identify NET patients who were prescribed SA., Results: We identified 15 articles, reporting on 161 unique patients, 72 with carcinoid syndrome (CS) and 89 without. There was substantial agreement between reviewers at the full-text stage (κ = 0.69). Three of the articles, all with low risk of bias, accounted for most of the cases (149/161; 93%). Among the 72 NET patients with CS prior to antidepressant usage, CS was exacerbated in 6 cases (8%), only 3 (4%) of whom chose to discontinue the antidepressant. The remaining 89 patients had no prior CS symptoms, and none developed CS following antidepressant usage. Overall, no instances of carcinoid crisis or death were reported., Conclusions: We found no evidence for serious adverse outcomes related to SA usage in NET patients. Previous authors have recommended avoiding antidepressants in NET, but our findings do not support those recommendations. Oncologists should nonetheless monitor for symptom exacerbation when prescribing SA to patients with NET.

Calcitonin (CT) is a marker for both initial diagnosis and monitoring of patients with residual or recurrent medullary thyroid carcinoma (MTC). In Japan, serum CT had been measured by radioimmunoassay (RIA) until recently. Electrochemiluminescence immunoassay (ECLIA) became commercially available in 2014, and this technique is now the only method used to examine CT concentration. The purposes of this study were to investigate the correlations between the CT concentration measured with ECLIA (ECLIA-CT) and RIA (RIA-CT) and to explore the clinical characteristics of patients with elevated ECLIA-CT. CT concentrations of 348 sera samples from 334 patients with various thyroid disorders including nine MTC were measured using both assays. The correlation analysis revealed an excellent correlation between ECLIA-CT and RIA-CT among the cases with CT level >150 pg/mL by both assays (r s = 0.991, p < 0.001). However, 63% of all samples exhibited undetectable ECLIA-CT, while their RIA-CTs were measured between 15 and 152 pg/mL. The ECLIA-CTs in all patients who underwent total thyroidectomy for non-MTC showed low concentrations. High ECLIA-CT was observed in patients with MTC or pancreas neuroendocrine tumor. ECLIA-CT was also increased in 14 other male patients with non-MTC, including four with renal failure. Multivariate logistic regression analysis showed that male sex, negative TgAb, and lower estimated glomerular filtration rate were independent factors to predict detectable ECLIA-CT (≥0.500 pg/mL). These results indicate that ECLIA-CT correlates well with RIA-CT in higher range and is affected by sex, TgAb, and renal function.

Composite tumor of larynx, a recently included entity in the current WHO classification, is often a difficult pathological diagnosis, especially in small biopsies. We report a case of laryngeal composite tumor, initially misdiagnosed as squamous cell carcinoma, which later turned out to be composite in nature, with associated neuroendocrine (small cell carcinoma) component. This report emphasizes the need for obtaining deeper biopsies and their thorough pathological examination to improve the diagnostic accuracy. Keywords: combined small cell carcinoma; composite tumor; larynx; small cell carcinoma; squamous cell carcinoma.

Metastatic neuroendocrine tumors to breast are very rare with less than 30 cases reported worldwide. The first case was reported in 1957 according to literature. Among these 13 cases reported as breast lump as initial presentation. As the tumor is not so common, the radiological features are not well defined leading to misdiagnosis. Bilateral breast metastasis from pancreatic neuroendocrine tumors has not been mentioned in the literature. Here, we present a case of pancreatic neuroendocrine tumor with metastasis to bilateral breast., (© 2019 Wiley Periodicals, Inc.)

Rationale: Endometrial neuroendocrine carcinoma is a rare histological subtype of endometrial cancer, divided into low-grade neuroendocrine carcinoma (carcinoid) and high-grade neuroendocrine carcinoma (small cell and large cell neuroendocrine carcinoma). It is characterized by high invasiveness and poor prognosis. L/SCNEC is an extremely rare pathological type of endometrial carcinoma, and the number of reports on this condition is few globally., Patient Concerns: A 54-year-old Chinese female presented with vaginal bleeding., Diagnoses: Outpatient hysteroscopy and endometrial biopsy were performed, and the pathological examination revealed that cervix was invaded by endometrial malignancy. The patient underwent a laparoscopic radical hysterectomy was diagnosed with the mixed large and small cell neuroendocrine carcinoma (L/SCNEC) of the endometrium combined with serous carcinoma III C2 (FIGO2009)., Interventions: Chemotherapy-radiotherapy-chemotherapy "sandwich" treatment was performed as postoperative therapy., Outcomes: After three chemotherapy circles, the patient showed no evidence of further disease progression., Lessons: L/SCNEC is a rare and invasive disease. Once diagnosed, comprehensive treatments including surgery, radiotherapy, and chemotherapy can prolong the survival of patients and improve the prognosis.

We herein report two cases of miliary lung metastases from genital carcinoma in uterine cervix and endometrium. Notably, these patients were unable to receive any anti-tumor chemotherapy due to rapid progression causing respiratory failure, and they ultimately died of disease progression within only a month after the first visit to our hospitals. A postmortem examination confirmed the diagnosis of genital large-cell neuroendocrine carcinoma (LCNEC). Chest physicians should be aware of genital LCNEC with a dismal prognostic entity as an important differential diagnosis of miliary lung metastases.

