0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Detection of the Proto-oncogene eIF4E in Larynx and Hypopharynx Cancers FREE

Scott Franklin, MD; Thuy Pho; Fleurette W. Abreo, MD; Raja Nassar, PhD; Arrigo De Benedetti, PhD; Fred J. Stucker, MD; Cherie-Ann O. Nathan, MD
[+] Author Affiliations

From the Department of Otolaryngology–Head and Neck Surgery, Louisiana State University Medical Center and Veterans Administration Medical Center, Shreveport (Drs Franklin, Stucker, and Nathan and Ms Pho); Department of Mathematics and Statistics, Louisiana Tech University, Ruston (Dr Nassar); and Departments of Pathology (Dr Abreo) and Biochemistry/Molecular Biology (Dr De Benedetti), Louisiana State University Medical Center.


Arch Otolaryngol Head Neck Surg. 1999;125(2):177-182. doi:10.1001/archotol.125.2.177.
Text Size: A A A
Published online

Background  The proto-oncogene eIF4E has been found to be elevated in head and neck squamous cell carcinomas. In an earlier prospective study overexpression of eIF4E, detected by Western blot analysis, in histologically normal surgical margins correlated with an increased local-regional recurrence rate during a 1-year follow-up.

Objective  To test the reverse hypothesis that absence of overexpression of eIF4E in the surgical margins is a predictor for long-term survival in patients with squamous cell carcinoma of the head and neck.

Design  A retrospective analysis was performed on 31 patients who underwent surgery for squamous cell carcinoma of the larynx or hypopharynx. Immunohistochemical analysis was used to detect eIF4E on paraffin-embedded sections of the tumor and the histologically negative surgical margins.

Results  All 31 patients overexpressed eIF4E in the tumors. Thirteen patients had no detectable level of eIF4E in the margins, and only 1 had a local-regional recurrence. The average disease-free interval in this group of patients was 82.08 months. The remaining 18 patients all overexpressed eIF4E in the surgical margins (eIF4E score range, 5-80). Twelve (67%) of these patients developed a recurrence; the average disease-free interval was 31.95 months. Cox regression analysis showed that eIF4E in the margin (P=.01), nodes (P=.06), site (P=.02), and age (P=.02) had significant effects on the disease-free interval. The Kaplan-Meier survival curves were significantly different for eIF4E-positive and eIF4E-negative margins (P=.002).

Conclusions  eIF4E in the surgical margins is an independent prognostic factor and its absence in surgical margins may predict long-term survival. Detecting eIF4E in the margins may improve survival by determining which patients would benefit from further resection or adjuvant therapy.

Figures in this Article

THE TRANSLATION initiation factor eIF4E binds to the m7GpppX cap of messenger RNA (mRNA) in the first step of mRNA recruitment, and unwinds the secondary structure at the 5‘ untranslated region (5‘UTR) of mRNA as part of the eIF4F complex.1,2 The latter function is critical during scanning for exposing and locating the translation start site. eIF4E has recently been identified as a powerful oncogene when overexpressed in model cell lines.3,4 The oncogenic function of eIF4E is mediated in part by a specific increase in synthesis of certain growth factors, since conditioned medium from cells transformed with eIF4E is strongly mitogenic.5,6 A large translational increase of 2 powerful cytokines and angiogenic inducers: fibroblast growth factor 2 and vascular permeability factor was subsequently confirmed.5,7 Also, a reduction of eIF4E with antisense RNA in MDA-435 cells suppresses the tumorigenic and angiogenic properties, consistent with loss of fibroblast growth factor 2 synthesis.8

We recently reported in a prospective study that eIF4E protein detected by Western blot analysis was elevated in all head and neck squamous cell carcinomas (HNSCC) and not in benign lesions of the head and neck.9 Its overexpression in histologically normal surgical margins correlated with a higher rate of local recurrence. Kaplan-Meier survival curves for eIF4E-positive and eIF4E-negative margins were significantly different by the log-rank test (P=.02); however, the average length of follow-up was only 7.8 months for the patients with eIF4E-positive margins and 13.6 months for the patients with eIF4E-negative margins. We therefore performed a retrospective study to determine whether the presence or absence of eIF4E in the surgical margins of patients with HNSCC could predict patients who would have a recurrence or be disease free on a long-term follow-up of at least 5 years.

