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The best chemoradiation regimen to treat locally and regionally advanced head and neck squamous cell carcinoma (HNSCC) is yet to be established.We compared overall survival (OS) and adverse events following chemoradiation regimens (high-dose [HDC] or low-dose [LDC] cisplatin, or carboplatin [CB]) in HNSCC cases selected from SEER-Medicare linked database.Of the 1335 cases who underwent radiotherapy, 264 received HDC, 259 received LDC, and 353 received CB, concurrently. Compared to chemoradiation with HDC, using LDC or CB, or radiotherapy alone were associated with an increasingly worse OS; hazard ratios were 1.33, p = 0.03; 1.35, p = 0.02; and 2.12, p 0.001; respectively. There were no differences in the rates of adverse events between the three chemoradiation regimens.Chemoradiation regimen using HDC appears to be the best primary treatment for locally and regionally advanced HNSCC. Nonetheless, prospective large studies are warranted to further determine its absolute benefit.

Objective The study aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on head and neck oncologic care at a tertiary care facility. Study Design This was a cross-sectional study conducted between March 18, 2020, and May 20, 2020. The primary planned outcome was the rate of treatment modifications during the study period. Secondary outcome measures were tumor conference volume, operative volume, and outpatient patient procedure and clinic volumes. Setting This single-center study was conducted at a tertiary care academic hospital in a large metropolitan area. Methods The study included a consecutive sample of adult subjects who were presented at a head and neck interdepartmental tumor conference during the study period. Patients were compared to historical controls based on review of operative data, outpatient procedures, and clinic volumes. Results In total, 117 patients were presented during the review period in 2020, compared to 69 in 2019. There was an 8.4% treatment modification rate among cases presented at the tumor conference. There was a 61.3% (347 from 898) reduction in outpatient clinic visits and a 63.4% (84 from 230) reduction in procedural volume compared to the prior year. Similarly, the operative volume decreased by 27.0% (224 from 307) compared to the previous year. Conclusion Restrictions related to the COVID-19 pandemic resulted in limited treatment modifications. Transition to virtual tumor board format observed an increase in case presentations. While there were reductions in operative volume, there was a larger proportion of surgical cases for malignancy, reflecting the prioritization of oncologic care during the pandemic.

Introduction: The study objective was to identify practice patterns in oropharyngeal cancer management from 2010 to 2016 among human papillomavirus (HPV)-associated and non-HPV-associated oropharyngeal squamous-cell carcinoma (OPSCC) patients. Methods: The National Cancer Database was utilized to identify OPSCC patients from 2010 to 2016. Frequency distributions and multivariable analyses were generated to identify practice patterns and predictors of treatment modality. Results: A total of 35,956 patients with nonmetastatic OPSCC were included. HPV status was not associated with a treatment modality preference. At academic centers, the proportion of HPV-associated OPSCC patients versus non-HPV-associated OPSCC patients undergoing surgical management was similar (35.7%; 35.9%). Community cancer programs treated patients less often surgically but with no significant treatment preference based on HPV status. Within each facility type, HPV status was not a predictor of surgical or nonsurgical management. Conclusion: HPV association does not appear to significantly influence treatment modality preference among OPSCC patients. The proportion of OPSCC patients undergoing surgical treatment declined from 2010 to 2016.

In the drive towards faster patient access to treatments, health technology assessment (HTA) agencies are increasingly faced with reliance on evidence from surrogate endpoints, leading to increased decision uncertainty. This study undertook an updated survey of methodological guidance for using surrogate endpoints across international HTA agencies. We reviewed HTA and economic evaluation methods guidance from European, Australian and Canadian HTA agencies. We considered how guidelines addressed the methods for handling surrogate endpoints, including (1) level of evidence, (2) methods of validation, and (3) thresholds of acceptability. Across the 73 HTA agencies surveyed, 29 (40%) had methodological guidelines that made specific reference to consideration of surrogate outcomes. Of the 45 methods documents analysed, the majority [27 (60%)] were non-technology specific, 15 (33%) focused on pharmaceuticals and three (7%) on medical devices. The principles of the European network for Health Technology Assessment (EUnetHTA) guidelines published in 2015 on the handling of surrogate endpoints appear to have been adopted by many European HTA agencies, i.e. preference for final patient-relevant outcomes and reliance on surrogate endpoints with biological plausibility and epidemiological evidence of the association between the surrogate and final endpoint. Only a small number of HTA agencies (UK National Institute for Care and Excellence; the German Institute for Medical Documentation and Information and Institute for Quality and Efficiency in Health Care; the Australian Pharmaceutical Benefits Advisory Committee; and the Canadian Agency for Drugs and Technologies in Health) have developed more detailed prescriptive criteria for the acceptance of surrogate endpoints, e.g. meta-analyses of randomised controlled trials showing strong association between the treatment effect on the surrogate and final outcomes. As the decision uncertainty associated with reliance on surrogate endpoints carries a risk to patients and society, there is a need for HTA agencies to develop more detailed methodological guidance for consistent selection and evaluation of health technologies that lack definitive final patient-relevant outcome evidence at the time of the assessment.

Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.

Objectives/hypothesis Obstructive sleep apnea (OSA) is associated with higher risk of morbidity and mortality related to cardiovascular disease (CVD). Due to overlapping clinical risk factors, identifying high-risk patients with OSA who are likely to develop CVD remains challenging. We aimed to identify baseline clinical factors associated with the future development of CVD in patients with OSA. Study design Retrospective analysis of prospectively collected data. Methods We performed a retrospective analysis of 967 adults aged 45 to 84 years and enrolled in the Multi-Ethnic Study of Atherosclerosis. Six machine learning models were created using baseline clinical factors initially identified by stepwise variable selection. The performance of these models for the prediction of additional risk of CVD in OSA was calculated. Additionally, these models were evaluated for interpretability using locally interpretable model-agnostic explanations. Results Of the 967 adults without baseline OSA or CVD, 116 were diagnosed with OSA and CVD and 851 with OSA alone 10 years after enrollment. The best performing models included random forest (sensitivity 84%, specificity 99%, balanced accuracy 91%) and bootstrap aggregation (sensitivity 84%, specificity 100%, balanced accuracy 92%). The strongest predictors of OSA and CVD versus OSA alone were fasting glucose >91 mg/dL, diastolic pressure >73 mm Hg, and age >59 years. Conclusion In the selected study population of adults without OSA or CVD at baseline, the strongest predictors of CVD in patients with OSA include fasting glucose, diastolic pressure, and age. These results may shape a strategy for cardiovascular risk stratification in patients with OSA and early intervention to mitigate CVD-related morbidity. Level of evidence 3 Laryngoscope, 2021.