AMPA receptor (AMPAR) antibodies are a group of recently discovered antibodies which target the neuronal synaptic proteins causing B-cell (immune) mediated neuronal damage, resulting in various neurologic syndromes depending on the area of central nervous system involvement. These syndromes are mostly reversible if treated early. Tumour association has been reported in up to 60% of cases in the most recent case series with lung, breast, ovarian cancers and thymomas being the most commonly associated malignancies with these antibodies. We present here the first case of AMPAR encephalitis associated with medullary thyroid cancer. Our patient presented with cognitive dysfunction and behavioural changes over a period of 3 weeks, with a full recovery after starting immunotherapy, once the diagnosis of AMPAR limbic encephalitis was established. This case highlights the importance of early diagnosis and management of AMPAR encephalitis as these patients respond well to immunotherapy and can have an almost complete recovery., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor account for 1-2% of thyroid cancer. In this study, we aim to examine the characteristics and survival of patients with MTC., Methods: A retrospective cohort study utilizing the National Cancer Data Base, 2004-2014. The study population included adults with either MTC (cases) or with differentiated thyroid cancer (DTC) (controls)., Results: A total of 2,776 MTC and 171,631 DTC patients were included. The median follow-up time for MTC was 55.5 months (interquartile range: 31.2-84.6 months). As compared to DTC, patients with MTC were more likely to be ≥ 45-year old, male, and Black (p < 0.001). Neck dissection improved survival in patients with stage III [HR: 0.26, 95%CI: (0.10, 0.64), p = 0.004]. In patients with stages I and II, neck dissections did not add significant survival benefit to thyroidectomy [stage I, HR: 1.00, 95%CI: (0.54, 1.86), p = 0.99],[stage 2, HR: 0.72, 95%CI: (0.40, 1.29), p = 0.27]. However, neck dissections upgraded staging to N1A and N1B in 17.7% and 14.3% of patients with clinically N0 neck, respectively. In stage IV, thyroidectomy with neck dissection had the highest 5-year survival (84.9%), but this was not significantly different from thyroidectomy alone (84.1%); Patients who had thyroidectomy and EBRT with or without neck dissection had a lower survival than thyroidectomy alone (p < 0.01)., Conclusions: Neck dissection performed on patients with clinically N0 neck, is important for accurate staging and associate with improved survival in advanced stages. Thyroidectomy and neck dissection in stage IV not only have palliative role but also add survival advantage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A 45-year old woman who underwent several surgeries for tumors associated with von Hippel-Lindau disease (VHL) was referred to our hospital due to a pancreatic tumor and liver tumors. She was diagnosed with pancreatic neuroendocrine tumor (NET) with a Ki67 index of 40% based on the examination of a biopsy specimen of the liver tumors. She was treated with everolimus for 6 months and sunitinib for 6 weeks as first- and second-line therapies. She survived for 13 months. At autopsy the diagnosis of pancreatic neuroendocrine tumor (NET)-G3 was confirmed. We herein report an aggressive clinical course of VHL-related NET G3. The further accumulation of cases is required to reach a consensus on treatment for this disease.

Tumor heterogeneity of a primary histologic cancer type has major implications for cancer research and therapeutics. An important and understudied aspect of this heterogeneity is the role of transcription factors that serve as "lineage oncogenes" in a tumor type. A demonstration that different subgroups have distinct dependencies on lineage-specific transcription factors is highlighted in a relatively homogenous cancer type: the pulmonary neuroendocrine cancer small cell lung carcinoma (SCLC). Identification of these factors is providing new insights into the origin of the heterogeneity and subtype-specific vulnerabilities in SCLC and provides a template for studying heterogeneity in other cancer types., (© 2018 Pozo et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Medullary thyroid cancer (MTC) is a rare cancer that has historically been managed by endocrinologists. In 2011, the first of several multi- targeted tyrosine kinase inhibitors was approved as treatment for MTC. These drugs have changed the management of MTC to teams that include oncologists and oncology nurses., Objectives: This article illustrates MTC diagnostics, surveillance, management of adverse drug reactions, and disease progression through a case study., Methods: An overview of MTC is offered, followed by an in-depth case study that examines MTC from the patient's perspective., Findings: Oncology nurses can influence patient outcomes through the provision of patient education, support, and management of disease and treatment complications.