The cure rate for HNSCC is poor, primarily because of a high rate of local recurrence due to inadequate surgical resection.10,11 Tumor markers will play an important role in determining prognosis of patients.12,13 The role of tumor markers in the surgical resection margins of patients with head and neck cancer may improve the cure rate in this group of patients by determining those who would benefit from more resection at the time of surgery or by administering additional therapy in the form of postoperative radiation therapy.

STUDY POPULATION

Thirty-one previously untreated patients who underwent surgery for a HNSCC of the larynx or hypopharynx at Louisiana State University Medical Center and the Veterans Hospital in Shreveport between 1980 and 1990 were studied. If any margins on the final pathology report were positive for cancer the patient was excluded from the study. A total of 83 "histologically tumor-free" surgical margins were analyzed. Medical charts were reviewed for the following factors: age, race, tumor size, node status, primary tumor site, histological grade of the tumor, postoperative radiation therapy, disease-free interval, and recurrence status.

SAMPLES

Paraffin-embedded tissue blocks from the primary tumor and all surgical margins were obtained. One slide from each block was stained with hematoxylin-eosin and reviewed by a pathologist. All tumor slides revealed malignant cells and all slides of surgical margins showed no signs of carcinoma. A second slide was used for immunohistochemical staining.

IMMUNOHISTOCHEMICAL STAINING

Five-micrometer-thick sections from each paraffin-embedded block were cut and placed on superfrost plus slides. The slides were baked at 60°C for 1 hour, deparaffinized in xylene, and rehydrated in graded solutions of alcohol. Slides were immersed in 4% hydrogen peroxide and 60% methanol for 30 minutes to remove endogenous peroxide activity, and then permeablized in 0.1% Triton-X detergent in phosphate-buffered saline. Immunostaining was performed with 1:500 dilution of rabbit anti-eIF4E antiserum that was prepared in our laboratory.14 The slides were incubated for 1 hour with the primary antibody and then washed for 10 minutes in phosphate-buffered saline. The high-resolution streptavidin-conjugated detection system (Supersensitive Detection Kit; Biogenex, San Ramon, Calif) was used according to the manufacturer's instructions using 3-amino-9-ethylcarbazole as the chromogen. Normal epithelium from a patient with Zenker diverticulum was used as a control. Negative controls with an omission of the antiserum from the primary incubation were included.

All slides were evaluated for expression of eIF4E by light microscopy, in a blinded manner, by 2 independent investigators who were unaware of the clinical details. Immunostaining for eIF4E was evaluated in both the primary tumor slides and the margin slides. Positive staining in the primarytumor slide was defined as presence of perinuclear staining in the malignant cells. Positive staining in the margin slides was defined as the presence of perinuclear staining in the basal layer cells of the mucosal margins.

Gradation of staining depended on intensity of staining and percentage of cells staining. Scores were ranked as no staining, weak staining, intermediate staining, and strong staining. Values of 0, 100, 200, and 300 were assigned to the intensity of staining. Tumor eIF4E scores were determined by multiplying the intensity of staining value by the percentage of cells staining positive. The details of this semiquantitative method for reporting immunohistochemical assay results have been described previously.15 The eIF4E scores were similarly determined for each margin and the margin with the highest score was used for the analysis.

STATISTICAL ANALYSIS

The data on patient characteristics and surgical margins were analyzed statistically with SAS Version 6.07 software (SAS Institute, Cary, NC). Time to recurrence was calculated from surgery to the date of the first documented recurrence. Contingency tables and the χ2 test were used to evaluate the association of eIF4E in the surgical margins with tumor size, lymph node status, site, and grade. The Kaplan-Meier method and the log-rank test were used to determine the effects of eIF4E expression in the surgical margin on the time until recurrence. Cox regression analysis was used to test for the effect of each of the different variables in the study (controlling for the other covariates) on time until recurrence. The variables entered in the regression model were age, race, tumor site, tumor size, node status, histological grade of tumor, eIF4E levels in the tumor, and eIF4E levels in the surgical margin. Node status and eIF4E levels in the margins were expressed as 2 categories each (0 and 1), with 0 representing N0 status and no overexpression of eIF4E in the margins, and 1 representing N1, N2, N3 nodal status and eIF4E overexpression in the margins.

