p63
, a member of the
p53
gene family, encodes multiple proteins that may either transactivate
p53
responsive genes (TAp63) or act as a dominant-negative factor toward
p53
and
p73
(ΔNp63). p63 is ...expressed in many epithelial compartments and
p63
−/− mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that p63 is expressed in normal urothelium. This study reports that p63 is regulated in bladder carcinogenesis and that p63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain p63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of ΔNp63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that
p63
−/− mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, p63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium.
Background We found that a computer model developed by the American Joint Committee on Cancer (AJCC) melanoma staging committee had limitations for predicting prognosis of patients staged by sentinel ...lymph node (SLN) biopsy. We sought to develop a model that more accurately predicts prognosis in this population. Study Design Using a data set obtained from a prospective multi-institutional study of 2,507 patients with clinically node-negative melanomas ≥1.0 mm Breslow thickness, we developed a prognostic model using a Cox regression formula incorporating a number of significant clinicopathologic factors. The AJCC model and our model were used to predict 5-year survival from this test data set. The concordance correlation coefficient (CCC) was determined and chi-square tests were performed. Our new prognostic model was validated using an independent data set of 1,001 patients. Results Using the test data set, the CCC for the AJCC model was 0.875; chi-square tests demonstrated statistically significant differences between observed and predicted survivals for numerous clinicopathologic factors. The CCC for our model was 0.976 and none of the chi-square tests was statistically significant. Our model performed similarly well in SLN-negative patients (CCC 0.929) and SLN-positive patients (CCC 0.889). The AJCC model performed well in SLN-negative patients (CCC 0.854), but not in SLN-positive patients (CCC 0.626). Using the validation data set, similar findings were obtained. Conclusions Our prognostic model provides superior survival estimates compared with the AJCC model for patients undergoing SLN biopsy. This online tool is available at www.melanomacalculator.com , and will provide important information that can be used to guide adjuvant therapy decisions and stratification in clinical trials.
Basal cell and squamous cell skin cancers Miller, Stanley J; Alam, Murad; Andersen, James ...
Journal of the National Comprehensive Cancer Network,
08/2010, Volume:
8, Issue:
8
Journal Article
Cdc25C and p53 have been reported to be physiological targets of checkpoint kinase 2 (Chk2). Surprisingly, although Chk2 purified from DNA damage sustaining cells has dramatically increased ability ...to phosphorylate Cdc25C when compared with untreated cells, its ability to phosphorylate p53 is weak before treatment, and there is no increase in its activity toward p53 after DNA damage by γ irradiation or the radiomimetic agent neocarzinostatin. Furthermore, introduction of Chk2 short interfering RNA into three different human tumor cell lines leads to marked reduction of Chk2 protein, but p53 is still stabilized and active after DNA damage. The results with Chk1 short interfering RNA indicate as well that Chk1 does not play a role in human p53 stabilization after DNA damage. Thus, Chk1 and Chk2 are unlikely to be regulators of p53 in at least some human tumor cells. We discuss our results in the context of previous findings demonstrating a requirement for Chk2 in p53 stabilization and activity.
Opinion statement
Team work is the key to successful breast conservation therapy. Patient education and the informed consent process should include a discussion about the importance of margin status. ...Specimen management is critically important to obtain the highest quality information about margins. Operating technique should avoid trauma to or disruption of the specimen surface. The specimen should be oriented for the pathologist using standard techniques including sutures, clips, or colored inks. Specimen radiography is mandatory to confirm complete resection of the target tissues and can be used to direct additional margin resections during the initial procedure. With a well-designed and oriented specimen, the pathologist can give an accurate description of the margin distance for both the invasive and in situ components of the cancer. In most cases, decision-making about margins will be straightforward. Positive margins should be re-excised or the treatment is converted to mastectomy. Clear margins (>5 mm) require no further surgical therapy. “Close” margins (1–4 mm) will remain a point of controversy because of conflicting reports from clinical series. At UAB, decision for re-excision is made on a case-by-case basis. Routinely 2 mm is considered adequate, however, volume of disease and intraductal component are important considerations when making recommendations.
Merkel cell carcinoma, version 1.2014 Bichakjian, Christopher K; Olencki, Thomas; Alam, Murad ...
Journal of the National Comprehensive Cancer Network,
03/2014, Volume:
12, Issue:
3
Journal Article
Peer reviewed
Open access
Merkel cell carcinoma is a rare, aggressive cutaneous tumor that combines the local recurrence rates of infiltrative nonmelanoma skin cancer with the regional and distant metastatic rates of thick ...melanoma. The NCCN Guidelines for Merkel Cell Carcinoma provide recommendations on the diagnosis and management of this aggressive disease based on clinical evidence and expert consensus. This version includes revisions regarding the use of PET/CT imaging and the addition of a new section on the principles of pathology to provide guidance on the analysis, interpretation, and reporting of pathology results.
Background
Sentinel lymph node (SLN) biopsy for melanoma often detects minimal nodal tumor burden. Although all node-positive patients are considered stage III, there is controversy regarding the ...necessity of adjuvant therapy for all patients with tumor-positive SLN.
Methods
Post hoc analysis was performed of a prospective multi-institutional study of patients with melanoma ≥ 1.0 mm Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for patients with SLN metastasis. Kaplan–Meier analysis of disease-free survival (DFS) and overall survival (OS) was performed. Univariate and multivariate Cox regression analyses were performed. Classification and regression tree (CART) analysis also was performed.
Results
A total of 509 patients with tumor-positive SLN were evaluated. Independent risk factors for worse OS included thickness, age, gender, presence of ulceration, and tumor-positive non-SLN (nodal metastasis found on completion lymphadenectomy). As the number of tumor-positive SLN and the total number of tumor-positive nodes (SLN and non-SLN) increased, DFS and OS worsened on Kaplan–Meier analysis. On CART analysis, the 5-year OS rates ranged from 84.9 % (women with thickness < 2.1 mm, age < 59 years, no ulceration, and tumor-negative non-SLN) to 14.3 % (men with thickness ≥ 2.1 mm, age ≥ 59 years, ulceration present, and tumor-positive non-SLN). Six distinct subgroups were identified with 5-year OS in excess of 70 %.
Conclusions
Stage III melanoma in the era of SLN is associated with a very wide range of prognosis. CART analysis of prognostic factors allows discrimination of low-risk subgroups for which adjuvant therapy may not be warranted.
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