Renee A. Desmond

Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status.

The current TNM classification system does not consider tumor length or the number of lymph nodes in the staging and classification scheme for patients with esophageal carcinoma. Using data from the National Cancer Institute SEER Program, the authors explored the effect of tumor length and number of positive lymph nodes on survival in patients with esophageal carcinoma.

Temporal trends (1973-1997) in survival of patients with esophageal adenocarcinoma in the United States: a glimmer of hope?

OBJECTIVE:The incidence and mortality related to esophageal adenocarcinoma (EAC) has been rising in the United States. Meanwhile, the number of diagnostic and therapeutic procedures has increased in number and improved technologically. However, the impact of these advances on the survival of EAC in clinical practice remains unknown.METHODS:Patients with histologically proven EAC between 1973 and 1997 were identified in registries of the Surveillance, Epidemiology, and End Results database, and analyzed in 5-yr time periods. The observed and relative survival rates were calculated. The joint influence of the time of diagnosis, stage and grade of cancer, demographic features, surgical therapy, and radiotherapy were assessed in Cox proportional hazard survival analyses.RESULTS:Between 1973 and 1997, we identified 4835 patients with EAC. The 1-yr and 5-yr observed survival rates increased from 34% and 5% during 1973–1977 to 44% and 13% during 1993–1997 (p < 0.05). In the Cox survival analysis, the more recent year of diagnosis, early stage of tumor, younger age at presentation, receiving radiotherapy or surgery were independent predictors of reduced risk of mortality. The proportion of patients with in situ EAC and those with local spread increased progressively from 0.3% and 17.7% in 1973–1977 to 2.3% and 25.3%, respectively, in 1993–1997 (p < 0.05). The proportion of patients receiving radiation therapy either before or after surgery has increased from 7% in 1973–1977 to 16% in 1993–1997 (p < 0.05).CONCLUSIONS:The short- and long-term survival of patients with EAC has improved slightly in the United States over the past 25 yr. Some of the improvement may be related to an increase in the number of younger patients, and in cases with in situ and localized cancers. However, the overall survival of patients with EAC remains dismal.

Dosimetric factors associated with long-term dysphagia after definitive radiotherapy for squamous cell carcinoma of the head and neck.

PURPOSE Intensification of radiotherapy and chemotherapy for head-and-neck cancer may lead to increased rates of dysphagia. Dosimetric predictors of objective findings of long-term dysphagia were sought. METHODS AND MATERIALS From an institutional database, 83 patients were identified who underwent definitive intensity-modulated radiotherapy for squamous cell carcinoma of the head and neck, after exclusion of those who were treated for a second or recurrent head-and-neck primary lesion, had locoregional recurrence at any time, had less than 12 months of follow-up, or had postoperative radiotherapy. Dosimetric parameters were analyzed relative to three objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy (PEG) tube dependence at 12 months, aspiration on modified barium swallow, or pharyngoesophageal stricture requiring dilation. RESULTS Mean dose greater than 41 Gy and volume receiving 60 Gy (V(60)) greater than 24% to the larynx were significantly associated with PEG tube dependence and aspiration. V(60) greater than 12% to the inferior pharyngeal constrictor was also significantly associated with increased PEG tube dependence and aspiration. V(65) greater than 33% to the superior pharyngeal constrictor or greater than 75% to the middle pharyngeal constrictor was associated with pharyngoesophageal stricture requiring dilation. CONCLUSIONS Doses to the larynx and pharyngeal constrictors predicted long-term swallowing complications, even when controlled for other clinical factors. The addition of these structures to intensity-modulated radiotherapy optimization may reduce the incidence of dysphagia, although cautious clinical validation is necessary.