Thirty of the patients were male and 1 was female. Patients ranged in age from 49 to 82 years (mean, 63 years). Nineteen patients were white and 12 were black. Five of the tumors occurred in the hypopharynx and 26 were in the larynx. Twenty of the patients had advanced stage III or IV disease and all received postoperative radiation therapy.

eIF4E was overexpressed in the tumors of all 31 patients. The perinuclear staining was seen in the tumor cells with overexpression of eIF4E, whereas no staining was observed in adjacent normal tissues or the negative control obtained from a smoker with a Zenker diverticulum. The perinuclear staining of a tumor is well depicted in Figure 1, B. Figure 1, A, is a hematoxylin-eosin section of the same tumor. The average eIF4E score for a tumor was 181. However, heterogenity of staining in the tumor was noted. Tumors that incited a desmoplastic response stained more intensely for eIF4E.

Place holder to copy figure label and caption
Figure 1.

Immunohistochemical staining of eIF4E in squamous cell carcinomas and surgical margins of the larynx. A, Squamous cell carcinoma (hematoxylin-eosin, ×20); B, squamous cell carcinoma with intense reddish brown perinuclear staining (anti-eIF4E stain, ×20); C, histologically normal surgical margin in a patient without recurrence (hematoxylin-eosin, ×20); D, histologically normal margin, no recurrence (anti-eIF4E stain, ×40)—note no staining in the basal cell layer; E, histologically normal surgical margin in a patient with a recurrence (hematoxylin-eosin, ×40); and F, histologically normal surgical margin in a patient with a recurrence showing reddish-brown perinuclear staining of the basal layer (anti-eIF4E stain, ×40).

Graphic Jump Location

A total of 83 margins were examined for the 31 patients (average number of margins per patient was 2.7). All surgical margins were histologically negative for tumor. Thirteen patients had no expression of eIF4E in the basal cell layer of the surgical margins (Figure 1, C and D) while 18 patients had at least 1 surgical margin overexpress eIF4E (Figure 1, E and F). A comparison of both groups is shown in Table 1. In the eIF4E-negative group, the average disease-free interval was 82.02 months and only 1 patient (8%) experienced a local recurrence. The average eIF4E tumor score was 140 and the surgical margin score was 0, as no detectable level of eIF4E was seen in the basal cell layer. In the eIF4E-positive group, the average disease-free interval was 31.95 months and 12 (67%) of the 18 patients had a recurrence. There were 4 local and 8 regional recurrences. The average eIF4E tumor score for this group was 211 and the average surgical margin score was 20.83.

Table Graphic Jump LocationTable 1. Histologically Negative Surgical Margins

The Cox regression analysis indicated that eIF4E in the surgical margin (P=.01), nodal status (P=.06), site (P=.02), and age (P=.02) had significant effects on time until recurrence. Nodal status (positive or negative), although not significant at the 5% level, was declared significant since the P value was close to .05. Table 2 presents the outcome of this analysis. It is seen from the risk ratio column that the hazard of recurrence for a patient with eIF4E in the margin was 5.94 times that of a patient with no eIF4E expression provided that the 2 patients were alike with regard to the other variables in Table 2. 1 Similarly, the hazard of recurrence for positive node status was 3.34 times that for negative node status. Also, the hazard of recurrence for hypopharynx tumor was 4.9 times that for tumors of the larynx. In the case of age, for each 1-year increase in age, the hazard of recurrence increased by an estimated 9.8%.

Table Graphic Jump LocationTable 2. Maximum Likelihood Estimates and Risk Ratios From Cox Regression Analysis

The Kaplan-Meier method using the log-rank test showed that the estimated probability of no recurrence at a given time in months for eIF4E- positive and eIF4E-negative margins were significantly different (P=.002). These are presented in Figure 2.

