scholarly journals Absent p53 Immunohistochemical Staining in a Pituitary Carcinoma

2001 ◽  
Vol 28 (2) ◽  
pp. 174-178 ◽  
Author(s):  
Krishna Kumar ◽  
Robert J.B. Macaulay ◽  
Michael Kelly ◽  
Tyler Pirlot
Keyword(s):  
Pituitary Adenoma ◽  
Chromogranin A ◽  
P53 Protein ◽  
Pituitary Hormones ◽  
Pituitary Carcinoma ◽  
Nuclear Accumulation ◽  
Protein Accumulation ◽  
Pituitary Neoplasms ◽  
Null Cell ◽  
Cranial Nerve Palsies

ABSTRACT:Background:Carcinomatous transformation of pituitary adenomas is uncommon, and is generally accompanied by nuclear accumulation of p53 protein. Pituitary carcinoma lacking accumulation of p53 protein is very rare, only two such cases being previously reported.Methods:A patient presented with visual disturbance and cranial nerve palsies and was found to have a suprasellar mass. He underwent both transphenoidal and transfrontal excision of a nonfunctioning pituitary adenoma which recurred several times. The third recurrence was accompanied by multiple dural-based metastases. Despite aggressive surgical management, he continued to develop additional intracranial lesions and died two years after the discovery of metastatic disease. Specimens from 1984, 1995, 1997 and 1998 were available for histological and immunocytochemical analysis. Antibodies recognizing the pituitary hormones (ACTH, PRL, GH, FSH, LH and TSH), as well as cytokeratin, epithelial membrane antigen (EMA), glial fibrillary acidic protein (GFAP) and chromogranin A were applied to investigate the lineage of the neoplasm. Antisera specific for Ki-67 (MIB-1) and p53 protein were also applied to further delineate the biology of the tumour.Results:Although cytokeratin and chromogranin A were detected in neoplastic cells, no expression of pituitary hormones was demonstrable, indicative of a nonfunctioning, null-cell pituitary adenoma. Nuclear pleomorphism and mitotic activity increased with subsequent resections. Abnormal accumulation of p53 protein was not observed, neither in early resections nor in the metastatic deposits.Conclusions:Failure to demonstrate p53 protein accumulation does not ensure a favourable outcome for pituitary adenoma. Accordingly, pituitary carcinoma may occur in the absence of p53 accumulation. The factors which underlie aggressive behaviour of pituitary neoplasms are uncertain but are under investigation.

scholarly journals Steroidogenic Factor 1, Pit-1, and Adrenocorticotropic Hormone: A Rational Starting Place for the Immunohistochemical Characterization of Pituitary Adenoma

2016 ◽  
Vol 141 (1) ◽  
pp. 104-112 ◽  
Author(s):  
William C. McDonald ◽  
Nilanjana Banerji ◽  
Kelsey N. McDonald ◽  
Bridget Ho ◽  
Virgilia Macias ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Gold Standard ◽  
Anterior Pituitary ◽  
Adrenocorticotropic Hormone ◽  
Pituitary Hormones ◽  
Ease Of Use ◽  
Null Cell ◽  
Steroidogenic Factor 1 ◽  
Α Subunit ◽  
Anterior Pituitary Hormones

Context.—Pituitary adenoma classification is complex, and diagnostic strategies vary greatly from laboratory to laboratory. No optimal diagnostic algorithm has been defined. Objective.—To develop a panel of immunohistochemical (IHC) stains that provides the optimal combination of cost, accuracy, and ease of use. Design.—We examined 136 pituitary adenomas with stains of steroidogenic factor 1 (SF-1), Pit-1, anterior pituitary hormones, cytokeratin CAM5.2, and α subunit of human chorionic gonadotropin. Immunohistochemical staining was scored using the Allred system. Adenomas were assigned to a gold standard class based on IHC results and available clinical and serologic information. Correlation and cluster analyses were used to develop an algorithm for parsimoniously classifying adenomas. Results.—The algorithm entailed a 1- or 2-step process: (1) a screening step consisting of IHC stains for SF-1, Pit-1, and adrenocorticotropic hormone; and (2) when screening IHC pattern and clinical history were not clearly gonadotrophic (SF-1 positive only), corticotrophic (adrenocorticotropic hormone positive only), or IHC null cell (negative-screening IHC), we subsequently used IHC for prolactin, growth hormone, thyroid-stimulating hormone, and cytokeratin CAM5.2. Conclusions.—Comparison between diagnoses generated by our algorithm and the gold standard diagnoses showed excellent agreement. When compared with a commonly used panel using 6 IHC for anterior pituitary hormones plus IHC for a low-molecular-weight cytokeratin in certain tumors, our algorithm uses approximately one-third fewer IHC stains and detects gonadotroph adenomas with greater sensitivity.