Background Chronic rhinosinusitis (CRS) causes a great deal of morbidity. There are a multitude of causal factors, though their precise contribution to symptom severity has yet to be defined. We hypothesized that exposure to both primary and secondhand tobacco smoke would correlate with more severe symptoms of CRS. Methods This is a prospective cross-sectional study performed at an academic tertiary care medical center from 2010 to 2013. A total of 85 consecutive patients with chronic sinusitis were screened; 70 with medically refractory CRS requiring functional Endoscopic sinus surgery (FESS) were enrolled. Recent tobacco exposure was assessed using serum cotinine levels. Sinonasal mucosa was biopsied to assess ciliary architecture. Demographics, medical history, tobacco and environmental exposures, and computed tomography (CT) imaging were also collected. Two quality of life (QOL) surveys were administered: one disease specific, Sinonasal Outcomes Test-20 (SNOT-20), and one general, Short Form-12 (SF-12). Results were correlated with the aforementioned exposures. Results The 70 patients had an average age of 46 years, and 42% were male. Variables that correlated with worse SNOT-20 scores included serum cotinine (r = 0.43, p = 0.002), number of cigarettes smoked daily (r = 0.27, p = 0.03), and number of secondhand cigarettes exposed to per day (r = 0.29, p = 0.04). There were no significant correlations between SNOT-20 scores and Lund-MacKay or axonemal ultrastructural abnormalities (AUA)-ciliary scores. The two five-variable models best predicted disease-specific QOL. Conclusions Increased amounts of serum cotinine and primary and secondhand smoke exposure were associated with worse sinonasal QOL. This study establishes an objective relationship between smoke exposure and patient-perceived severity of CRS, emphasizing the importance of tobacco cessation counseling as part of management.

BACKGROUND Lateral skull base tumors often necessitate temporal bone resection (TBR), although clinical outcomes can be unfavorable. Factors influencing survival and recurrence after TBR for cutaneous and salivary malignancies were evaluated. METHODS Twenty-six TBR subjects were included. Survival and recurrence outcomes were estimated at 1, 2, and 5 years postresection. Prognostic factors were analyzed using univariate and multivariate Cox regression. RESULTS Two years postresection, the overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) rates were 61%, 74%, and 49%, respectively, and 51%, 63%, and 45% at 5 years. On univariate analysis, preoperative facial nerve dysfunction and intraoperative nerve sacrifice worsened OS, DSS, and RFS. Prior surgery and adjuvant radiation independently predicted reduced OS, DSS, and RFS on multivariate analysis. CONCLUSIONS Mortality is highest in the first 2 years following resection. Preoperative facial nerve dysfunction, facial nerve sacrifice, and prior radiation are negative predictors of survival and recurrence.

Background Neurological disorders are considered one of the greatest burdens to global public health and a leading cause of death. Stem cell therapies hold great promise for the cure of neurological disorders, as stem cells can serve as cell replacement, while also secreting factors to enhance endogenous tissue regeneration. Adult human multipotent stem cells (MSCs) reside on blood vessels, and therefore can be found in many tissues throughout the body, including palatine tonsils. Several studies have reported the capacity of MSCs to differentiate into, among other cell types, the neuronal lineage. However, unlike the case with embryonic stem cells, it is unclear whether MSCs can develop into mature neurons. Methods Human tonsillar MSCs (T-MSCs) were isolated from a small, 0.6-g sample, of tonsillar biopsies with high viability and yield as we recently reported. Then, these cells were differentiated by a rapid, multi-stage procedure, into committed, post-mitotic, neuron-like cells using defined conditions. Results Here we describe for the first time the derivation and differentiation of tonsillar biopsy-derived MSCs (T-MSCs), by a rapid, multi-step protocol, into post-mitotic, neuron-like cells using defined conditions without genetic manipulation. We characterized our T-MSC-derived neuronal cells and demonstrate their robust differentiation in vitro. Conclusions Our procedure leads to a rapid neuronal lineage commitment and loss of stemness markers, as early as three days following neurogenic differentiation. Our studies identify biopsy-derived T-MSCs as a potential source for generating neuron-like cells which may have potential use for in vitro modeling of neurodegenerative diseases or cell replacement therapies.

Background Human adult stem cells hold the potential for the cure of numerous conditions and degenerative diseases. They possess major advantages over pluripotent stem cells as they can be derived from donors at any age, and therefore pose no ethical concerns or risk of teratoma tumor formation in vivo. Furthermore, they have a natural ability to differentiate and secrete factors that promote tissue healing without genetic manipulation. However, at present, clinical applications of adult stem cells are limited by a shortage of a reliable, standardized, and easily accessible tissue source which does not rely on specimens discarded from unrelated surgical procedures. Method Human tonsil-derived mesenchymal progenitor cells (MPCs) were isolated from a small sample of tonsillar tissue (average 0.88 cm3). Our novel procedure poses a minimal mechanical and enzymatic insult to the tissue, and therefore leads to high cell viability and yield. We characterized these MPCs and demonstrated robust multipotency in vitro. We further show that these cells can be propagated and maintained in xeno-free conditions. Results We have generated tonsillar biopsy-derived MPC (T-MPC) lines from multiple donors across a spectrum of age, sex, and race, and successfully expanded them in culture. We characterized them by cell surface markers, as well as in vitro expansion and differentiation potential. Our procedure provides a robust yield of tonsillar biopsy-derived T-MPCs. Conclusions Millions of MPCs can be harvested from a sample smaller than 1 g, which can be collected from a fully awake donor in an outpatient setting without the need for general anesthesia or hospitalization. Our study identifies tonsillar biopsy as an abundant source of adult MPCs for regenerative medicine. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0619-x) contains supplementary material, which is available to authorized users.