Place holder to copy figure label and caption
Figure 2.

Kaplan-Meier curves showing probability of having no local recurrence based on eIF4E expression in surgical margins.

Graphic Jump Location

Figure 3 presents comparisons of the probability of no recurrence for the 4 categories (eIF4E-positive and eIF4E-negative margins with positive and negative nodal status).The log-rank test indicates that the probability curves were heterogeneous (P<.001). The eIF4E-positive margin and positive node class gave the smallest probability estimates. The contingency χ2 analysis was performed to determine whether eIF4E in the margins was associated with tumor size, nodal status, site, grade, or postoperative radiation. The analysis showed that only eIF4E in the margins and postoperative radiation were associated (P=.047).

Place holder to copy figure label and caption
Figure 3.

Comparisons of probability of no recurrence for the 4 groups, ie, eIF4E-positive (4E+) and eIF4E-negative (4E−) margins with positive (N+) and negative (N0) nodal status.

Graphic Jump Location

Research in head and neck cancer has recently focused on the role of 2 types of genes involved in the regulation of the cell cycle: proto-oncogenes and tumor-suppressor genes. The p53 tumor suppressor gene is one of the most common genetic alterations in HNSCC.1618 Sixty percent of primary SCC of the larynx displayed nuclear p53 overexpression as revealed by immunostaining with monoclonal antibody.19 Detection of p53 mutations in histologically negative surgical resection margins was found to predict local recurrence.20,21 However, not all SCC tumors are p53-positive; hence, the incidence of detecting positive margins with p53 would be even less.19,22 The proto-oncogene eIF4E is elevated in all HNSCC analyzed by Western blot and not in benign lesions that show normal levels of expression, making eIF4E a useful tumor marker.9

In this study we used immunohistochemistry to assess eIF4E expression in the specimens. Immunohistochemical staining has advantages over Western blots. Histological correlation can be obtained and it has the potential for use during surgery as an adjunct to standard hematoxylin-eosin stains. Consistently elevated expression of eIF4E was detected in all 31 tumors analyzed. The average score of eIF4E in tumors of patients who had a recurrence was 216, while patients without a recurrence had an average eIF4E tumor score of 156. However, the colorimetric staining in the tumor plateaus out because of a saturation effect. Therefore, a more accurate and objective method of quantitating levels in the tumor would be Western blot analysis or immunofluorescence, a technique that continues to be optimized. The immunohistochemistry method did allow easy detection and quantitation of the surgical margins due to the normal absence of eIF4E in the basal layer of the margins. Tumors that incited a strong desmoplastic response stained more intensely than the nondesmoplastic tumors. eIF4E plays a role in tumor angiogenesis through formation of stromal elements and this may explain why tumors that incite a desmoplastic response have a higher expression of eIF4E. It may be that eIF4E causes a higher stromal response to recruit elements to cause increased vascularization. eIF4E has been shown to play a role in tumor progression by inciting tumor angiogenesis through the translational increase of both fibroblast growth factor 2 and vascular permeability factor.8

Immunohistochemical staining of normal mucosa from the head and neck using Zenker diverticulum and mucosa from the soft palate of a patient who underwent an uvulopalatopharyngolasty showed that eIF4E staining was absent in the basal germinative layer of the epithelium. There appeared to be nonspecific diffuse staining of the superficial layers. The basal layers of the histologically negative surgical margins did not show any perinuclear staining for eIF4E. However, the histologically negative surgical margins that did stain positive for eIF4E in the basal layers of the mucosa correlated with local-regional recurrence. It is interesting that eIF4E was not elevated in the basal cell layer, which is the germinative layer of the mucosa, showing that eIF4E is not simply a marker for proliferating cells. Some margins displayed atypia. However, only a few stained positive for eIF4E, and, again, these were in the patients who developed a recurrence. Hence, it was not morphologic changes such as dysplasia, but rather eIF4E positivity, that was an important factor in determining recurrence, suggesting that cancer cells may be missed when they appear normal or that eIF4E overexpression may denote a very early step in malignant transformation.

