Cherie Ann O Nathan

Cancer-specific targeting of an adenovirus-delivered herpes simplex virus thymidine kinase suicide gene using translational control.

Two technical hurdles, gene delivery and target specificity, have hindered the development of effective cancer gene therapies. In order to circumvent the problem of tumor specificity, the suicide gene, HSV‐1 thymidine kinase (HSV‐Tk), was modified with a complex 5′ upstream‐untranslated region (5′‐UTR) that limits efficient translation to cells expressing high levels of the translation initiation factor, eIF4E. Since previous studies have shown that most tumor cells express elevated levels of eIF4E, tumor‐specific gene delivery was optimized by incorporation of the 5′‐UTR‐modified suicide gene (HSV‐UTk) into an adenovirus vector (Ad‐CMV‐UTk). The efficacy of this novel approach of targeting suicide gene expression and limiting cytotoxicity by means of translational restriction was tested in vitro with the use of the human breast cancer cell lines (MCF‐7, MDA‐MB435, and ZR‐75‐1). As controls, normal MCF10A, HMEC, and HMSC cell lines that express relatively low levels of eIF4E were used. Real‐time reverse‐transcription polymerase chain reaction (RT‐PCR) was used to quantify HSV‐Tk mRNA for cells infected with Ad‐CMV‐UTk as well as with Ad‐CMV‐Tk (a control adenovirus in which HSV‐Tk is not regulated at the level of translation). Translation of HSV‐Tk in the Ad‐infected cells was measured by Western blot analysis. In addition, cytotoxicity was determined following treatment with the pro‐drug ganciclovir (GCV) using an MTT viability assay. Finally, microPET imaging was used to assess cancer cell‐specific expression of HSV‐Tk and expression in normal tissues in vivo after intraperitoneal injection of Ad‐CMV‐Tk or Ad‐CMV‐UTk. These data collectively showed enhanced cancer cell‐specific gene expression and reduced normal tissue gene expression for the Ad‐HSV‐UTk compared to the Ad‐CMV‐Tk, leading to increased cancer cell‐enhanced GCV cytotoxicity. These results indicate that translational targeting of suicide gene expression in tumor cells in vitro and in vivo is effective and may provide a platform for enhanced cancer gene therapy specificity. Copyright

Competitive PCR to detect eIF4E gene amplification in head and neck cancer

The protein eukaryotic initiation factor 4E (eIF4E) binds to messenger ribonucleic acid (mRNA) as the initial step in protein synthesis. Overexpression of eIF4E results in upregulation of specific proteins essential to cell growth and division. Overexpression of eIF4E has been found in head and neck squamous cell carcinoma (HNSCC) and breast carcinoma. This studys purpose is to determine whether eIF4E overexpression is present and associated with eIF4E gene amplification in HNSCC.

Confocal Laser Endomicroscopy in the Detection of Head and Neck Precancerous Lesions

Objective This study aimed to determine the feasibility of using probe-based confocal laser endomicroscopy (pCLE) in the diagnostic differentiation of non-neoplastic lesions from precancerous and cancerous lesions of head and neck patients. Study Design Diagnostic test evaluation. Setting Louisiana State University Health Shreveport. Subjects and Methods Intravenous injection of fluorescein was given to patients with precancerous and cancerous head and neck lesions (n = 21) followed by the use of a 1.8-mm GastroFlex probe in the oral cavity with subsequent biopsies of selected areas. Probe-based confocal laser endomicroscopy images were compared to histologic evaluation of visualized sites using sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Results The dorsal surface of the tongue was not well visualized. The remaining nonkeratinized subsites, including the buccal mucosa, floor of mouth, and ventral tongue, were well visualized. Diagnoses based on pCLE images correlated well with the gold standard diagnoses based on tissue histology. The overall sensitivity for diagnosis of dysplasia versus nondysplasia was 80.0% (95% confidence interval [CI], 62.0-98.0), specificity and PPV were 100%, and the NPV was 80.0% (95% CI, 60.0-100.0). The overall specificity, sensitivity, PPV, and NPV for pCLE diagnosis of carcinoma versus nondysplasia were 100%. The overall sensitivity for diagnosis of carcinoma versus dysplasia was 85.7% (95% CI, 73.0-99.0), specificity and PPV were 100%, and the NPV was 80.0% (95% CI, 60.0-100.0). Conclusion The pCLE is a promising method for differentiating between nondysplastic, precancerous, and cancerous lesions of the head and neck.