Prognostic Value of p53 for Local Failure in Mastectomy-Treated Breast Cancer Patients

2000 ◽  
Vol 18 (9) ◽  
pp. 1906-1913 ◽  
Author(s):  
R.C. Zellars ◽  
S.G. Hilsenbeck ◽  
G.M. Clark ◽  
D.C. Allred ◽  
T.S. Herman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
P53 Protein ◽  
Local Relapse ◽  
Nodal Status ◽  
Local Failure ◽  
Nuclear Accumulation ◽  
Protein Accumulation ◽  
Breast Cancer Patients ◽  
Increased Risk

PURPOSE: The loss of p53 function is a recognized adverse prognostic factor in invasive breast cancer. Several studies have shown a relationship between the nuclear accumulation of p53 protein (a surrogate marker of p53 inactivation) and poor disease-free and overall survival. In general, however, these studies did not report the prognostic value of p53 for local failure, which we have therefore assessed retrospectively here. MATERIALS AND METHODS: Accumulation of p53 protein was evaluated by immunohistochemistry in 1,530 mastectomy-treated breast cancer patients (259 radiation therapy [RT]– and 1,271 mastectomy only [No RT]–treated patients). Statistical comparisons were made between p53 protein accumulation, estrogen/progesterone receptors, nodal status, tumor size, and local failure rate (LFR). Local failure was defined as tumor recurrence involving the chest wall and/or the ipsilateral supraclavicular/axillary lymph nodes. The median follow-up period was 62 months. RESULTS: In the No RT group, the LFR was 9.1% and 16.5% in p53-negative and p53-positive patients, respectively (P < .001). Multivariate analysis revealed that p53 protein accumulation was significantly associated with an increased risk of local relapse (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2 to 2.4). Nodal status and tumor size were also significant factors. In the RT group, the LFR was 9.3% and 21.5% in p53-negative and p53-positive patients, respectively (P = .009). Multivariate analysis revealed that p53 protein accumulation was significantly associated with an increased risk of local relapse (RR, 2.5; 95% CI, 1.1 to 5.7), as was nodal status. CONCLUSION: Nuclear accumulation of p53 protein is independently associated with a significantly increased local failure rate in breast cancer patients treated with mastectomy, with or without radiation.

scholarly journals p53-dependent and p53-independent activation of apoptosis in mammary epithelial cells reveals a survival function of EGF and insulin.

1995 ◽  
Vol 128 (6) ◽  
pp. 1185-1196 ◽  
Author(s):  
G R Merlo ◽  
F Basolo ◽  
L Fiore ◽  
L Duboc ◽  
N E Hynes
Keyword(s):  
Mammary Epithelial Cells ◽  
P53 Protein ◽  
Survival Function ◽  
Mammary Epithelial ◽  
Nuclear Accumulation ◽  
Temperature Sensitive ◽  
Dna Damaging Agents ◽  
A Cells ◽  
Hc11 Cells ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein has been implicated as a mediator of programmed cell death (PCD). A series of nontransformed mammary epithelial cell (MEC) lines were used to correlate p53 function with activation of PCD. Treatment of MECs expressing mutant, inactive, or no p53 with DNA-damaging agents did not induce apoptosis. Upon introduction of temperature-sensitive p53 into HC11 cells, which lack wild-type (wt) p53, PCD was observed after mitomycin treatment at 32 degrees, when the ts p53 protein is in wt conformation. Thus, wt p53 mediates activation of PCD in response to mitomycin in HC11 cells. Treatment of the MCF10-A cells, which express wt p53, with various DNA-damaging agents led to nuclear accumulation of p53. Only mitomycin treatment led to an increase in the number of apoptotic nuclei. ErbB-2-transformed MCF10-A cells responded to mitomycin, cisplatin, and 5-Fl-uracil, suggesting that signaling from activated ErbB-2 enhances the cells ability to respond to DNA damage. A combination of high cell density and serum-free medium induces apoptosis in all MECs tested, irrespective of their p53 status. Under these conditions, EGF or insulin act as survival factors in preventing PCD. These data might elucidate some aspects of breast involution and tumorigenesis.

scholarly journals Requirement of ATM in Phosphorylation of the Human p53 Protein at Serine 15 following DNA Double-Strand Breaks

1999 ◽  
Vol 19 (4) ◽  
pp. 2828-2834 ◽  
Author(s):  
Kazumi Nakagawa ◽  
Yoichi Taya ◽  
Katsuyuki Tamai ◽  
Masaru Yamaizumi
Keyword(s):  
Heat Shock ◽  
Ataxia Telangiectasia ◽  
Xeroderma Pigmentosum ◽  
P53 Protein ◽  
Double Strand Breaks ◽  
Nuclear Accumulation ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Absolute Requirement ◽  
Primary Fibroblasts

ABSTRACT Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.

scholarly journals Chronology of p53 protein accumulation in gastric carcinogenesis.

Gut ◽  
1995 ◽  
Vol 36 (6) ◽  
pp. 848-852 ◽  
Author(s):  
M E Craanen ◽  
P Blok ◽  
W Dekker ◽  
G J Offerhaus ◽  
G N Tytgat
Keyword(s):  
P53 Protein ◽  
Gastric Carcinogenesis ◽  
Protein Accumulation

scholarly journals An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3174 ◽  
Author(s):  
Xin Xue ◽  
Gang Bao ◽  
Hai-Qing Zhang ◽  
Ning-Yi Zhao ◽  
Yuan Sun ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Drug Target ◽  
P53 Protein ◽  
Pharmacophore Model ◽  
Cellular Level ◽  
Complex Structures ◽  
Ligand Complex ◽  
Null Cell ◽  
Protein Protein Interaction ◽  
First Time

: The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of Ki from 102 to 103 nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs.

scholarly journals Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab

2018 ◽  
Vol 103 (10) ◽  
pp. 3925-3930 ◽  
Author(s):  
Andrew L Lin ◽  
Philip Jonsson ◽  
Viviane Tabar ◽  
T Jonathan Yang ◽  
John Cuaron ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Liver Metastasis ◽  
Effective Treatment ◽  
Somatic Hypermutation ◽  
Treatment Options ◽  
Pituitary Tumors ◽  
Pituitary Carcinoma ◽  
Tumor Resistance ◽  
Clinical Sequencing ◽  
Acth Secreting

Abstract Context Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. Case A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Molecular Evaluation Both prospective clinical sequencing with Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. Conclusion Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

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