Head and neck surgeons rely on the standard histopathological assessment of surgical margins to ensure total excision of the tumor. There is a high rate of local recurrence in HNSCC, occurring in up to 50% of patients with microscopically negative surgical margins.2325 Current techniques may not detect small numbers of cancer cells at the margins of resection or cells that may promote the process of tumorigenesis by inciting stromal elements and vascular endothelia required for tumor progression. The failure rate in the treatment of HNSCC is based largely on local recurrence from inadequate resection. The process of malignant transformation begins at the molecular level prior to any phenotypic abnormalities. The ability to detect these molecular changes at the time of surgery may aid in more complete resection, thus decreasing local recurrence rates.

The Cox regression analysis showed that eIF4E-positive margins (controlling for the other variables) significantly increased the risk of recurrence. Node status alone was marginal in significance. The most striking observation was the high probability of recurrence for an individual patient with the combination of eIF4E-positive margin status and lymph node metastases (Figure 3). Differences among the other 3 curves in Figure 3 may not be as meaningful because of the small number of observations (ranging from 3 to 10) within each of the 4 classes.

To our knowledge, this is the first study in which immunohistochemistry has been used to correlate recurrence with overexpression of eIF4E in tumors and surgical margins of head and neck cancers. Somewhere in the multistep process of tumorigenesis, elevation of eIF4E is a necessary event in the progression of solid tumors. The ability to detect this progression at the molecular level in the surgical margins of patients with HNSCC may allow improved survival in these patients by decreasing the local recurrence rate. This will enable improved treatment outcomes by further resection during surgery or including adjuvant postoperative therapy.

Accepted for publication July 16, 1998.

This work was supported by a research training grant from the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc, Alexandria, Va (Dr Nathan).

Presented at the joint annual meeting of the American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons, Palm Beach, Fla, May 15, 1998.

Reprints: Cherie-Ann Nathan, MD, Department of Otolaryngology–Head and Neck Surgery, LSU Medical Center, 1501 Kings Hwy, PO Box 33932, Shreveport, LA 71130 (e-mail: cnatha@lsumc.edu).