Objective: The study aimed to assess the impact of the coronavirus (COVID-19) pandemic on head and neck oncologic care at a tertiary care hospital. The pandemic caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has led to policies designed to limit its spread. Policies including eliminating routine appointments, statewide stay-at-home orders, and restricting surgical cases to emergent surgeries have limited access to care. Therefore, we hypothesized that treatment modifications would be implemented for patients and cancer consultations would decrease compared to historical data. Methods: Information regarding treatment modifications was collected prospectively during interdepartmental tumor conferences from March 18, 2020 to May 20, 2020. Information regarding patient demographics, tumor characteristics, and incidence of new cancer consultations was collected via chart review. Treatment modifications were categorized as follows: Elimination of Systemic Therapy, Treatment Delay, Change to Non-Surgical Management, or Alteration in Adjuvant Therapy. Rationales for modification were similarly grouped as follows: Operating Room Limitations, Medical Co-Morbidities, COVID-19 positive, Patient concern, or System limitations. We determined the rate of treatment modifications and the frequencies of rationales and modification types. Demographic and tumor characteristics were compared between this population and a retrospectively collected cohort from 2019. Results: 117 patients were presented during the review period in 2020. There were 69 patients presented across the same time period in 2019. There were no differences in demographic characteristics between the groups. There was no difference between the tumor or nodal stages of the presented cases year over year. During the 2020 time period there were more total case presentations and new cancer cases compared to the 2019 time period. Of the 117 cases presented during the study period, there were 10/117 (8.4%) treatment modifications. The most common reason for modification was limited PPE supply. The most common modification was treatment delay. The second most common modification was change from primary surgical management to nonsurgical management. Treatment modifications occurred most commonly early in the review period and declined subsequently. Conclusions: Despite the ongoing pandemic and resulting state and institutional restrictions, there was no appreciable reduction in new cancer consultations for head and neck cancer. There were a small number of treatment modifications, particularly early in the course of our state and institutional response to the virus. However, over the 2-month period examined, patient care for these patients remained largely unaffected. While the restriction in elective surgical care was implemented across the state of Maryland, the oncologic triage and emergency surgery prioritization sustained the volume of oncologic practice. Citation Format: Joshua A. Thompson, Reju Joy, Joshua E. Lubek, Ranee Mehra, Jason K. Molitoris, Rodney J. Taylor, Jeffrey S. Wolf, Matthew E. Witek, Kyle M. Hatten. Evaluating the impact of the coronavirus (COVID-19) pandemic on treatment paradigms in head and neck cancer at a tertiary care hospital [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-017.

6536 Background: For patients with primary untreated locally advanced head and neck squamous cell carcinoma (PULA-HNSCC), high dose once every 3 weeks cisplatin (HDC; 100 mg/m2) added to curative radiotherapy (RT) prolongs survival, but is associated with severe toxicities. Concurrent chemoradiation (CRT) with low dose weekly cisplatin (LDC; 30-40 mg/m2), carboplatin (C), or RT alone is often substituted for HDC. We estimated and compared overall survival (OS) and acquired toxicities among Medicare beneficiaries treated with CRT using HDC, LDC, C, or RT. Methods: Patients diagnosed from 2004-2011 with PULA-HNSCC (stages III-IVB AJCC 6th and 7th editions) of the oropharynx (OPC), hypopharynx (HP), or larynx (L) who received definitive RT or CRT were identified using the linked SEER-Medicare database. An analytic cohort of patients receiving CRT with HDC, LDC, or C was constructed using well-established eligibility criteria. OS was estimated and compared between patients grouped by treatment received utilizing a multivariable stratified propensity scores weighted Cox regression model, including demographic and disease characteristics. Toxicities were compared using exact common odds-ratio and Fisher’s tests. Results: We identified 1,335 patients that received RT: OPC (n = 731), HP (n = 174), or L (n = 430). Out of those, patients were treated with HDC (n = 264), LDC (n = 259), C (n = 353), or RT alone (n = 459). Median OS (years) was 5.61 (95% CI = 4.58-7.69) for HDC, 3.7 (95% CI = 3.1-4.79) for LDC, 3.1 (95% CI = 2.48-3.86) for C, and 1.36 (95% CI = 1.19-1.58) for RT, respectively. OS was significantly greater for HDC than for LDC (HR = 1.35, 95% CI = 1.06-1.72, p= 0.02), C (HR = 1.41, 95% CI = 1.12-1.76, p= 0.003), or RT (HR = 2.1, 95% CI = 1.68-2.61, p= < 0.001). Treatment with HDC compared to LDC was not associated with increased prevalence of dysphagia or neutropenia. HDC was associated with hearing loss when assessed at 9-12 months post-diagnosis ( p =0.03). Conclusions: In SEER-Medicare beneficiaries with PULA-HNSCC of the OPC, HP, or L, OS was significantly better for HDC than LDC when accounting for baseline clinical and demographic characteristics and propensity score weights. Toxicities were similar between regimens, except for an increased incidence of the late acute toxicity of hearing loss in HDC. A regimen of HDC improves OS, but needs to be carefully assessed against increased toxicity risk, with hearing loss in particular.

Background Racial outcome disparities have been observed in head and neck squamous cell carcinoma (HNSCC) with diminished survival for black patients compared with white patients. Methods We retrospectively analyzed 1318 patients with primary HNSCC treated at the University of Maryland Greenebaum Cancer Center (UMGCC) from 2000 to 2010. Results Of all the patients, 65.9% were white, 30.7% were black, and 3.3% were of other races. Black patients were less likely to present with oral cavity cancer, and more likely to present with laryngeal or hypopharyngeal cancers. White patients were more likely to have early stage disease, especially in the oral cavity. Black race was independently associated with worse overall survival (OS) in the entire cohort. Black patients had a significantly worse OS among oral cavity and oropharyngeal cancers, with the largest disparity in oropharyngeal cancer. However, in multivariate analysis, race was only still significant in oropharyngeal cancer. Conclusion We observed differences by race in distribution of disease site, stage, and OS. Survival disparity in the entire cohort was driven mostly by differences among oropharyngeal cancer.