This study aimed to identify factors influencing long-term outcome in complete or partial postoperative hypoparathyroidism (parathyroid hormone ≤10 or >10 ng/l, respectively) in medullary thyroid carcinoma (MTC). It was designed as retrospective, long-term follow-up with single-center outpatient visits. Quality of treatment, renal calcification, and function were evaluated. In 33 patients with MTC and postoperative hypoparathyroidism, current medication includes: calcium (73%), calcitriol (73%), alfacalcidol (6%), dihydrotachysterol (3%), and cholecalciferol supplements (21%). Mean hypoparathyroidism duration was 15.9±9.4 years. Initially, 15% of patients received high cholecalciferol dosages. Initial calcium dosages were higher (1 542±1 179 mg/day) than final dosages (1 188 ± 595 mg/day) (p<0.05); calcitriol dosages remained constant. Over the median observation period of about 12 years it was found that serum calcium was within the target range (2.0-2.3 mmol/l) in 63% of visits, decreased (<2.0 mmol/l) in 20.4%, high-normal (2.4-2.6 mmol/l) in 15.8%, and increased (>2.65 mmol/l) in 0.9% of visits. Calcitriol dosages were 0.73±0.22 μg/day and 0.47±0.20 μg/day in patients with complete (n=13) and partial (n=20) hypoparathyroidism, respectively (p=0.008). Renal function decreased slightly during follow-up (eGFR: 102±22 vs. 90±27 ml/min). eGFR was negatively correlated with hypoparathyroidism duration (r=-0.35, p=0.05). Of 9 patients with renal calcification, 5 had received high initial cholecalciferol doses. eGFR was lower in patients with than in those without calcification (77±17 vs. 95±29 ml/min) (p=0.07). At least one tetanic episode occurred in 60.6% of patients, and 9% had repeated tetanic complaints. In conclusion, severity of hypoparathyroidism affects treatment: Partial hypoparathyroidism required lower calcitriol dosages than complete hypoparathyroidism. Renal calcifications occurred more frequently in patients treated initially with high cholecalciferol dosages. Impaired renal function was related to hypoparathyroidism duration and renal calcification., (© Georg Thieme Verlag KG Stuttgart · New York.)

Thyroid cancer is the most common endocrine malignancy and accounts for nearly 1% of all of human cancer. Thyroid cancer has four main histological types: papillary, follicular, medullary, and anaplastic. Papillary, follicular, and anaplastic thyroid carcinomas are derived from follicular thyroid cells, whereas medullary thyroid carcinoma (MTC) originates from the neural crest parafollicular cells or C-cells of the thyroid gland. MTC represents a neuroendocrine tumor and differs considerably from differentiated thyroid carcinoma. MTC is one of the aggressive types of thyroid cancer, which represents 3-10% of all thyroid cancers. It occurs in hereditary (25%) and sporadic (75%) forms. The hereditary form of MTC has an autosomal dominant mode of inheritance. According to the present classification, hereditary MTC is classified as a multiple endocrine neoplasi type 2 A & B (MEN2A & MEN2B) and familial MTC (FMTC). The RET proto-oncogene is located on chromosome 10q11.21. It is composed of 21 exons and encodes a transmembrane receptor tyrosine kinase. RET regulates a complex network of signal transduction pathways during development, survival, proliferation, differentiation, and migration of the enteric nervous system progenitor cells. Gain of function mutations in RET have been well demonstrated in MTC development. Variants of MTC result from different RET mutations, and they have a good genotype-phenotype correlation. Various MTC related mutations have been reported in different exons of the RET gene. We proposed that RET genetic mutations may be different in distinct populations. Therefore, the aim of this study was to find a geographical pattern of RET mutations in different populations.

Ectopic-acromegaly is rare. Diagnosing ectopic-acromegaly is challenging given that the clinical and biochemical manifestations can be almost indistinguishable from those of patients with growth hormone secreting pituitary adenomas. This case report highlights the importance of clinical vigilance in differentiating between the two conditions. A 41-year-old Caucasian man presented with typical features of acromegaly with an enlarged pituitary and a lung lesion. Although excision of the lung mass showed a carcinoid tumour, normalisation of growth hormone factors did not occur soon enough. This led to a presumed diagnosis of a pituitary adenoma. However, no pituitary tumour was identified during trans-sphenoidal surgery. Postoperatively, the patient improved clinically and biochemically. Retrospective histological examination of the excised lung lesion showed a small proportion of tumour cells containing growth hormone releasing hormone (GHRH), suggesting ectopic-GHRH production from the lung neuroendocrine tumour. An open-and-close trans-sphenoidal surgery could have been avoided in this patient with ectopic-GHRH acromegaly., (2016 BMJ Publishing Group Ltd.)

Aim: To study the clinical and epidemiological profile of patients of breast cancer presenting at our center at New Delhi, India and to evaluate the applicability of Gail model 2 as a means of measuring 5-year and lifetime risk in our already diagnosed cases of breast cancer., Methods: This was a retrospective study conducted at Lady Hardinge Medical College Hospital in New Delhi, India, between January 2011 and July 2014. Two hundred and twenty two diagnosed cases of breast cancer were included. Information was collected retrospectively on a Performa from the medical record section and the Pathology department of the hospital.The predicted five-year and lifetime risk was calculated using GM2 prediction model from the NCI's breast cancer risk assessment tool website., Results and Conclusions: Breast cancer in India is a far more biologically aggressive disease than in the west with a widely different spectrum of presentation and behavior and late presentation in an advanced stage. The accepted risk factors routinely associated with breast cancer in western literature do not appear to be relevant in the Indian population. Accepted western models do not seem to apply in the Indian scenario.

Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild-type levels. We identified CtsZ, which is predominantly supplied by tumor-associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer., (© 2016 Akkari et al.; Published by Cold Spring Harbor Laboratory Press.)

Activating germline mutations in the RET proto-oncogene are responsible for about 98 % of the familial forms of medullary thyroid carcinoma (MTC), which represent 25 % of all MTC cases. The search for germline mutations in this gene is important for the recognition of hereditary forms of MTC and further identification of at-risk relatives who may benefit from early clinical intervention. Genotype-phenotype correlations are well established for most disease-causing RET mutations, allowing risk stratification. The association of a new RET variant with the MTC phenotype and familial predisposition requires the assessment of its functional and clinical significance. The aim of this study was to evaluate the oncogenic potential of two newly identified RET germline variants associated with late-onset MTC. In vitro functional assays were designed to address the transforming potential of novel RET variants, through their expression in non-transformed cells, and comparing their effect with wild-type RET. The new variants were identified in codons 515 (p.C515W) and 636 (p.T636M) located, respectively, in exons 8 and 11, thus resulting in amino acid substitutions in the extracellular region of the tyrosine kinase receptor RET. Through functional assays, we observed increased cell growth and proliferation, loss of contact inhibition, and a stimulation of cell migration, suggesting that these new RET variants hold some relevant transforming potential. The transforming potential of these novel RET variants was of low-grade, when compared to that of RET MEN2A-causing mutation p.C634R, probably explaining the mild phenotype characterized by late onset and low clinical aggressiveness.

Calcium, the fifth most common element in the body, plays major physiological functions. Measurement of blood calcium is one of the most commonly ordered laboratory tests in assessments of calcium homeostasis and disease diagnosis. Hypercalcemia is an increased level of calcium in the blood. This disorder is most commonly caused by primary hyperparathyroidism and malignancy. However, other less common causes of elevated calcium levels need to be considered when making a differential diagnosis. This review is intended to provide readers with a better understanding of calcium homeostasis and the causes and pathophysiology of hypercalcemia. Most importantly, this review describes useful approaches for laboratory scientists and clinicians to appropriately diagnose and assess hypercalcemia.

Background: Information on the genetic events leading to thyroid cancer in dogs is lacking., Hypothesis/objectives: Upregulation of the PI3K/Akt pathway has an important role in the tumorigenesis of thyroid carcinoma in dogs., Animals: Fifty-nine dogs with thyroid carcinoma and 10 healthy controls., Methods: Quantitative RT-PCR was performed for VEGFR-1, VEGFR-2, EGFR, PIK3CA, PIK3CB, PDPK1, PTEN, AKT1, AKT2, COX-2, and CALCA. Mutation analysis was performed for known hotspots of RAS (N, K, H), PIK3CA, BRAF, RET, and for the entire coding region of PTEN., Results: Forty-three dogs (73%) had follicular cell thyroid carcinoma (FTC) and 16 dogs (27%) had medullary thyroid carcinoma (MTC). The relative mRNA expressions of VEGFR-1 (P < .001), VEGFR-2 (P = .002), PDPK1 (P < .001), AKT1 (P = .009), and AKT2 (P < .001) were increased in FTC, and those of EGFR (P < .001), VEGFR-1 (P = .036), and PIK3CA (P = .019) were increased in MTC when compared to normal thyroid glands. Mutation analysis of K-RAS identified 2 activating missense mutations, which also have been described in thyroid cancer of humans. A G12R substitution was present in 1 FTC and an E63K substitution was present in 1 MTC. No functional mutations were found in the sequenced regions of H-RAS, N-RAS, PIK3CA, BRAF, RET, and PTEN., Conclusions and Clinical Importance: The increased expression of several genes associated with PI3K/Akt signaling suggests the involvement of this pathway in the pathogenesis of thyroid carcinoma in dogs, warranting further research on pathway activation and gene amplification. The mutations most frequently associated with thyroid cancer in humans are rare in dogs., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

An acute presentation after pregnancy of coeliac disease (CD) in the puerperium is a rare condition which has been described mostly in primigravidae in patients highly suspicious of latent CD. We report the case of a 37-year-old woman who was referred to our Hospital because of refractory watery diarrhea and malnutrition syndrome. Endoscopy of the upper gastrointestinal tract revealed the classic visual features of CD and in addition, some duodenal ulcers negative for Helicobacter pylori, which seems to be another clinical feature in patients with CD. The diagnosis of acute onset of fulminant postpartal CD (Marsh score stage 3c) was confirmed histologically. Remarkably, simultaneous well-differentiated neuroendocrine non-functioning pancreatic neuroendocrine carcinoma (PNET) was diagnosed on radiological abdominal imaging which was performed since serum gastrin was remarkably high, treated by distal pancreatectomy and splenectomy. This report is, to our knowledge, the first description of the two entities, CD and PNET occurring together. Since results of antral histological studies showed diffuse hyperplasia of G-cells, probably in response to hypergastrinaemia, enterochromaffin cell carcinogenesis might have served as a possible link between both diseases.

