Biomedical subjects

Maria A Kouvaraki

Publications and source records attributed to Maria A Kouvaraki.

11 recordsLinked to original sources

PubMed2006

Potential role of Jun activation domain-binding protein 1 as a negative regulator of p27kip1 in pancreatic adenocarcinoma.

Reduced expression of p27 has been associated with poor prognosis in most human cancers, including pancreatic adenocarcinoma. Jun activation domain-binding protein 1 (JAB1), an activator protein (AP-1) coactivator, previously implicated in p27 degradation, is overexpressed in various tumors and correlates with low p27 expression. We examined JAB1 and p27 in normal and neoplastic pancreatic tissues. Increased JAB1 expression was seen in pancreatic carcinoma samples but not in paired normal pancreatic tissues. Immunohistochemical analysis using tissue microarrays showed that JAB1 was overexpressed in all 32 (100%) pancreatic adenocarcinoma samples tested, predominantly nuclear in 23 (72%) samples and predominantly cytoplasmic in 9 (28%) tumors. When 10% was used as a cutoff for p27 positivity, p27 was expressed in 11 (34%) of tumors; however, p27 expression was localized in the nuclei of tumor cells in only 4 (13%) of the samples. Overexpression of the JAB1 in the pancreatic carcinoma cell lines Panc-1, Mia PaCa-2, and Panc-28 resulted in decreased p27 expression. Conversely, down-regulation of JAB1 by short interfering RNA substantially increased p27 expression and inhibited progression from G(1) to S phase of the cell cycle. Interestingly, JAB1-mediated p27 degradation was not impaired when S-phase kinase-interacting protein 2 (Skp2), an F-box protein required for the ubiquitination and consequent degradation of p27, was silenced. Thus, JAB1 may have an Skp2-independent p27 degradation mechanism in pancreatic cancer cells. These findings suggest that JAB1 overexpression is involved in the pathogenesis of pancreatic cancer through JAB1-mediated p27 degradation and that control of JAB1 expression is a novel therapeutic target in patients with pancreatic adenocarcinomas.

Adenocarcinoma↗

PubMed2006

Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1.

INTRODUCTION: Pancreatic endocrine tumors (PETs) occur in at least 50% of patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of disease-specific mortality. However, the timing and extent of surgery for MEN1-related PETs is controversial owing to the indolent tumor growth seen in most patients and the desire to avoid complications associated with insulin dependence. To help resolve this controversy, we retrospectively analyzed the clinical characteristics, surgical treatment, and clinical outcome of patients with MEN1-related PETs. METHODS: All patients had histologic or radiographic confirmation of a PET in the setting of MEN1. Disease progression was defined radiographically as the development of new pancreatic tumors or distant metastases. Progression-free survival (PFS) and overall survival (OS) were used as the endpoints of this analysis. RESULTS: We identified 98 patients with MEN1, 55 (56%) of whom had PETs, including 27 women and 28 men with a median age of 37 years (range 8-69 years) at the time of diagnosis. Functioning PETs were present in 35 (64%) of 55 patients, and nonfunctioning tumors were present in 20 (36%). Pancreatic surgery was performed in 38 (69%) of the 55 patients; and the first operation included enucleation (n = 4), total pancreatectomy (n = 3), Whipple procedure (n = 4), and distal pancreatectomy (n = 27). The median size of the resected tumors was 2.8 cm (range 0.6-11.0 cm). Recurrent disease developed in the residual pancreas in 7 (20%) of 35 at-risk patients a median of 7.8 years after the first operation, and distant metastases occurred in 5 (14 %) of 36 surgically treated patients without distant metastasis (2 patients had distant metastases when surgery on the primary tumor was performed) at a median of 2.7 years following surgery. At last follow-up, 16 (29%) of 55 patients with PETs had died, 12 (22%) were alive with disease, 26 (47%) were alive without evidence of disease, and 1 (2%) was lost to follow-up. The median OS was 19.5 years (range 13-26 years) and was significantly longer for patients who had functioning PETs versus those with nonfunctioning tumors (P = 0.0007), for patients who underwent surgical resection of their PETs versus those who did not (P = 0.0043), and for patients with localized versus metastatic PETs at the time of diagnosis (P < 0.0001). Multivariate analysis revealed that younger age, hormonal function, and PET resection were independently associated with longer OS. CONCLUSIONS: Our data suggest that early diagnosis and surgical excision of MEN1-related PETs improves survival. However, translating these data into a surveillance strategy for the early detection of PETs is complex owing to the potential morbidity of pancreatic resection and the risk of long-term insulin dependence.

Adolescent↗

PubMed2006

Indications for operative intervention in patients with asymptomatic primary hyperparathyroidism: practice patterns of endocrine surgery.