We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3-positive RM–SCCHN patients, respectively. Three dose levels (500, 1,000, and 1,500 µg) of GL-0810 or GL-0817 with adjuvants Montanide (1.2 ml) and GM-CSF (100 µg/m2) were administered subcutaneously q2 weeks for a total of four vaccinations in HPV16 and MAGE-A3-positive RM–SCCHN patients, respectively. Nine and seven patients were enrolled in the HPV16 and MAGE-A3 cohorts, respectively. No dose-limiting toxicities were observed, and toxicity was predominantly local and grade 1 (erythema, pain, and itching at the injection site). In those patients who received all four vaccinations, 80 % (4/5) of the HPV16 cohort and 67 % (4/6) of the MAGE-A3 cohort developed antigen-specific T cell and antibody responses to the vaccine. Significant concordance between T cell and antibody responses was observed for both groups. No clear dose–response correlation was seen. All patients progressed by RECIST at first repeat imaging, except for one patient in the MAGE-A3 500 µg cohort who had stable disease for 10.5 months. The median PFS and OS for the MAGE-A3 cohorts were 79 and 183 days, respectively, and for the HPV16 cohort 80 and 196 days, respectively. GL-0810 and GL-0817 were well tolerated in patients with RM–SCCHN with T cell and antibody responses observed in the majority of patients who received all four vaccinations.

Background: Tracheoesophageal puncture (TEP) for post-laryngectomy speech rehabilitation can be performed at the time of laryngectomy (primary) or at a subsequent time (secondary). Traditionally, the secondary procedure is performed using a rigid esophagoscope. Diseases like esophageal stricture, limited neck extension, and soft-tissue fibrosis can make this procedure technically challenging or impossible. We developed a novel device to perform a secondary tracheoesophageal puncture using a flexible esophagoscope. Objective: To test the feasibility of a novel device used to create a secondary TEP in post-laryngectomy cadavers. Methods: In this study, we performed a total laryngectomy on 3 fresh cadavers to establish the feasibility of our prototype. In each cadaver, a flexible esophagoscope was passed into the pharynx with the prototype. The prototype was passed through a working port and deployed to distend the esophagus. The puncture was visualized and a wire was passed via the newly established fistula. The device was activated, securing the wire, and then the esophagoscope and device were removed. Results: There was 100% successful deployment of the prototype device, allowing rapid creation of the puncture and security of the guide wire in each cadaver. There was no evidence of collateral mucosal injury or esophageal perforation. Conclusions: The prototype device offers an alternative method to safely and efficiently perform a secondary TEP without the requirement of rigid esophagoscopy which can sometimes be technically impossible in this patient population.

(1) To evaluate the effectiveness of the superficial musculoaponeurotic system (SMAS) flap and free fat graft in reconstructing the parotidectomy defect. (2) To evaluate the long-term viability of the free fat graft following parotidectomy for benign and malignant disease, including in the postradiation setting.Prospective study of consecutive patients.Academic tertiary care medical center. Subjects and Methods Thirty-one consecutive patients underwent parotidectomy with SMAS flap and free fat graft reconstruction from 2006 to 2012. Data were compiled through a manual chart review.Twenty-three of the 31 total patients had benign disease, including pleomorphic adenoma, oncocytoma, and Warthin tumor. The 8 remaining patients (9 parotidectomies) underwent surgery for malignant disease, followed by postoperative radiation. The average age was 56 years (range, 16-84 years). The mean follow-up was 22.5 months. Satisfactory volumetric symmetry was achieved in all procedures for benign and malignant disease. Magnetic resonance imaging confirmed long-term fat graft viability in the postradiation setting. There was 1 case of Frey syndrome and no cases of unexpected, permanent facial nerve weakness among the patients.The combined technique of SMAS flap and free fat graft is effective for immediate reconstruction of the parotidectomy defect with minimal morbidity and low complication rates. This study demonstrates long-term viability of the free fat graft even in the setting of postoperative radiation.

The tumor volume has been established as a significant predictor of outcomes among patients with head-and-neck cancer undergoing radiotherapy alone. The present study attempted to add to the existing data on tumor volume as a prognostic factor among patients undergoing chemoradiotherapy.A total of 78 patients who had undergone definitive chemoradiotherapy for Stage III-IV squamous cell cancer of the hypopharynx, oropharynx, and larynx were identified. The primary tumor volumes were calculated from the treatment planning computed tomography scans, and these were correlated to the survival and tumor control data obtained from the retrospective analysis.The interval to progression correlated with the primary tumor volume (p = .007). The critical cutoff point for the tumor volume was identified as 35 cm(3), and patients with a tumor volume35 cm(3) had a significantly better prognosis than those with a tumor volume35 cm(3) at 5 years (43% vs. 71%, p = .010). Longer survival was also correlated with smaller primary tumor volumes (p = .022). Similarly, patients with a primary tumor volume35 cm(3) had a better prognosis in terms of both progression-free survival (61% vs. 33%, p = .004) and overall survival (84% vs. 41%, p =.001). On multivariate analysis, the primary tumor volume was the best predictor of recurrence (hazard ratio 4.7, 95% confidence interval 1.9-11.6; p = .001) and survival (hazard ratio 10.0, 95% confidence interval 2.9-35.1; p =.001). In contrast, the T stage and N stage were not significant factors. Analysis of variance revealed that tumors with locoregional failure were on average 21.6 cm(3) larger than tumors without locoregional failure (p = .028) and 27.1-cm(3) larger than tumors that recurred as distant metastases (p = .020).The results of our study have shown that the primary tumor volume is a significant prognostic factor in patients with advanced cancer of the head and neck undergoing definitive chemoradiotherapy and correlated with the treatment outcomes better than the T or N stage.

Background. We performed a pilot study using Trojan vaccines in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). These vaccines are composed of HLA-I and HLA-II restricted melanoma antigen E (MAGE)-A3 or human papillomavirus (HPV)-16 derived peptides, joined by furin-cleavable linkers, and linked to a "penetrin'' peptide sequence derived from HIV- TAT. Thirty-one patients with SCCHN were screened for the trial and 5 were enrolled. Methods. Enrolled patients were treated with 300 lg of Trojan peptide supplemented with Montanide and granulocyte-macrophage colony- stimulating factor (GM-CSF) at 4-week intervals for up to 4 injections. Results. Following vaccination, peripheral blood mononuclear cells (PBMCs) from 4 of 5 patients recognized both the full Trojan constructs and constituent HLA-II peptides, whereas responses to HLA-I restricted peptides were less pronounced. Conclusion. This treatment regimen seems to have acceptable toxicity and elicits measurable systemic immune responses against HLA-II restricted epitopes in a subset of patients with advanced SCCHN. V C 2012 Wiley Periodicals, Inc. Head Neck 34: 1734-1746, 2012

The Supreme Court has historically been reluctant to involve itself in environmental matters, especially those relating to the regulation of releases or emissions of harmful substances. The court has typically been content to allow the legislative branch to fashion appropriate regulations to address environmental issues and for the executive branch to enforce those regulations. The acceptance of certiorari in the Second Circuit's Connecticut v. AEP case was a surprise because it not only involves environmental regulation, but also the common law applicable to public nuisance actions seeking redress for climate change damage allegedly caused by emissions of greenhouse gases (GHGs). The AEP case is shaping up to be a blockbuster in the climate change debate in the United States, and the decision could have broad repercussions in not only future litigation involving climate change, but also GHG legislation and the insurance available to address damage due to weather-related events.