Local and Systemic Cytokine Levels in Relation to Changes in Vaginal Flora

BACKGROUND Bacterial vaginosis (BV) is associated with increased risk of obstetrical and gynecologic complications and acquisition of sexually transmitted diseases. Despite this, very little is known about the pathogenesis of this disease. METHODS Interleukin (IL)-1 beta , tumor necrosis factor- alpha , IL-6, and IL-8 concentrations in vaginal wash and serum samples from women with normal flora, intermediate flora, and BV (determined by Nugent criteria) were measured by enzyme-linked immunosorbent assay. RESULTS Cytokine levels were not different between women with intermediate flora and women with BV. Women with either intermediate flora or BV had significantly higher concentrations of IL-1 beta in vaginal wash samples than did women with normal flora. The presence of IL-1 beta in vaginal wash samples was associated with >30 Gardnerella or Prevotella morphotypes per high-power field, as detected by Gram staining of vaginal swab specimens. Variation in the numbers of Lactobacillus and Mobiluncus species did not influence local cytokine levels. Serum cytokine levels were not influenced by any changes in vaginal flora. CONCLUSIONS Women with intermediate flora generate significant cytokine responses. It is possible that the risks associated with BV may also affect women with intermediate flora and that appropriate treatment may reduce such risk.

Missing Data in Randomized Clinical Trials for Weight Loss: Scope of the Problem, State of the Field, and Performance of Statistical Methods

Background Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods. Methodology/Principal Findings We searched PubMed and Cochrane databases (2000–2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e−λt) where λ was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive. Conclusion/Significance Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.

Enteroviral Meningitis: Natural History and Outcome of Pleconaril Therapy

ABSTRACT Enteroviral meningitis causes appreciable morbidity in adults, including hospitalization, decreased activity, and headache. Limited data define the natural history of disease. No antiviral therapeutic agent has demonstrated improved outcome in controlled clinical trials. Pleconaril, an inhibitor of enterovirus replication, was tested in two placebo-controlled clinical trials. Of 607 randomized patients in a multicenter, double-blind placebo-controlled study of pleconaril (200 mg three times daily versus an identical-appearing placebo), 240 patients were confirmed to have enterovirus infection. The time to headache resolution was evaluated by using Kaplan-Meier survival methodology. A Cox regression model evaluated multivariate factors associated with disease resolution. Resolution of headache in patients with concomitant moderate to severe nausea at baseline occurred at a median of 9.5 days in the absence of therapy and was reduced to 7.0 days for pleconaril recipients (P = 0.009). For a headache score of >5 alone, treated patients resolved headache significantly more rapidly (P = 0.005). Males resolved headache 50% faster than females. Regardless of randomization group, patients with a baseline headache score of 5 or greater resolved headache 50% more slowly than patients with a baseline headache score of 4. No differences in either clinical or laboratory adverse events were noted. Over 50% of untreated patients had a persistent headache that was greater than 1 week in duration. Pleconaril shortened the course of illness compared to placebo recipients, especially in the early disease course. However, the benefit was achieved only modestly in a subgroup analysis of patients with more severe disease after adjusting for confounding variables.

A canine conditionally replicating adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model

Oncolytic adenoviruses, which selectively replicate in and subsequently kill cancer cells, have emerged as a promising approach for treatment of tumors resistant to other modalities. Although preclinical results have been exciting, single-agent clinical efficacy has been less impressive heretofore. The immunogenicity of adenoviruses, and consequent premature abrogation of replication, may have been a partial reason. Improving the oncolytic potency of agents has been hampered by the inability to study host-vector interactions in immune-competent systems, since human serotype adenoviruses do not productively replicate in animal tissues. Therefore, approaches such as immunomodulation, which could result in sustained replication and subsequently increased oncolysis, have not been studied. Utilizing the osteocalcin promoter for restricting the replication of a canine adenovirus to dog osteosarcoma cells, we generated and tested the first nonhuman oncolytic adenovirus. This virus effectively killed canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo. Canine osteosarcoma is the most frequent malignant disease in large dogs, with over 8000 cases in the United States annually, and there is no curative treatment. Therefore, immunomodulation for increased oncolytic potency could be studied with clinical trials in this population. This could eventually translate into human trials.