Small cell neuroendocrine carcinoma (SNEC) of the paranasal sinuses is an extremely rare and distinctive tumor with aggressive clinical behavior. Moreover, SNECs originating in the head and neck region have been reported to be highly aggressive and to have a poor prognosis. This report describes a patient with a maxillary sinus SNEC who was successfully treated with induction chemotherapy using cisplatin and etoposide followed by concurrent chemoradiation therapy with cisplatin and etoposide as radiosensitizers. The patient has remained free of recurrence during 7 years of follow-up. To the authors' knowledge, this is the first case report describing long-term survival in a patient with a resolved primary SNEC of the maxilla that was successfully treated with neoadjuvant chemotherapy and concurrent chemoradiotherapy. The clinical and pathologic features of the tumor and the optimal treatment of this patient are discussed., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

The transcription factor E2F1 belongs to the E2F family and plays a crucial role during cell cycle progression and apoptosis. Ser/Arg-Rich (SR) proteins are a family of RNA-binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing events. We previously identified the SR protein SRSF2 as a new transcriptional target of E2F1 and demonstrated that both proteins cooperate to induce apoptosis in non-small cell lung carcinoma. In this study, we postulated that SRSF2 is also involved in the proliferative functions of E2F1. Using IHC, we first demonstrate that SRSF2 and its phosphorylated form (P-SRSF2) are overexpressed in neuroendocrine lung tumors that are highly proliferative tumors expressing high levels of E2F1. Importantly, we show a direct correlation between cyclin E, an E2F1-target gene controlling S phase, and P-SRSF2 proteins levels (p = 0.0083), suggesting a role of SRSF2 in E2F1-mediated cellular proliferation. Accordingly, using neuroendocrine lung carcinoma cell lines, we demonstrate that SRSF2 is a cell cycle-regulated protein involved in entry and progression into S phase. We also provide evidence that SRSF2 interacts with E2F1 and stimulates its transcriptional control of cell cycle target genes such as cyclin E. Finally, we show that inhibition of AKT signaling pathway prevents SRSF2 phosphorylation and activity toward E2F1 transcriptional function. Taken together, these results identify a new role of SRSF2 in the control of cell cycle progression and reinforce the functional link between SRSF2 and E2F1 proteins.

Background: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients., Patients and Methods: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals., Results: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels., Conclusions: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Background: Parenchyma-sparing pancreatectomy (PSP), including enucleation and central pancreatectomy, has been investigated as an alternative to standard resection for pancreatic endocrine neoplasm, but the benefit/risk of these procedures remains little known., Methods: From 1998 to 2010, among 197 patients operated for well-differentiated pancreatic neuroendocrine tumors, 67 underwent PSP (45 enucleations and 22 central pancreatectomies) and 66 standard resections (35 pancreaticoduodenectomies and 31 distal pancreatectomies) for a tumor below 4 cm, without synchronous distant metastasis. Groups were compared regarding postoperative morbidity, mortality, long-term pancreatic function, and survival calculated using the Kaplan-Meier method., Results: Tumors operated by PSP had a median size of 15 mm, were mainly incidentally diagnosed (n = 46, 69 %), and nonfunctioning (n = 55, 82 %). Overall morbidity rate was higher after PSP than standard resection (SR) (76 vs 58 %, p = 0.0028), including more frequent pancreatic fistulas (69 vs 42 %, p = 0.003). Postoperative diabetes was less frequent following PSP than pancreaticoduodenectomy (5 vs 21 %; p = 0.022) but equivalent to the one observed after distal pancreatectomy (4 %, p = 1). Exocrine insufficiency was significantly less frequent after PSP than SR (3 vs 32 %; p < 0.0001). The overall and recurrence-free 5-year survival after PSP for nonfunctioning tumors was 96 and 98 %, respectively., Conclusion: In selected patients, with small and low-grade tumors, PSP are associated with excellent overall and recurrence-free survivals. These procedures are associated with an increased postoperative morbidity but an excellent postoperative pancreatic function. Therefore, they should be considered as a valid therapeutic option in selected well-differentiated pancreatic neuroendocrine tumors.

Poorly differentiated endocrine carcinomas (PDEC) are usually treated with cisplatin-based chemotherapy regimens. We here present a case with a dramatic response (both radiologically and biochemically) to the combination of temozolomide and bevacizumab, after failure of cisplatin and etoposide, with continued tumor shrinkage at 5 months. Temozolomide combined with bevacizumab might be a good treatment option in PDEC, perhaps even in a first-line setting. Prospective studies to answer this are warranted.