Climate change, characterized by higher surface and water temperatures, will likely lead to more frequent and severe storms, floods, rising sea levels, wildfires, and loss of a variety of species. The monetary loss attributable to these events could be enormous, resulting in a variety of first-party insurance claims and third-party lawsuits. The availability of insurance coverage to pay these claims will depend on the nature of weather-related losses and the particular policies in force. Insurers have also begun to develop products that pay to rebuild to “greener” standards after fortuitous losses, encourage lower carbon emissions, and provide incentives for the implementation of sustainable business and personal practices.

Antibody based manipulation of the CD137 (4-1BB) co-signaling pathway is an attractive option for the treatment of cancer and autoimmune disease. We developed a chimeric anti-human CD137 monoclonal antibody (GG) and characterized its function. As a component of planned preclinical studies, we evaluated the binding of GG to activated peripheral blood mononuclear cells (PBMCs) from cynomolgus macaque and baboon against human. Interestingly, GG only recognized human CD137, while a commercial anti-CD137 mAb (4B4-1), recognized activated PBMCs from both human and non-human primates (NHP). Subsequent analysis revealed that the amino acid sequence of CD137 is largely conserved between primate species ( approximately 95% identical), with the extracellular domain differing by only 9-10 amino acids. Based on these data, we generated mutant constructs in the extracellular domain, replacing NHP with human CD137 sequences, and identified 3 amino acids critical for GG binding. These residues are likely part of a conformational epitope, as a peptide spanning this region is unable to block mAb binding. These data demonstrate that subtle sequence variations of defined co-stimulatory molecules amongst primate species can be employed as a strategy for mapping residues necessary for antibody binding to conformational epitopes.

Objectives/Hypothesis: To determine if supraglottoplasty (SGP) is effective in reversing abnormal respiratory parameters in children with laryngomalacia and obstructive sleep apnea (OSA). Study Design: Retrospective case series at a tertiary referral children's hospital. Methods: Ten patients with laryngomalacia and OSA as documented by polysomnography underwent SGP between 2005 and 2007. Data collected included age, findings on flexible and rigid endoscopy, type of procedure performed, and postoperative course. The postoperative polysomnographies were reviewed to identify changes in obstructive apnea index, obstructive apnea/hypopnea index, respiratory disturbance index, and low arterial oxygen saturation (O2 nadir) after SGP. Results: All 10 patients were successfully extubated after SGP. There were no peri- or postoperative complications, and no patient required a subsequent airway procedure. Each patient had a postoperative nocturnal polysomnography performed after SGP at 11 weeks (range 2–29 weeks). Caregivers reported mild improvement (10%), significant improvement (70%), and complete resolution (20%) of stridor and nocturnal snoring at a follow-up visit 4 weeks after discharge. Marked improvements were observed in obstructive apnea index, obstructive apnea/hypopnea index, respiratory disturbance index and O2 nadir, all of which were statistically significant (P < .05). Conclusions: Polysomnography should be considered in the initial evaluation of infants with moderate laryngomalacia to rule out OSA. SGP is an effective treatment for infants with laryngomalacia and OSA. The significant benefits of the procedure outweigh thelow morbidity. Improvement after surgery was reliably confirmed by polysomnography in this study.

Strategies for vascular control and limiting warm ischemia time (WIT) vary between institutions for laparoscopic live donor nephrectomy (LLDN). We refined our technique and retrospectively determined whether it safely provides an allograft of comparable quality to published series.Fifty consecutive LLDN between February 2003 and November 2006 were reviewed. Key technical aspects include placing the perfused kidney and transected ureter entirely within an endocatch bag, with the string externalized through an extended lateral port site incision. Vessels are then controlled with clips, or a Satinsky clamp for right sided veins. The extraction incision is completed and the bag immediately withdrawn and placed on ice. WIT ends with perfusion with cold UW solution.The series includes 42 left and 8 right kidneys. 13/50 (26%) demonstrated anatomical complexity (more than one artery, vein and/or ureter). Average operative time was 178 minutes. Average WIT was 128 seconds. Conversion to open surgery occurred in two patients, one to define challenging anatomy, and another for hemorrhage from the renal artery stump. Average blood loss was 76 ml. Average length of stay was 3.6 days. Average recipient creatinine was 1.26 mg/dl at discharge. Delayed graft function occurred in three recipients. ATN/slow normalization of creatinine occurred in four. Graft survival at one year was 96%.The refined technique of LLDN mimics important principles of open donor nephrectomy. Controllable variables which may impact graft function are optimized. WIT is amongst the lowest reported for pure laparoscopy, without increasing complication rates, blood loss, or operative time.

Purpose: To examine the prognostic significance of expression of glutathione s-transferase π (GST-π) and p53 in patients treated with radiation alone for locally advanced head and neck cancer [Radiation Therapy Oncology Group (RTOG), trial 9003] or radiation ± concomitant chemotherapy as postoperative adjuvant therapy (RTOG trial 9501).Experimental Design: Immunohistochemical staining for p53 and GST-π was done on tissue samples from 393 patients in RTOG 9003 and 142 patients in RTOG 9501. Kaplan-Meier survival analyses were done.Results: Patients who had low expression of both markers had longer survival than patients who had high expression of both markers. In trial 9003, median survival was 2.4 years for patients with low expression of both markers versus 1.4 years for patients who had elevated expression of both markers (P = 0.07). These differences were highly significant in trial 9501 and were accounted for by the chemotherapy treated arm. In this group, patients with low expression of both markers had a median survival of 7.0 years compared with 1.4 years for patients with elevated expression of both markers (P = 0.006). In both trials, black patients had lower survival rates than did white patients and there was a trend toward higher expression of both markers in blacks compared with whites.Conclusion: Given the poor outcome of chemoradiotherapy treatment patients with elevated expression of both p53 and GST-π, these patients may not be appropriate candidates for chemoradiotherapy based on standard protocols. Some of the adverse outcome for black patients in both studies may be attributed to elevated expression of p53 and GST-π.