Transoral Robotic-Assisted Surgery for Head and Neck Squamous Cell Carcinoma: One- and 2-Year Survival Analysis

OBJECTIVE to report 2-year survival outcomes for head and neck squamous cell carcinoma using transoral robotic-assisted resection. DESIGN prospective case study. SETTING two tertiary care centers. PATIENTS eighty-nine patients from 2 tertiary care centers (University of Alabama at Birmingham and the Mayo Clinic in Rochester, Minnesota) with head and neck squamous cell carcinoma of all stages and subsites, who underwent transoral robotic-assisted resection between March 2007 and December 2008, with a median follow-up time of 26 months. MAIN OUTCOME MEASURES disease-free survival, cancer recurrence, and gastrostomy tube dependence RESULTS seventy-one patients had T1 (n = 29) or T2 (n = 42) tumors while 18 patients had T3 (n = 8) or T4 (n = 10) tumors. There were 24 patients with overall stage I or II disease and 65 with stage III or IV disease. At the time of the last follow-up visit (median, 26 months), there had been a total of 11 patients with recurrent cancer: 3 with local; 7, regional (2 of whom also had distant metastases); and 1, distant. Seven patients were treated for recurrent disease. Eighty-two patients had no evidence of disease, 1 patient died of the disease, 2 died of other disease, and 4 were alive with disease at the last follow-up visit. Results of Kaplan-Meier survival analysis showed that the 2-year recurrence-free survival rate for the cohort was 86.5%. None of the patients were gastrostomy tube dependent at the last follow-up visit. CONCLUSION the 2-year functional and oncologic results justify the continued treatment of select patients with head and neck squamous cell carcinoma with robotic-assisted surgical resection.

Locoregionally Advanced Head and Neck Cancer Treated With Primary Radiotherapy: A Comparison of the Addition of Cetuximab or Chemotherapy and the Impact of Protocol Treatment

PURPOSE The addition of platinum-based chemotherapy (ChRT) or cetuximab (ExRT) to concurrent radiotherapy (RT) has resulted in improved survival in Phase III studies for locoregionally advanced head and neck cancer (LAHNC). However the optimal treatment regimen has not been defined. A retrospective study was performed to compare outcomes in patients who were treated definitively with ExRT or ChRT. METHODS Cetuximab with concurrent RT was used to treat 29 patients with LAHNC, all of whom had tumors of the oral cavity, oropharynx, or larynx. All patients were T2 to T4 and overall American Joint Committee on Cancer Stage III to IVB, with a Karnofsky Performance Status (KPS) score of 60 or greater. ChRT was used to treat 103 patients with similar characteristics. Patients were evaluated for locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS). Median follow-up for patients alive at last contact was 83 months for those treated with ExRT and 53 months for those treated with ChRT. Cox proportional hazard models were used to assess independent prognostic factors. RESULTS The LRC, DMFS, and DSS were not significantly different, with 3-year rates of 70.7%, 92.4%, and 78.6% for ExRT and 74.7%, 86.6%, and 76.5% for ChRT, respectively. The OS was significantly different between the two groups (p = 0.02), with 3-year rates of 75.9% for ExRT and 61.3% for ChRT. OS was not significant when patients who were on protocol treatments of ExRT or ChRT were compared. Also, OS was not significant when multivariate analysis was used to control for potential confounding factors. CONCLUSION In our single-institution retrospective review of patients treated with ExRT or ChRT, no significant differences were found in LRC, DMFS, DSS, or OS.

Risk factors for bacterial vaginosis in women at high risk for sexually transmitted diseases.

Objective and Goal: Bacterial vaginosis (BV) is extremely common and is associated with adverse obstetrical and gynecological outcomes. The etiology of the microbiologic changes is unknown. The objective of this study was to determine risk factors associated with incident BV. Study: 96 women without BV were followed prospectively for 1 year for the development of BV. Thirty-seven of their male partners were also studied. Results: The incidence rate of BV was 2.33/person-year (95% CI, 1.63–2.50). Median time to development of BV was 81 days. Incident BV was significantly associated with exposure to a new sexual partner (RR, 1.13; 95% CI, 1.02–1.25; P = 0.02) and frequency of vaginal sex since last visit (RR, 1.07; 95% CI, 1.01–1.15; P = 0.03). Use of condoms with occasional partners was protective (RR, 0.80; 95% CI, 0.67–0.98; P = 0.003). In multivariate analysis, sex with a new partner since the prior visit was the only behavior found to be significantly associated with incident BV (RR, 1.74; 95% CI, 1.05–2.87; P = 0.03). Conclusion: These data support the sexual transmission of BV.