Although progastrin-releasing peptide (proGRP) is used as a serum tumor marker for small cell lung cancer (SCLC), high serum pro-GRP concentrations are observed in some non-small-cell lung cancers (NSCLCs). The characteristics of these NSCLCs are not well known. To determine the clinicopathological features of NSCLC in patients with elevated serum proGRP concentrations, serum proGRP values were assessed in 654 advanced lung cancer patients, and positive (>46pg/mL) NSCLC specimens were subjected to cytological and histopathological reevaluation. Serum proGRP concentrations were positive in 34 of 421 NSCLC patients (8.1%) and 186 of 233 SCLC patients (80%). Histological subtypes of the 34 NSCLC patients at diagnosis were 20 adenocarcinomas, 5 squamous cell carcinomas, 4 large cell carcinomas, and 5 large cell neuroendocrine carcinomas. Six of 27 cytology specimens contained characteristic neuroendocrine morphology. Immunohistochemical analysis showed that 11 of 17 tumors were positive for neuroendocrine markers (64.7%). Twenty of 34 serum proGRP-positive NSCLC patients received platinum-based chemotherapy, and the response rate was 55.0%. These results suggest that serum proGRP-positive NSCLCs may have neuroendocrine differentiation. In addition, serum proGRP-positive NSCLCs may have clinical characteristics that are different from other NSCLCs., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Endocrine tumours occur rarely in pregnant women but present clinicians with unique challenges. A high index of suspicion is often required to make a diagnosis since the symptoms and signs associated with many of these tumours, including insulinoma, adrenocortical carcinoma and phaeochromocytoma, mimic those of normal pregnancy or its complications, such as pre-eclampsia. The evidence base which informs management is very limited hence decisions on investigation and therapy must be individualised and undertaken jointly by the multidisciplinary medical team and the patient. The optimal strategy will depend on the nature and stage of the endocrine tumour, gestational stage, treatments available and patient wishes. Thus, surgical intervention, appropriately timed, may be considered in pregnancy for resectable adrenocortical carcinoma or phaeochromocytoma, but delayed until the postpartum period for well-differentiated thyroid cancer. Medical therapy may be required to reduce the drive to tumour growth, control symptoms of hormone excess and to minimise the risks of surgery, anaesthesia or labour., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

Background: In terms of prognosis, large cell neuroendocrine carcinoma (LCNEC) differs distinctively from other non-small cell lung cancers, with the prognosis of LCNEC being poor, even for early-stage disease. Improvements in survival require a biomarker capable of defining a subset of patients destined to do poorly so that these patients can be targeted for additional therapies, including chemotherapy. In this study, we focused on the Klotho gene, which is an anti-aging gene known to be a potential tumor suppressor. We investigated whether the immunohistochemical expression of Klotho can predict survival patients with resected LCNEC., Methods: The histological characteristics of patients receiving an initial diagnosis of LCNEC (n=30) at Tokyo Medical University Hospital were retrospectively reviewed, and multiple variables including stage, lymphangioinvasion, lymph node status and the expression of Klotho as identified using an immunohistochemical analysis, were assessed., Results: Immunostaining for Klotho was mostly cytoplasmic, and Klotho expression was seen in 10 patients (33.3%) but not in 20 patients (66.7%). The expression of Klotho was significantly associated with a good outcome of resected patients with LCNEC and Klotho(-) was associated with increased LCNEC risk by multivariate analysis (hazard ratio 4.92, 95% confidence interval 1.04-23.24, p=0.044). Neither lymph node status nor lymphangioinvasion were significantly associated with a poor survival. However, among patients without lymph node metastasis or angioinvasion, the survival benefit of Klotho expression in the primary tumor was significantly higher, compared with that of patients without Klotho expression., Conclusion: Klotho staining provides a new biomarker for a good outcome in patients with LCNEC, especially among patients without lymph node metastasis or lymphangioinvasion., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The aim of our study was to determine the integrity of the cell-cell adhesion E-cadherin-beta-catenin complex in neuroendocrine lung tumors (NELTs) and the possible involvement of Snail in its deregulation., Methods: The studied series consisted of formalin-fixed-paraffin-embedded tissue samples from 70 patients diagnosed with NELT (2000-2006) including tumors of low malignancy potential (3 tumorlets, 33 typical carcinoids), intermediate malignancy potential (3 atypical carcinoids) and tumors of high malignancy potential (10 large cell neuroendocrine carcinomas-LCNEC and 21 small cell carcinoma-SCLC). E-cadherin, beta-catenin and Snail expression were immunohistochemically evaluated and mRNA levels were assessed by Q-RT-PCR for E-cadherin and Snail., Results: Nuclear Snail signal was high in 46% tumors with the strongest level observed in high malignancy tumors. Furthermore, Snail levels correlated with tumor size, lymph node involvement and tobacco consumption. E-cadherin expression was downregulated in 24% cases and it was absent from the membrane in 31%, all of them cases of high malignancy potential. High E-cadherin levels and a membrane pattern were associated with tumor-free lymph node patients and inversely proportional to Snail protein expression. beta-catenin levels were weak in 43% and absent from the membrane in 59% cases. Interestingly, among high malignancy potential tumors, beta-catenin levels were significantly higher in LCNEC than in SCLC. The integrity of the E-cadherin-beta-catenin complex was retained in 37% cases, most of them carcinoid tumors, and correlated with low Snail levels, low malignancy potential and free lymph nodes., Conclusion: Snail nuclear expression and loss of integrity of cell adhesion complex E-cadherin/beta-catenin parallels higher malignancy potential in NELTs., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Large cell neuroendocrine tumors of the lung represent a recently reclassified subtype of lung cancer with features of both small cell and non-small cell lung cancer. We review diagnostic difficulties, typical presentations, and the natural history of this tumor. We review treatment data, and suggest that as in more common types of lung cancer, multi-modality therapy may be the most promising course of treatment., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