While environmental incidents tend to occur infrequently, they are often serious enough to disrupt the operations of the entities that experience releases of hazardous materials. The consequences of such events may include third-party claims for bodily injury and property damage, orders to clean up contamination, and regulatory actions against responsible parties. Fortunately, environmental insurance is available to provide protection against the financial consequences of a wide variety of pollution events. This article looks at the role of the broker in assisting clients to identify, analyze, and insure against environmental liability. With properly drafted policies and active participation in the claims management process, the broker can play a significant role in assuring that an environmental insurance policy responds as anticipated when an unexpected incident threatens a client's operations.

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between FcγRIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, FcγRIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m2 i.v. every 2 weeks) and lenalidomide (25 mg daily). FcγRIIIa genotype and ex vivo ADCC were correlated with clinical response, progression-free survival (PFS), and overall survival (OS). In vitro, healthy donors with a FcγRIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirty-six patients had FcγRIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. FcγRIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than FcγRIIIa and may offer a functional assay to select patients suitable for cetuximab therapy. Cancer Immunol Res; 3(5); 567–74. ©2015 AACR.

Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer.

Objective We report a multigeneration family where colorectal cancer and cancer of multiple diverse anatomic sites, inclusive of transitional cell carcinoma of the upper uroepithelial tract, were manifested in several relatives. Methods A specific pattern of cancer of the colorectum, endometrium, ovary, small bowel, and transitional cell carcinoma, with a vertical distribution of this cancer phenotype through multiple generations, was consonant with a diagnosis of hereditary nonpolyposis colorectal cancer. Results Germline mutation testing identified the MSH2 mutation, which segregated with the cancer phenotype. This family study clearly demonstrates the value of genetic testing in the management and treatment decision process. Conclusions We document, perhaps for the first time, how molecular genetic testing in hereditary nonpolyposis colorectal cancer can aid in the identification of a potential renal transplant donor for a relative with the MSH2 mutation who is experiencing renal insufficiency secondary to transitional cell carcinoma.

Lactoferrin, a naturally occurring glycoprotein found in breast milk, has previously been shown to have antimicrobial properties and recently has been demonstrated to inhibit malignant tumor growth, presumably through immunomodulation. We hypothesized that intratumoral injection of human and murine recombinant lactoferrin would decrease the growth of malignant tumors in vivo. Using an orthotopic murine model for both squamous cell carcinoma and fibrosarcoma of the floor of the mouth, we administered lactoferrin directly into the tumors using variable dosing strategies. Additionally, we performed in vitro experiments to assess whether the effects of lactoferrin are due to direct cytotoxicity. Our results revealed growth inhibition of 50% (p = 0.03)and 54% (p = 0.01) as compared with controls for both human and murine tumor cells in immunodeficient and immunocompetent mice, respectively. There was a more dramatic effect in immunocompetent models which may identify immunomodulation as an important mechanism of action for lactoferrin. Support for immunomodulation as a possible mechanism was the lack of any difference between controls and the experimental groups in vitro. Lactoferrin proved effective in reducing malignant tumor growth in a murine model. These properties offer hope for its use as a primary or adjuvant chemotherapeutic agent. Further investigation focused on mechanism and delivery is needed.

Human prostatic acid phosphatase (PAcP) is a prostate epithelium-specific differentiation antigen. The cellular form of PAcP functions as a neutral protein-tyrosine phosphatase, and is involved in regulating prostate cell growth. Although some information on the PAcP gene structure has been obtained, little is known regarding the cis- and trans-acting factors that regulate its expression. Due to the biological importance of PAcP, we investigated the regulation of its expression. A region upstream of the PAcP gene from -2899 to +87 base pairs was linked to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene. Sequential deletions of the sequence between -2899 and -205 revealed that, in addition to the basic promoter, the region between -1258 and -779 represents a positive regulatory element. This -1258/-779 fragment could enhance the PAcP promoter activity in PC-3 and DU 145 human prostate cancer cells, but not in non-prostate cancer cells, including WI-38 lung diploid cells, A-431 epidermoid carcinoma cells, and HeLa cervix epitheloid carcinoma cells. Furthermore, this cis-element together with the promoter sequence could drive a high level of expression of green fluorescent protein (GFP) in PC-3 cells, but not in HeLa cells. The prostate-specific expression was further examined by injecting naked plasmid DNA into the prostate and the hamstring muscle of mice. The fluorescence pattern clearly showed that the level of GFP expression is consistently higher in prostate cells than in muscle cells of the intact animal. The data collectively indicate that region between -1258 and -779 is involved in governing the cell type-specific expression of the PAcP gene.

Objective Our objective was to determine the proportion of patients disease free in the neck, with the primary site controlled, who have been treated with a selective neck dissection (SND) for squamous cell carcinoma (SCCa) of the upper aerodigestive tract, and who had cervical metastasis less than 3 cm. Study Design A cohort of patients who fit the inclusion/exclusion criteria was identified retrospectively. Then all surviving patients were followed for a minimum of 2 years. Methods A group of 52 patients who had 58 selective neck dissections for cervical metastases from SCCa of the upper aerodigestive tract were identified. The mean age was 56 years (range, 20–85 y), there were 40 males and 12 females, and mean follow-up was 24.5 months (range, 1–64 mo). Twenty-six patients had clinically negative (cN0) neck examinations and 26 had clinically positive neck examinations. Postoperative radiation was given for extracapsular spread, greater than 2 positive nodes, T3, T4, or recurrent disease if the patient had not received radiation before surgery. These radiation criteria excluded 18 patients from postoperative radiation treatment. Results Kaplan-Meier survival analysis showed that the regional control rate with the primary site controlled was 0.94. Six patients developed recurrent neck disease. Three of these 6 patients were surgically salvaged. Four recurrences were in the dissected field and 2 were out of the dissected field (level V). Conclusions With similar indications for radiation therapy, the regional control rate in this cohort is comparable to control rates obtained with modified radical neck dissection.