Induction chemotherapy followed by concomitant chemoradiation-induced regression of advanced cervical lymphadenopathy in head and neck cancer as a predictor of outcome

OBJECTIVE: We sought to determine whether induction chemotherapy followed by concomitant chemoradiation (ICCR)-induced advanced neck disease regression could predict outcome, especially the need for complete neck dissection in patients with N2-3 stage IV head and neck cancer (HNC). METHODS: A retrospective study of 339 patients evaluated for treatment of stage IV HNC during the years 1988 to 1997 revealed 36 individuals with N2-3 cervical lymphadenopathy who were treated with ICCR. Responses to treatment, patterns of failure, and survival rates were analyzed. RESULTS: Primary and regional tumor regressions were complete in 21 patients (58%), partial in 9 (25%), and absent in 6 (17%); the corresponding local failure rates were 5%, 44%, and 33% (P < 0.02). The regional failure rates were 24%, 89%, and 83%, respectively (P < 0.001); distant failure rates were 10%, 0%, and 0% (P > 0.99). The estimated 2-year survival rates for complete and partial/nonresponders were 57% and 20%, respectively (P < 0.02). CONCLUSION: Patients with advanced regional metastases of HNC who respond completely to ICCR have an excellent chance for survival. However, such ICCR-induced complete regression of regional tumor cannot reliably predict ultimate neck disease control.

Extracapsular dissection versus superficial parotidectomy for benign parotid tumors

BACKGROUND Surgery for benign parotid tumors has undergone several evolutionary steps over the past century. Prior to the 1930s, the focus of parotid surgery was to limit the risk of facial nerve paralysis, which made intracapsular enucleation the most common procedure performed. However, it became widely recognized that the postoperative risk of recurrence was unacceptably high, even for benign disease. Thus, surgeons began advocating for the superficial parotidectomy (SP) and/or partial parotidectomy, which decreased the recurrence rate to its current level of approximately 2%. With the decrease in recurrence also came the unwanted side effects of increased facial nerve injury, Frey’s syndrome, and salivary fistula. Recently, extracapsular dissection (ECD) has emerged as an adjunctive method for removing benign parotid tumors. Extracapsular dissection can be differentiated from intracapsular enucleation, which involves incising the tumor capsule and “shelling out” the neoplasm, thus resulting in high rates of recurrence due to incomplete resection and seeding of the tumor within the parotid bed. Extracapsular dissection is conducted by careful dissection around the tumor capsule under magnification without preidentification of the facial nerve. The use of this technique has demonstrated decreased surgical complications from benign parotid tumor resection for a certain subset of patients. The evidence supporting the use of ECD for benign parotid tumors, which meet certain criteria, will be the focus of this article. LITERATURE REVIEW The larger studies reporting on ECD for benign parotid tumors have primarily come from Europe. In terms of patient selection, most studies advocate for smaller, superficial-lobe, mobile tumors. In the largest series of ECD by McGurk et al., which retrospectively compared 503 patients who underwent ECD to 159 who received a SP, the authors utilized both a 4-cm cutoff for consideration of an ECD as well as intraoperative determination of tumor mobility to decide between the two techniques. In one study by Piekarski et al., the risk of facial paresis after ECD of tumors 4 cm or greater was 21% compared to 4% for those for whom the tumor was less than 4 cm. Although all of the authors agree that ECD should be reserved for those tumors with benign etiology, some indicate that preoperative fine needle aspiration (FNA) is not necessary and others argue that it should be routinely used due to the high sensitivity and specificity. Because most of the studies are conducted in Europe, ultrasound was the imaging modality of choice for two of the groups, with computed tomography and/or magnetic resonance imaging reserved for suspected bony and/or deep lobe involvement, respectively. A consensus is generally reached that the tumors that demonstrate worrisome features intraoperatively should undergo a more extensive surgery than ECD, regardless of the FNA result, due to the 20% false-negative rate for malignancy seen on FNA. This point also highlights the need for the technique to be utilized by experienced parotid surgeons who can identify suspicious characteristics for parotid malignancy as well as perform an appropriate parotid surgery for the particular histology. As mentioned above, ECD is conducted by careful dissection around the tumor capsule under magnification without preidentification of the facial nerve. A loose areolar plane, approximately 2to 3-mm adjacent to the tumor capsule, is the described plane of dissection. Iro et al. advocate for the use of intraoperative facial nerve neuromonitoring and bipolar cautery to prevent injury to the branches of the facial nerve that can sit adjacent to the tumor capsule. Given the pseudopods of tumor that are readily described in pleomorphic adenomas, magnification is encouraged to better visualize these outcroppings and avoid capsular rupture. From the Department of Otolaryngology/Head and Neck Surgery, Louisiana State University Health–Shreveport, Shreveport, Louisiana, U.S.A The authors of this original manuscript have no financial disclosures and no conflict of interest. Editor’s Note: This Manuscript was accepted for publication on September 24, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Vikas Mehta, MD, Co-Director of Head and Neck Surgical Oncology Feist-Weiller Cancer Center, 1501 Kings Highway, Rm 9-203, Shreveport, LA 71130. E-mail: dr.vikasmehta@gmail.com