This retrospective study analyzes, whether patients suffering from extensive hepatic metastatic disease treated with SIRT can become suitable candidates for RFA.Within 38 months 46 patients (26 female, 20 male; age 32-75 years) bearing an extensive hepatic metastatic disease were treated with SIRT. Patients suffered from metastases of breast cancer (16/46), colorectal cancer (CRC) (21/46), neuroendocrine (3/46), and other primary carcinomas (6/46). The indication for SIRT was otherwise untreatable metastases confined to the liver. Forty-three patients received single-session whole-liver radioembolization treatment using Yttrium90 resin microspheres with a mean activity of 2.13GBq. In 1 patient SIRT was confined to the left and in 2 patients to the right liver lobe. In 3 patients major complications (2/3 gastric ulceration and 1/3 oedematous pancreatitis) and in 24 patients minor complications occurred (acute abdominal/epigastric pain and/or nausea). Follow-up CT and/or MRI were obtained in 44 of 46 patients. In 5 of 44 patients tumor load decreased substantially (3/5 breast cancer, 1/5 CRC and 1/5 pancreatic cancer) making RFA feasible. The patients were referred for RFA after the first 3-month follow-up. RFA of the liver was successful in all cases in terms of complete ablation. In selected patients radioembolization is able to downstage liver metastases to an extent making a subsequent RFA suitable and therefore allows increasing the number of patients with a "complete response" after a minimally invasive therapy., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Neuroendocrine tumors, although rare, are currently diagnosed with increasing frequency, owing to improved imaging techniques and a greater clinical awareness of this condition. To date, BON is a very well established and characterized human pancreatic neuroendocrine tumor cell line used to study the signal transduction and genetic regulation of neuroendocrine tumors secretion and growth. The secretory activity of BON cells is known to release peptides, such as chromogranin A, neurotensin, and biogenic amines, as 5-HT, permitting an assessment of their biological activity. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), released from the enteric neurons in the gastrointestinal tract by binding to its high affinity receptor PAC1, has been previously shown to regulate the secretory activity and growth of the neuroendocrine-derived enterochromaffin-like cells in the stomach. This led us to speculate that PACAP might also play an important role in regulating the growth of human neuroendocrine tumors. Accordingly, in the current study, we have shown that BON cells express PAC1 receptors, which are rapidly internalized upon PACAP activation. Furthermore, PAC1 receptor activation, in BON cells, couple to intracellular Ca(2+) as well as cAMP responses and induce the release of intracellular 5-HT, activate mitogen activated protein kinases, and stimulate cellular growth. These data indicate that PACAP functionally can stimulate 5-HT release and promote the growth of the BON neuroendocrine tumor cell line. Therefore, PACAP and its receptors regulate neuroendocrine tumor secretory activity and growth in vivo, and this knowledge will permit the development of novel diagnostic and therapeutic targets for managing neuroendocrine tumors in humans.

Background: Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy., Methods: To investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of beta-cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10)., Results: Immunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete-scute homolog-1 (mash-1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes-1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete-scute homolog-1 (HASH-1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic beta-cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash-1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2., Conclusions: These results suggest that Ngn3 and Nkx2.2 expression are markers for site-specific metastasis and/or transcriptionally regulated genes that are required for organ-specific metastasis. This study indicates that a pathway similar to pancreatic beta-cell differentiation is involved in NE differentiation of prostate cancer., ((c) 2007 Wiley-Liss, Inc.)

A 56-year-old male with a history of cutaneous neuroendocrine (Merkel cell) carcinoma presented with a solid mass of the left kidney, measuring 10 cm in largest diameter. On histology, the tumour was composed of loosely packed uniform cells with round-to-oval nuclei and scant cytoplasm. Immunohistochemically, the tumour cells diffusely expressed pancytokeratin and neuroendocrine markers, such as chromogranin A, synaptophysin and CD56 (NCAM). Distinct paranuclear dot-like expression of cytokeratin 20 showed the lesion to be metastatic Merkel cell carcinoma. This is the first reported case of Merkel cell carcinoma metastatic to the kidney mimicking primary neuroendocrine renal cancer. We discuss the differential diagnosis of the tumour and perform a systematic literature review, including potential indications for renal tumour biopsy in patients with a history of nonrenal malignancy.