Background Digital subtraction angiography (DSA) is considered the gold standard for the evaluation of head and neck vascular abnormalities. It serves as a useful diagnostic and, in many cases, therapeutic tool for treatment of acute head and neck bleeding. Case description We report the case of a patient who presented with life threatening, uncontrollable epistaxis several weeks after resection of a large recurrent chondrosarcoma of the nasal cavity and anterior skull base. A DSA study, with an adjunctive C-arm computed tomography (CT) (Dyna CT), was ultimately helpful in revealing and precisely localizing a large anterior ethmoidal artery pseudoaneurysm adjacent to the tumor resection cavity. Conclusion This additional information helped define the arterial anatomy in postoperative region, allowed precise localization and direct ligation of the pseudoaneurysm to resolve the bleeding with a favorable patient outcome.

En bloc transplantation of pediatric kidneys into adults is a suitable measure to help correct the shortage of available kidneys. This practice, however, is not widespread because of the high incidence of vascular complications. Our institution has previously described a vicryl mesh technique for en bloc kidneys, with an attempt to reduce the incidence of vascular complications. The purpose of this study was to evaluate the long-term results of recipients with en bloc kidneys stabilized with this technique. The charts of 644 adult renal transplants performed between July 1987 and July 1999 were reviewed. During this period, 14 adult patients have received 14 pairs of en bloc pediatric kidneys using the vicryl mesh technique. All patients received OKT3 as an induction immunosuppression with cyclosporine started 10-14 d after the transplant. The median donor age was 24 months (range 14-84 months), and the median recipient age was 49 yr (range 23-68 yr). The mean recipient weight was 79 kg (range 60-114 kg). The mean cold ischemia time was 14.2 hr. None of the patients developed vascular or urological complications. Delayed graft function and moderate acute rejection occurred in one patient each. At a mean follow-up of 51 months (range 7-96 months), all 14 patients maintained excellent renal function with a mean creatinine of 1.01 mg/dL. Renal measurements pre-operatively and at follow-up ultrasound examinations were available in 9 patients, and the mean length of the kidneys had grown approximately 5.0 cm. These data demonstrate that minimal vascular and immunological complication rates can be achieved with pediatric en bloc kidneys using the vicryl mesh envelope technique.

Purpose: Understanding cell proliferation regulation in hormone refractory prostate cancer may provide answers for novel solutions. Protein tyrosine phosphatases have been thought to have key roles in regulating cell proliferation and be involved in oncogenesis, although to our knowledge their functional roles in human prostate cancer remain unknown. Human prostatic acid phosphatase (PAcP), a major phosphatase in prostate epithelium, has been shown to function as a neutral protein tyrosine phosphatase in these cells. We evaluated the biological significance of cellular prostatic acid phosphatase expression in human prostate cancer cells.Materials and Methods: Immunohistochemical testing of human prostate cancer archival specimens was done to evaluate the expression of cellular PAcP. Immunoprecipitation and immunoblotting were performed to determine cellular PAcP and SH2 domain-bearing tyrosine phosphatase-1 levels as well as tyrosine phosphorylation of c-ErbB-2/neu in different human prostate cancer cells...

Urinary tract anomalies or dysfunction leaves the bladder unsuitable for urine drainage in a significant proportion of children presenting for kidney transplantation. We reviewed a multi-institutional experience to determine the ramifications of kidney transplantation in children with bladder augmentation or urinary diversion.During a 28-year period 18 boys and 12 girls 1.7 to 18 years old (mean age 12.1) received 31 kidney transplants. Cause of end stage renal disease was renal dysplasia in 8 cases, posterior urethral valves in 5, obstructive uropathy in 5, neurogenic bladder/chronic pyelonephritis in 4, spina bifida/chronic pyelonephritis in 3, prune belly syndrome in 3 and reflux in 2.Of the patients 17 had augmented bladder (ileum 9, ureter 5, sigmoid 2 and stomach 1), 12 had incontinent urinary conduits (8 ileum, 6 colon) and 1 had a continent urinary reservoir. Surgical complications included 1 case each of stomal stenosis, stomal prolapse, renal artery stenosis, urine leak, enterovesical fistula and wound dehiscence. Medical complications included urinary tract infection in 21 cases and metabolic acidosis in 5. A bladder stone developed in 1 patient. There was no correlation between the incidence of symptomatic urinary tract infections and type of urinary drainage. Acidosis was more common in patients with augmented bladder (4 of 17 versus 1 of 14) but there was no correlation between the bowel segment used and the occurrence of acidosis. Graft survival was 90% at 1 year, 78% at 5 years and 60% at 10 years. Etiology of graft loss included chronic rejection in 6 cases, noncompliance in 4 and acute rejection in 1. There were no deaths.Drainage of transplanted kidneys into an augmented bladder or urinary conduit is an appropriate management strategy when the native bladder is unsuitable or absent. Patients with kidney transplants drained into augmented bladder or urinary conduit are at increased risk for urine infection. Graft survival is not adversely affected compared to historical controls when a kidney transplant is drained into a urinary conduit or augmented bladder.

Purpose: The dire shortage of cadaveric kidneys has led to a gradual expansion of donor criteria in the transplant community. The use of kidneys with anatomical fusion anomalies is uncommon and has not been well defined in the literature. We evaluated the surgical strategies and postoperative outcomes of transplanting cadaveric kidneys with congenital fusion anomalies.Materials and Methods: Three cadaveric kidneys with congenital fusion anomalies were procured and transplanted between May 1994 and November 1999. None of the 3 donors had any significant urological history. All fusion anomalies were identified during the organ procurement process.Results: Anomalies included 1 L-shaped cross-fused ectopic and 2 horseshoe kidneys. All 3 kidneys were procured en bloc. One horseshoe kidney with a narrow isthmus was split and the 2 kidneys were transplanted into separate recipients, while the other horseshoe kidney was transplanted en bloc into a single recipient. The L-shaped kidney was transplanted en bloc int...