BACKGROUND: Currently, many patients with primary hyperparathyroidism (PHPT) are diagnosed when they are considered to be "asymptomatic." The need for parathyroidectomy in these patients has been questioned. A consensus statement drafted after the National Institutes of Health (NIH) 2002 Workshop on Asymptomatic PHPT provided guidelines for management of such patients but has been criticized for being too conservative. The purpose of this survey was to determine the impact of these guidelines on practice patterns of endocrine surgeons. METHODS: Members of the American Association of Endocrine Surgeons (AAES) were surveyed to determine whether previously published consensus guidelines for management of asymptomatic patients with PHPT are used to base the decision of whether to offer parathyroidectomy and to ascertain what parameters are considered indicators to proceed with operative intervention. AAES members were asked about the management of patients with asymptomatic PHPT, specialty characteristics, and demographics. RESULTS: Of 257 AAES members, 96 (37%) responded to the survey. Although the majority of the respondents were aware of and followed the NIH consensus conference guidelines, the majority of surgeons (80%) would operate on a patient with PHPT who did not meet these criteria but had other nonspecific symptoms. Surgeons favored operative intervention when preoperative localization studies were positive, even if the criteria of the NIH guidelines were not fulfilled. Most of the responders who would operate on all patients with PHPT, regardless of objective parameters, were surgeons with a high-volume practice (>30 parathyroidectomies per year). The presence of multiple endocrine neoplasia (MEN) syndromes did not alter the decision to operate on asymptomatic patients. CONCLUSIONS: Endocrine surgeons do not base the decision to intervene operatively in patients with PHPT solely on objective criteria. Most high-volume, experienced endocrine surgeons believe that subjective complaints warrant operative intervention.

Adult↗

PubMed2005

Surgical treatment of non-functioning pancreatic islet cell tumors.

Pancreatic endocrine tumors (PETs) are rare neoplasms originating from the amine precursor uptake and decarboxylation (APUD) stem cells. Although the majority of PETs are sporadic, they frequently occur in familial syndromes. PETs may cause a variety of functional syndromes or symptoms of local progression if they are non-functional. General neuroendocrine tumor markers are highly sensitive in the diagnostic assessment of a PET. Imaging studies for tumor localization and staging include computer tomography (CT) scan, magnetic resonance imaging (MRI), In(111)-octreotide scan, MIBG, and endoscopic ultrasonography (EUS). Treatment of PETs often requires a multi-modality approach; however, surgical resection remains the only curative therapy for localized (non-metastatic) disease. Treatment of metastatic disease includes biologic agents, cytotoxic chemotherapy, and liver-directed therapies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors.

Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype- phenotype correlations to stratify mutations into three risk levels.

Carcinoma, Medullary↗

PubMed2005

Surgical management of thyroid carcinoma.

Thyroid carcinoma has a unique biologic behavior characterized by early spread to regional lymph nodes and occasional extrathyroidal soft tissue extension but a low incidence of distant metastasis and infrequent disease-related death. Therefore, controversy exists over the proper extent of thyroidectomy and regional lymph node dissection in patients with differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). The modest disease-specific mortality makes it unlikely that the extent of surgery will ever be the subject of a prospective randomized trial. Although more extensive cervical surgery may have only a limited effect on the duration of survival in patients with DTC, it may significantly improve quality of life by minimizing cervical recurrence. The high rates of cervical recurrence in patients with DTC and MTC have alerted physicians to the importance of fine-needle aspiration biopsy and ultrasonography for the diagnosis, preoperative staging, and follow-up of thyroid cancer. In patients with MTC, death caused by disease is uncommon in the absence of radiographically evident distant metastasis at the time of thyroidectomy. Cervical recurrence is even more common with MTC, and the need for compartment-oriented lymphadenectomy is accepted as standard surgical treatment to minimize disease recurrence. Postoperatively, calcitonin (CT) levels can be used to guide clinical management, but basal CT levels should not be used to direct the timing of prophylactic thyroidectomy in affected high-risk patients with familial MTC.

Biopsy, Fine-Needle↗

PubMed2004

Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas.

PURPOSE: The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). PATIENTS AND METHODS: Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. RESULTS: Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. CONCLUSION: Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.

Adult↗

PubMed2004

Preventable reoperations for persistent and recurrent papillary thyroid carcinoma.

BACKGROUND: Cervical recurrence occurs in up to 25% of patients with papillary thyroid carcinoma (PTC) due either to the aggressive biology of PTC or to inadequate treatment. This retrospective study was designed to determine the frequency of inadequate surgical or medical therapy as a cause of persistent or recurrent PTC. METHODS: We identified all patients who underwent reoperation for persistent (within 6 months of initial or pre-referral operation) or recurrent (greater than 6 months after initial or pre-referral operation) PTC from 1992 to 2003. Medical records including initial preoperative imaging, operative, and histopathology reports were reviewed. The initial surgical procedure was considered incomplete if all gross neoplasm was not removed or if "node plucking" was performed, and a subsequent recurrence occurred in the same cervical compartment. RESULTS: Seventy-two consecutive patients underwent reoperation for persistent (17) or recurrent (55) PTC. Of the 17 patients with persistent PTC, reoperation was judged to have been possibly preventable in 14 (82%) due to inadequate preoperative imaging or incomplete initial surgery. Of the 55 patients with recurrent PTC, reoperation was judged to have been possibly preventable due to incomplete initial surgery in 14 (25%). Based on the National Comprehensive Cancer Network guidelines, 33 (46%) of 72 patients with persistent or recurrent PTC received inadequate initial local treatment. CONCLUSIONS: Reoperation in 28 (39%) of 72 patients with persistent or recurrent PTC was potentially preventable. Accurate preoperative staging and adherence to the suggested National Comprehensive Cancer Network treatment guidelines may minimize the need for cervical reoperation.