The World Health Organisation (WHO) classification (2000) is widely used to classify neuroendocrine carcinomas (NECs), yet its prognostic value needs to be confirmed. In this study, patients with metastatic NECs (n=119) were classified according to WHO guidelines into well differentiated and poorly differentiated (WDNECs and PDNECs). Histological differentiation based on WHO criteria had the highest impact on overall survival (OS) (PDNECs : WDNECs hazard ratio (HR)=4.02, P=0.02); however, PDNECs represented only a small percentage of patients (8%). In a WDNEC-restricted analysis, abnormal liver function tests (LFTs) and elevated urinary 5-hydroxyindoleacetic acid (u5HIAA) were independent prognostic factors for survival (HR=2.65, P=0.006 and HR=2.51, P=0.003, respectively) and were used to create a WDNEC-specific prognostic model (low risk=both normal, intermediate risk=one of them abnormal, high risk=both abnormal). Low-risk WDNECs had the most favourable prognosis (median OS, mOS 8.1 years), which was significantly better compared to both intermediate-risk and high-risk WDNECs (mOS 3.2 and 1.4 years, with P=0.01 and P<0.001, respectively). High-risk WDNECs displayed the shortest OS (1.3 years), which was similar to that of PDNECs (P=0.572). This analysis supports the prognostic value of WHO classification for metastatic NECs arising from the gastroenteropancreatic tract; however, risk stratification using readily available u5HIAA and LFTs may be necessary for the heterogeneous group of WDNECs.

The molecular mechanism(s) for prostate cancer progression to androgen independence are poorly understood. We have recently shown that Foxa1 and Foxa2 proteins are differentially expressed in epithelial cells during murine prostate development, growth, and adult function. Currently, the role of Foxa proteins in prostate cancer development and progression is unknown. Foxa protein expression was investigated in the LPB-Tag LADY mouse prostate cancer models, in human prostate cancer specimens, and various prostate cancer cell lines using Western blot and immunostaining analysis. In vitro transient transfection, studies were performed to investigate Foxa/prostate-specific gene regulation. Foxa1 was strongly expressed in areas of prostatic intraepithelial neoplasia (PIN) in both the androgen dependent 12T-7f and in the metastatic, androgen independent 12T-10 LADY models. Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice. Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas. Foxa proteins were also differentially expressed in three prostate cancer cell lines. Importantly, in vitro functional assays demonstrated that Foxa2 could activate androgen-dependent prostate-specific genes in an androgen receptor and ligand-independent manner. These results suggest that Foxa proteins are important in prostate carcinogenesis. In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence. As such, Foxa proteins may represent novel targets for therapeutic intervention., (Copyright 2005 Wiley-Liss, Inc.)

Serous cystadenomas of the pancreas have been classified as benign exocrine tumors. There have been rare cases of malignant behavior, and in exceptional cases, coexisting neoplasms have been reported. We report a case of a coexistent neuroendocrine tumor identified within a serous cystadenoma in a 78-year-old woman, which was discovered incidentally after complete resection of the tumor. Given the unpredictable metastatic potential of neuroendocrine tumors of the pancreas, we advocate complete resection of all pancreatic cystic tumors, combined with careful sampling of the pathological specimen to rule out a coexistent potentially malignant neoplasm.

Background: The role of neuroendocrine (NE) cells in prostate cancer remains unclear. A useful model is necessary to study the biology of NE cells. We herein describe the establishment and characterization of an immortalized cell line from an NE-10 allograft of murine prostatic NE carcinoma., Methods: A novel cell line, designated NE-CS, was developed from an NE-10 allograft that was established from the ventral prostate of the LPB-T-antigen (Tag) transgenic mouse, line 10 (12T-10). We investigated the growth, karyotype, electron microscopic findings, expression of Tag and androgen receptor (AR), and tumorigenesis of the cells in athymic mice., Results: The immortal cell line NE-CS was maintained in vitro for more than 2 years. The NE-CS cells had dendritic-like extensions with dense core granules in the cytoplasm and produced serotonin and somatostatin in conditioned medium. The cells expressed neither Tag nor AR. They showed androgen-independent growth in vitro and a hypotetraploid karyotype similar to the original NE-10 allograft. The NE-CS cells, which were subcutaneously inoculated into athymic mice, formed tumors with the NE phenotype. The tumors exhibited accelerated growth compared to the original NE-10 allograft., Conclusions: The established cell line has characteristics of NE differentiation and tumorigenic ability. This cell line may be a promising model to understand the molecular mechanisms associated with the acquisition of hormone refractory prostate cancer., (Copyright 2004 Wiley-Liss, Inc.)

By means of patch-clamp technique we examined changes in volume-regulated chloride current (ICl,swell) at neuroendocrine differentiation of androgen-dependent LNCaP prostate cancer cells. In those cells with neuroendocrine differentiation resulted from an increase in the intracellular cAMP, ICl,swell became much faster in response to applying external hypotonic solution and cell swelling. Changes in final rectification and voltage-dependent inactivation were not detected, as compared to the control cells. The differentiation also diminished ICl,swell blockade by Ca2+ transported via store-operated channels (SOC). On the base of our data we suggest that potentiation of the current at neuroendocrine differentiation, at least in part, resulted from a decrease in an inhibitory effect of Ca2+, transported into a cell through SOC, on volume-sensitive chloride current. Accelerated current in those cells might be induced by cytoskeleton rearrangement at the neuron-like growth.