Sonenberg  N mRNA 5′ cap-binding protein eIF4E and control of cell growth. Translational Control. Plainville, NY Cold Springs Harbor Laboratory Press1996;245- 269
Shantz  LPegg  A Overproduction of omithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res. 1994;542313- 2316
Lazaris-Karatzas  AMontine  KSonenberg  N Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature. 1990;345544- 546
Link to Article
De Benedetti  ARhoads  RE Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology. Proc Natl Acad Sci U S A. 1990;878212- 8216
Link to Article
Kevil  CCarter  PHu  BDe Benedetti  A Translational enhancement of FGF-2 by eIF4E factors and alternate utilization of CUG and AUG codons for translational initiation. Oncogene. 1995;112339- 2348
Koromilas  ALararis-Karatzas  ASonenberg  N mRNAs containing extensive secondary structure in their 5‘ non-coding region translate efficiently in cells overexpressing initiation factor eIF4E. EMBO. 1992;114153- 4158
Kevil  CDe Benedetti  APayne  DCoe  LLaroux  SAlexander  J Translation regulation of vascular permeability factor by eukaryotic initiation factor 4E: implications for tumor angiogenesis. Int J Cancer. 1996;65785- 790
Link to Article
Nathan  COCarter  PLiu  L  et al.  Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas. Oncogene. 1997;151087- 1094
Link to Article
Nathan  COLiu  LLi  BAbreo  FNandy  IDe Benedetti  A Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer. Oncogene. 1997;15579- 584
Link to Article
Gilbert  HKagan  R Recurrence patterns in squamous cell carcinoma of the oral cavity, pharynx, and larynx. J Surg Oncol. 1974;6357- 380
Link to Article
Looser  KShah  JStrong  E The significance of "positive" margins in surgically resected epidermoid carcinomas. Head Neck. 1978;1107- 111
Link to Article
Caminero  MNunez  FSuarez  CAblanedo  PRiera  JDominguez  F Detection of p53 protein in oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1996;122769- 772
Link to Article
Michalides  Rvan Veelen  NKristel  P  et al.  Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1997;123497- 502
Link to Article
Kerekatte  VSmiley  KHu  B  et al.  The proto-oncogene/translation factor eIF4E: a survey of its expression in breast carcinomas. Int J Cancer. 1995;6427- 31
Link to Article
Pavelic  ZPavelic  KCarter  CPavelic  L Heterogenity of c-myc expression in histologically similar infiltrating ductal carcinomas of the breast. J Cancer Res Clin Oncol. 1992;11816- 22
Link to Article
Nees  MHomann  NDischer  H  et al.  Expression of mutated p53 occurs in tumor-distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors. Cancer Res. 1993;534189- 4196
Dolcetti  RDoglioni  CMaestro  R  et al.  p53 over-expression is an early event in the development of human squamous cell carcinoma of the larynx: genetic and prognostic implications. Int J Cancer. 1990;52178- 182
Link to Article
Somers  KDMerrick  MLopez  M  et al.  Frequent p53 mutations in head and neck cancer. Cancer Res. 1992;525997- 6000
Maestro  RDolcetti  DGasparotto  C  et al.  High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. Oncogene. 1992;71159- 1166
Brennan  JMao  LHruban  R  et al.  Molecular assessment of histopathological staging in squamous cell carcinoma of the head and neck. N Engl J Med. 1995;332429- 435
Link to Article
Ball  VRight  PTejada  ERadpour  S p53 immunostaining of surgical margins as a predictor of local recurrence in squamous cell carcinoma of the oral cavity and oropharynx. Ear Nose Throat J. 1997;76818- 823
Field  JSpandidos  DMalliri  A  et al.  Elevated p53 expression with a history of heavy smoking in squamous cell carcinoma of the head and neck. Br J Cancer. 1991;64573- 577
Link to Article
Jesse  RSugarbaker  E Squamous cell carcinoma of the oropharynx: why we fail. Am J Surg. 1976;132435- 438
Link to Article
Kowalski  LMargrin  JWaksman  G  et al.  Supraomohyoid neck dissection in the treatment of head and neck tumors: survival results in 212 cases. Arch Otolaryngol Head Neck Surg. 1993;119958- 963
Link to Article
Davidson  TNahum  AAstarita  R Microscopic controlled excisions for epidermoid carcinoma of the head and neck. Otolaryngol Head Neck Surg. 1981;89244- 251

Figures

Place holder to copy figure label and caption
Figure 1.

Immunohistochemical staining of eIF4E in squamous cell carcinomas and surgical margins of the larynx. A, Squamous cell carcinoma (hematoxylin-eosin, ×20); B, squamous cell carcinoma with intense reddish brown perinuclear staining (anti-eIF4E stain, ×20); C, histologically normal surgical margin in a patient without recurrence (hematoxylin-eosin, ×20); D, histologically normal margin, no recurrence (anti-eIF4E stain, ×40)—note no staining in the basal cell layer; E, histologically normal surgical margin in a patient with a recurrence (hematoxylin-eosin, ×40); and F, histologically normal surgical margin in a patient with a recurrence showing reddish-brown perinuclear staining of the basal layer (anti-eIF4E stain, ×40).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Kaplan-Meier curves showing probability of having no local recurrence based on eIF4E expression in surgical margins.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Comparisons of probability of no recurrence for the 4 groups, ie, eIF4E-positive (4E+) and eIF4E-negative (4E−) margins with positive (N+) and negative (N0) nodal status.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Histologically Negative Surgical Margins
Table Graphic Jump LocationTable 2. Maximum Likelihood Estimates and Risk Ratios From Cox Regression Analysis