Adenocarcinoma, Papillary↗

PubMed2003

Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1).

The Jun activation domain-binding protein 1 (JAB1), aside from being an activator protein 1 coactivator, is involved in degradation of the cyclin-dependent kinase inhibitor p27. We examined JAB1 and p27 protein expression in invasive breast carcinoma specimens and the association of this expression with clinical outcome. JAB1 was detected immunohistochemically in 43 of 53 (81%) tumors; 32 (60%) breast carcinomas showed high JAB1 expression (>50% of cells positive) and reduced or absent p27 levels (P = 0.02, Mann-Whitney U test). Tumors with high p27 expression were rarely positive for JAB1. All eight patients with JAB1-negative tumors had no evidence of relapse or disease progression at a median follow-up of 70 months. Immunoblotting showed strong JAB1 expression in breast carcinoma samples but not in paired normal breast epithelial samples. Targeted overexpression of JAB1 by regulated adenovirus in breast cancer cell lines also reduced p27 levels by accelerating degradation of p27. Thus, the JAB1:p27 ratio may be a novel indicator of aggressive, high-grade tumor behavior, and control of JAB1 could be a novel target for experimental therapies.

Adenoviridae↗

PubMed2003

Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer.

BACKGROUND: Cervical recurrence occurs in up to 30% of patients with differentiated thyroid carcinoma. We retrospectively compared preoperative transcutaneous ultrasonography and physical examination (PE) results in the detection of local-regional metastases (lymph node and soft tissue) in patients with thyroid cancer. METHODS: Data were collected retrospectively from the medical records of patients with thyroid carcinoma who underwent preoperative ultrasonography. Patients were divided into 3 groups: group 1, those undergoing primary thyroid/neck surgery; group 2, those undergoing reoperation for persistent disease; and group 3, those undergoing reoperation for recurrent thyroid carcinoma. For each group, we recorded the frequencies with which ultrasonography detected disease in a neck compartment (central or lateral) that was normal on PE. RESULTS: Two hundred twelve patients underwent operation for primary, persistent, or recurrent papillary (n=130), medullary (n=61), or follicular/Hürthle cell (n=21) carcinoma. Ultrasonography detected additional sites of metastatic disease not appreciated on PE in 21 (20%) of 107 group 1 patients, 9 (32%) of 28 group 2 patients, and 52 (68%) of 77 group 3 patients. The surgical procedure performed was altered by the information obtained from preoperative ultrasonography in 82 (39%) of the 212 patients. Of the 107 group 1 patients, cervical recurrence has been detected in only 6 (6%) at a median follow-up of 36 months, in spite of 67 (63%) having tumors larger than 2 cm or lymph node metastases. CONCLUSIONS: Preoperative high-quality ultrasonography detected lymph node or soft-tissue metastases in neck compartments believed to be uninvolved by PE in 39% of patients. Ultrasound findings altered the operative procedure in these patients, facilitating complete resection of disease and potentially minimizing local-regional recurrence.

Adenocarcinoma↗

PubMed2002

Genotype-phenotype analysis in multiple endocrine neoplasia type 1.

HYPOTHESIS: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is an autosomal dominant disorder caused by germline mutations in the MEN1 gene and characterized by multiple endocrine tumors, most notably in the parathyroid glands, pituitary, and pancreas. The syndrome demonstrates variable expressivity and considerable genetic heterogeneity. Patient data were examined for possible associations between genotype and phenotype. DESIGN: We reviewed recorded medical data from 1975 to 2001 on patients with MEN 1 and compared specific types and locations of MEN1 gene mutations with manifestations of the syndrome. PATIENTS AND RESULTS: We identified 109 affected patients from 24 MEN 1 kindreds. The phenotypic expression of MEN 1 in affected individuals included hyperparathyroidism in 74%, pancreatic endocrine tumors in 51%, and pituitary tumors in 35%. Twelve of 14 insulinomas occurred in patients with pituitary tumors. Mutation analysis was completed in 14 of 24 kindreds (80 of the 109 patients). Mutations were most common in exons 2 (31%), 9 (15%), and 10 (23%). All 21 patients with frameshift mutations (and known pancreatic endocrine tumor status) had such tumors. Pituitary tumors were associated with frameshift mutations in exon 2. CONCLUSIONS: The type and location of MEN1 mutations may be associated with the phenotypic expression of specific tumors. Such information may assist in the genetic counseling and surveillance of at-risk patients. A specific genotype-phenotype correlation is unlikely because of the heterogeneity of the mutations in the MEN1 gene.

Adult↗