Improvements in survival and disparities for advanced-stage laryngeal cancer

IMPORTANCE Laryngeal cancer survival rates have declined over the past 2 decades. Primary surgical therapy may increase survival rates in advanced-stage tumors. OBJECTIVE To compare survival outcomes for initial surgical treatment of advanced-stage primary tumors in the Louisiana health system with outcomes in the National Cancer Database (NCDB). DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis was conducted at an academic tertiary referral hospital. Patients diagnosed as having laryngeal carcinoma between 1998 and 2007 were identified via a tumor registry. Louisiana State University Health-Shreveport (LSU Health) data and national data from 2000 to 2010 were obtained from the NCDB of the American College of Surgeons. INTERVENTIONS Treatment of laryngeal cancer. MAIN OUTCOMES AND MEASURES Age, sex, race/ethnicity, socioeconomic status, laryngeal subsite, stage, primary treatment modality, and observed survival were analyzed and compared. RESULTS A total of 165 patients treated at LSU Health met the inclusion criteria. One hundred seventeen (70.91%) presented with advanced-stage (III/IV) disease, compared with 46.67% nationwide (P < .01). For stage IV disease our 5-year survival rate was 55.54% (95% CI, 43.35%-66.11%)compared with 31.60% (95% CI, 30.40%-32.90%) nationally (P < .05). Our proportion of uninsured patients was 23.73% vs 5.05% of patients nationally (P < .001), and our patients traveled further distances for care with 60.47% traveling 50 miles or more, compared with 15.87% nationally (P < .001). Sixty-four of the patients with advanced-stage disease (54.70%) underwent primary surgical therapy to include total laryngectomy. Data from the NCDB indicate that the rate of laryngectomy declined from 40% to 60% in the 1980s to 32% in 2007. CONCLUSIONS AND RELEVANCE Louisiana State University Health-Shreveport treated more uninsured patients with advanced-stage laryngeal cancer compared with national data but demonstrated higher survival rates for those with advanced-stage disease. The results also demonstrate that we have continued a high rate of primary surgical therapy for advanced-stage disease, despite the national trend toward organ preservation. We believe that upfront laryngectomy may explain our higher survival rates for advanced-stage laryngeal cancer.

Total laryngectomy and T3-T4 laryngeal cancer without other adverse histopathology

Objective We sought to determine the postoperative management, incidence of tumor recurrence in the neck, and outcome in laryngeal cancer patients whose risk for tumor relapse is not clear. Study Design and Setting Thirty patients (27 of whom had transglottic tumors) met the study criteria (resected T3-T4 laryngeal cancer, histologically negative cervical nodes, and no other adverse histopathology). A group of 12 patients who underwent surgery alone was compared with a second group of 18 patients with similar characteristics but who received postoperative radiotherapy. Results Overall survival at five years was 50% in the surgery alone group and 61% in the combined therapy group (P = 0.63). Among the 28 evaluable patients with a median follow-up of 44 months, the relapse rate in the neck was 25% in the surgery alone group and was 0% in the postoperatively irradiated group (P = 0.07). Recurrences in the neck remained uncontrolled in two of the three patients at the time of death. Conclusion and Significance Postoperative radiotherapy deserves consideration in selected cases of T3-T4 laryngeal cancer without adverse histopathology.

Cavernous sinus involvement by extramedullary plasmacytoma of the sphenoid sinus. An argument for the use of adjuvant chemotherapy.

A 63-year-old man with cavernous sinus involvement from extramedullary plasmacytoma (EMP) of the sphenoid sinus is described. Transient resolution of retro-orbital headache and continued progression of the locally extensive tumor were noted after chemotherapy was given following a poor response to 5400 cGy of local irradiation. To determine whether adjunctive chemotherapy will improve the outcome of these particular patients, we propose that a randomized trial comparing radiotherapy to chemoradiation be conducted.

Complicated cirrhosis of the liver in patients with head and neck cancer

It is widely recognized that many patients with head and neck cancer (HNC) have a history of ethanol abuse. However, the exact incidence of complicated cirrhosis of the liver (CCL) among these individuals is not known, though it is recognized to be uncommon. Because of its rarity and the question (prompted by the recently encountered case 3), “Are efforts toward management of HNC in a patient with CCL an exercise in futility?” we present 5 cases evaluated at our hospitals between January 1996 and February 2000 (Table 1).

Primary payer status, individual patient characteristics, and hospital-level factors affecting length of stay and total cost of hospitalization in total laryngectomy

Medicaid and uninsured patients anecdotally incur higher cost and length of stay because of nonmedical, discharge‐related factors. The purpose of this study was to investigate the association between primary payer and length of stay and cost, controlling for comorbidities and complications, in patients undergoing total laryngectomy.