Background: The selection of patients for solitary pancreas transplantation (PTA) requires identification of individuals who will not develop acute renal dysfunction in response to immunosuppressants. A cyclosporine challenge test (CCT) was developed to predict post-PTA kidney dysfunction secondary to calcineurin inhibitor immunosuppressants. We now report on the long-term follow-up of patients who received a PTA after undergoing a CCT. Methods: Twelve potential PTA recipients were administered cyclosporine A (CsA) for 6 wk. Creatinine clearance (CrCl) was measured at 2, 4, and 6 wk. Those who did not fail the CCT received PTA. Baseline and post-transplant CrCl were retrospectively evaluated in the original cohort and in a group of matched patients who received PTA without a CCT. Results: Of the original 12 recipients evaluated with the CCT, 6 received PTA. CrCl was followed for a mean of 45.8 months. Of the 4 who remained alive, 2 went on to develop renal failure (CrCl < 30 mL/min) at 18 and 65 months post-transplant. The baseline CrCl was higher in PTA recipients who had not been selected to be studied with CCT than those that were (117 ± 32 vs 78 ± 13 mL/min). By 12 months post-PTA, the CrCl was no longer different between the groups selected to be screened with CCT and those that were not. Conclusions: CCT may help predict risk for short-term changes in renal function ( < 18 months) in response to CsA. CCT may be most helpful in candidates for PTA with borderline renal insufficiency (60-80 mL/min).

Human prostatic acid phosphatase (PAcP) is a prostate epithelium-specific differentiation antigen. To understand the regulation of expression of the PAcP gene, we studied the cis-regulatory elements of its promoter. A DNA fragment from −2899 to +87 base pairs (bp) of PAcP gene was fused to the chloramphenicol acetyltransferase (CAT) reporter gene and introduced into PC-3 and LNCaP human prostate cancer cells. The expression of the CAT gene driven by the PAcP promoter was assessed in transient expression assays. Sequential 5′ deletions of the promoter were constructed and analyzed to reveal the positive and the negative regulatory elements that are involved in regulating the transcription of the PAcP gene. Our data showed that the proximal sequence −1305/+87 bp directs a high level of the CAT activity in both cell lines. Deletion of the region from −1305 to −779 resulted in approximately a 10- and three-fold decrease of the PAcP promoter activity in PC-3 and LNCaP cells, respectively. Interestingly, an inverse correlation of the CAT activity with the cell growth was observed when the reporter gene was driven by the −1305/+87 fragment, but not by the −779/+87 fragment. Two regions of transcriptional suppression were identified and located in positions from −2899 to −2583, and from −2583 to −1305 bp. Furthermore, the activity of the core promoter region from −779 to +87 bp can be activated by a SV-40 enhancer. The results, thus, clearly demonstrate the presence of positive and negative cis-elements in the promoter region of the PAcP gene.

We evaluated tumor uptake and systemic distribution of intravesically instilled iododeoxyuridine (IUdR) in patients with superficial bladder cancer.We performed 24 intravesical instillation studies in 11 patients with a mean age of 71 years. Radio-iodinated IUdR was administered through a Foley catheter. Gamma camera imaging was done after instillation and after 5 to 7 bladder irrigations. Tumor uptake was estimated by region of interest analysis. Bladder biopsy samples and surgical tumor specimens were tested for acid insoluble (deoxyribonucleic acid incorporated) radioactivity. Blood samples were obtained and analyzed for systemic absorption.Imaging was positive in all patients with bladder cancer. Average tumor uptake plus or minus standard deviation was 0.185+/-0.120% of the instilled dose. Preferential uptake of IUdR in the tumor was observed in all 6 patients undergoing tissue analysis. The tumor-to-normal bladder ratio ranged from 3.2 to 74,000 (median 202). Systemic absorption of IUdR was minimal. Blood sample analysis performed after intravesical instillation in all 11 cases revealed an average uptake of 3.2x10(-5)% instilled dose per ml. (range 0.69x10(-5) to 6.7x10(-5)) in the systemic circulation. Instillation within 24 hours after transurethral bladder tumor resection in 5 cases resulted in a higher but not dangerous average systemic uptake of 7.3x10(-4)% instilled dose per ml. (range 1.3x10(-5) to 2.6x10(-3)). Instillation 1 to 4 weeks after transurethral surgery in 8 cases resulted in no increased systemic absorption with an average blood level of 3.4+/-1.8x10(-5)% instilled dose per ml. There was no detectable distribution of radioactivity into other organs, including the thyroid. We noted no evidence of systemic toxicity in the study.Intravesical instillation of radio-iodinated IUdR achieves selective localization in the bladder tumor with minimal uptake by the normal bladder and minimal systemic absorption. The use of intravesical IUdR therapy for bladder cancer appears to be promising and requires further study.

Environmental legacies are unpleasant leftovers of the industrial development of this nation. Unlike family legacies, which usually involve assets that are to be distributed among the heirs, environmental legacies most often involve liabilities. These liabilities were created by releases of contaminants, and exposures to toxic materials that have caused and, in some cases, will continue to cause, bodily injury and property damage. In most cases, resolving liability claims also requires the remediation of contaminated sites or the removal of asbestos‐containing building materials. The sources of historic pollution include: onsite disposal of hazardous materials generated by industrial processes; steady‐state discharges of solids, liquids, and gases from manufacturing operations into the air, surfacewater or groundwater; leaks and spills from underground and above‐ground storage tanks; intentional dumping of materials that were not known to be hazardous (and in some cases, intentional dumping of those that ...

Objectives. We conducted a multicenter retrospective study to determine the results of treatment for prostate cancer in solid organ transplant recipients. Methods. A retrospective analysis of all patients diagnosed with prostate cancer after organ transplantation at five centers was conducted. Data were obtained by chart review and a multipoint data sheet was used to abstract the data from the patient charts. Results. Eighteen cases of prostate cancer were identified from six institutions. Most (84%) of the cancers were clinically localized at the time of diagnosis. Nine (50%) of 18 patients underwent radical prostatectomy, which was the predominant mode of treatment. Overall survival at a mean follow-up of 32 months was 66%, with a cancer specific mortality of 16%. Mortality was 13% for the 15 patients with localized disease and 33% for the 3 patients with metastatic disease at the time of diagnosis. Conclusions. Most of the patients with prostate cancer being detected after solid organ transplantation were diagnosed with localized disease. Aggressive therapeutic intervention as in the general (nontransplant) population yields good results and should be pursued. Diligent surveillance for prostate cancer in this population using periodic digital rectal examination, serum prostate-specific antigen, and prostate needle biopsy as needed will ensure earlier cancer detection and allow for definitive therapeutic intervention.

Background. Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. Methods. A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). Results. A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011).