References

Sonenberg  N mRNA 5′ cap-binding protein eIF4E and control of cell growth. Translational Control. Plainville, NY Cold Springs Harbor Laboratory Press1996;245- 269
Shantz  LPegg  A Overproduction of omithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res. 1994;542313- 2316
Lazaris-Karatzas  AMontine  KSonenberg  N Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature. 1990;345544- 546
Link to Article
De Benedetti  ARhoads  RE Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology. Proc Natl Acad Sci U S A. 1990;878212- 8216
Link to Article
Kevil  CCarter  PHu  BDe Benedetti  A Translational enhancement of FGF-2 by eIF4E factors and alternate utilization of CUG and AUG codons for translational initiation. Oncogene. 1995;112339- 2348
Koromilas  ALararis-Karatzas  ASonenberg  N mRNAs containing extensive secondary structure in their 5‘ non-coding region translate efficiently in cells overexpressing initiation factor eIF4E. EMBO. 1992;114153- 4158
Kevil  CDe Benedetti  APayne  DCoe  LLaroux  SAlexander  J Translation regulation of vascular permeability factor by eukaryotic initiation factor 4E: implications for tumor angiogenesis. Int J Cancer. 1996;65785- 790
Link to Article
Nathan  COCarter  PLiu  L  et al.  Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas. Oncogene. 1997;151087- 1094
Link to Article
Nathan  COLiu  LLi  BAbreo  FNandy  IDe Benedetti  A Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer. Oncogene. 1997;15579- 584
Link to Article
Gilbert  HKagan  R Recurrence patterns in squamous cell carcinoma of the oral cavity, pharynx, and larynx. J Surg Oncol. 1974;6357- 380
Link to Article
Looser  KShah  JStrong  E The significance of "positive" margins in surgically resected epidermoid carcinomas. Head Neck. 1978;1107- 111
Link to Article
Caminero  MNunez  FSuarez  CAblanedo  PRiera  JDominguez  F Detection of p53 protein in oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1996;122769- 772
Link to Article
Michalides  Rvan Veelen  NKristel  P  et al.  Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1997;123497- 502
Link to Article
Kerekatte  VSmiley  KHu  B  et al.  The proto-oncogene/translation factor eIF4E: a survey of its expression in breast carcinomas. Int J Cancer. 1995;6427- 31
Link to Article
Pavelic  ZPavelic  KCarter  CPavelic  L Heterogenity of c-myc expression in histologically similar infiltrating ductal carcinomas of the breast. J Cancer Res Clin Oncol. 1992;11816- 22
Link to Article
Nees  MHomann  NDischer  H  et al.  Expression of mutated p53 occurs in tumor-distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors. Cancer Res. 1993;534189- 4196
Dolcetti  RDoglioni  CMaestro  R  et al.  p53 over-expression is an early event in the development of human squamous cell carcinoma of the larynx: genetic and prognostic implications. Int J Cancer. 1990;52178- 182
Link to Article
Somers  KDMerrick  MLopez  M  et al.  Frequent p53 mutations in head and neck cancer. Cancer Res. 1992;525997- 6000
Maestro  RDolcetti  DGasparotto  C  et al.  High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. Oncogene. 1992;71159- 1166
Brennan  JMao  LHruban  R  et al.  Molecular assessment of histopathological staging in squamous cell carcinoma of the head and neck. N Engl J Med. 1995;332429- 435
Link to Article
Ball  VRight  PTejada  ERadpour  S p53 immunostaining of surgical margins as a predictor of local recurrence in squamous cell carcinoma of the oral cavity and oropharynx. Ear Nose Throat J. 1997;76818- 823
Field  JSpandidos  DMalliri  A  et al.  Elevated p53 expression with a history of heavy smoking in squamous cell carcinoma of the head and neck. Br J Cancer. 1991;64573- 577
Link to Article
Jesse  RSugarbaker  E Squamous cell carcinoma of the oropharynx: why we fail. Am J Surg. 1976;132435- 438
Link to Article
Kowalski  LMargrin  JWaksman  G  et al.  Supraomohyoid neck dissection in the treatment of head and neck tumors: survival results in 212 cases. Arch Otolaryngol Head Neck Surg. 1993;119958- 963
Link to Article
Davidson  TNahum  AAstarita  R Microscopic controlled excisions for epidermoid carcinoma of the head and neck. Otolaryngol Head Neck Surg. 1981;89244- 251

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 36

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles