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Purpose Hematology/oncology clinical pharmacists’ work activities have been described in previous literature, but time spent on pharmacist tasks has not been well characterized. Random work sampling (WS) is a form of activity assessment to determine the proportion of time spent in various types of work. Based on results from previous WS evaluations at University of Utah and its Huntsman Cancer Hospital, activities were changed to maximize time dedicated to clinical activities and pharmacists’ benefit to providers and patients in both inpatient and ambulatory care settings. Therefore, updated random WS evaluations were completed during spring 2019 and fall 2020. Methods Personal digital assistant (PDA) devices were used to record hematology/oncology clinical pharmacists’ onsite or remote location and work activity data. Data were collected 8 times per hour on weekdays, with a goal of 275 observations per pharmacist. Results were then classified as clinical, professional, or technical activities. Results In 2019, 9,079 observations were recorded by 31 onsite pharmacists. In 2020, 28 pharmacists recorded 8,803 observations (5,524 during onsite work and 3,279 during remote work). The overall distribution of pharmacists’ work activities remained stable between 2019 and 2020, with 89% of activities classified as clinical or professional. Pharmacists spent a smaller proportion of time on in-person communication in 2020, balanced by increases in chart review and text-based communication. Onsite pharmacists reported a larger proportion of clinical activities, while remote pharmacists reported a larger proportion of professional activities. Conclusion Continued WS assessment of work activity patterns will allow identification of opportunities to streamline workflows, maximize pharmacist engagement in clinical activities, and development of remote work policy.

The recent development of 3D tissue spheroids aims to address current limitations with traditional 2D cell cultures in various studies, including cancer drug screening and environmental toxin testing. In these studies, measurements of cellular viability are commonly utilized to assess the effects of drug or toxins. Existing methods include live/dead assays, colorimetric assays, fluorescence calcium imaging, and immunohistochemistry. However, those methods involve the addition of histological stains, fluorescent proteins, or other labels to the sample; some methods also require sample fixation. Fixation-based methods preclude the possibility of longitudinal study of viability, and confocal fluorescence imaging-based methods suffer from insufficient delivery of labels near the center of 3D spheroids. Here, we demonstrate the use of label-free optical coherence tomography (OCT) for quantitative cellular viability imaging of 3D tissue spheroids. OCT intensity and decorrelation signals acquired from neurospheroids exhibited changes correlated with cellular viability as manipulated with ethanol. Interestingly, when we repeated the imaging while cells gradually became less viable, the intensity and decorrelation signals exhibited different time courses, suggesting that they may represent different cellular processes in cell death. More quantitative measurements of viability using dynamic light scattering optical coherence microscopy (DLS-OCM) will be also presented. DLS-OCM enables us to obtain 3D maps of the diffusion coefficient, and we found that the diffusion coefficient of intra-cellular motility correlated with cellular viability manipulated by changes in temperature and pH. Finally, applications of these novel methods to human-cell 3D spheroids will be discussed.

The deformation of viscoelastic droplets rising in non-Newtonian fluids is examined experimentally. Similarly to the case of bubbles and Newtonian droplets traveling in viscoelastic fluids, a critical volume exists but there is no jump in velocity nor a drastic change in droplet geometry. Nevertheless, a tail appears as well as a negative wake. For large-enough volumes, the thickness of the tail is much larger than that for the Newtonian droplets; this is also true for the magnitude of the negative wake and for the extension of the tail. The head of the droplet is subjected to a bi-axial elongation which deforms the spherical part of the droplet converting it into an elongated shape. This elongated shape blends into a tail and the droplet is converted into a viscous elongated teardrop. The tail is then subjected to a uniaxial extensional flow under the action of elongational stresses along the length of the tail. This extensional flow is counteracted by the shear stresses acting on the interface between the tail and the outer surrounding fluid. This interaction will determine the tail breakup. The influence of the elastic properties of the surrounding fluid and the extensional viscosity of the droplet will be responsible for the length and thickness of the tail as well as for its breakup mechanism.

Dynamic light scattering optical coherence microscopy (DLS-OCM) integrates DLS, which measures diffusion or flow of particles by analyzing fluctuations in light scattered by the particles, and OCM, which achieves single-cell resolution by combining coherence and confocal gating, integratively enabling cellular-resolution 3D mapping of the diffusion coefficient, and flow velocity. The diffusion coefficient mapping has a potential for the non-destructive measurement of cellular viability in the standard unit but has not been validated yet. Here, we present DLS-OCM imaging of intra-cellular motility (ICM) as a surrogate of cellular viability. For this purpose, we have simultaneously obtained and compared ICM-contrast DLS-OCM images and calcium fluorescence-contrast images of retinal ganglion cells, and then characterized the responses of the measured ICM to a change in cellular viability induced by environmental conditions such as temperature and pH. The diffusion-coefficient-represented ICM exhibits consistent changes with the manipulated cellular viability.

DLS-OCT is tested to serve as a means to image the cellular viability with a single-cell resolution in mouse retinal tissue. Multiple metrics have been tested for representation of cellular or tissue viability, including intensity signal, decorrelation, and diffusion coefficient.

To determine if tumor biomarkers were predictive of outcome in a prospective cohort of patients with advanced larynx cancer treated in a phase II clinical trial.Prospectively collected biopsy specimens from 58 patients entered into a Phase II trial of organ preservation in advanced laryngeal cancer were evaluated for expression of a large panel of biomarkers, and correlations with outcome were determined.Tissue microarrays were constructed from pretreatment biopsies and stained for cyclin D1, CD24, EGFR, MDM2, PCNA, p53, survivin, Bcl-xL, Bcl-2, BAK, rhoC, and NFκB. Pattern of invasion and p53 mutations were assessed. Correlations with overall survival (OS), disease-specific survival (DSS), time free from indication of surgery, induction chemotherapy response, and chemoradiation response were determined. Cox models were used to assess combinations of these biomarkers.Low expression of BAK was associated with response to induction chemotherapy. Low expression of BAK and cytoplasmic NFκB was associated with chemoradiation response. Aggressive histologic growth pattern was associated with response induction chemotherapy. Expression of cyclin D1 was predictive of overall and disease-specific survival. Overexpression of EGFR was also associated with an increased risk of death from disease. Bcl-xL expression increased significantly in persistent/recurrent tumors specimens when compared to pretreatment specimens derived from the same patient (P = 0.0003).Evaluation of biomarker expression in pretreatment biopsy specimens can lend important predictive and prognostic information for patients with advanced larynx cancer.

Background The purpose of this study was to describe the relationship of p16 and epidermal growth factor receptor (EGFR) expression with survival in surgically treated patients who had oropharyngeal or oral cavity squamous cell carcinoma (SCC). Methods Tissue from 36 patients with oropharyngeal SCC and 49 patients with oral cavity SCC treated between 1997 and 2001 was imbedded and immunostained using a tissue microarray. Results The p16 was positive in 57% and 13% of patients with oropharyngeal SCC and oral cavity SCC, respectively. EGFR was positive in 60% and 63% of patients with oropharyngeal SCC and oral cavity SCC, respectively. In patients with oropharyngeal SCC, p16 expression was associated with improved disease-specific survival (DSS), overall survival (OS), and time to recurrence (TTR) (p < .01, < .01, and

Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib.Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual.From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths.Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.

The purpose of this work was to determine SEPT9_v1 expression levels in head and neck squamous cell carcinoma (HNSCC) and to analyze whether SEPT9_v1 expression is relevant to clinical outcomes. Recently, the SEPT9 isoform SEPT9_v1 has been implicated in oncogenesis, and methylation of the SEPT9 promoter region was reported in HNSCC. These findings led us to hypothesize that SEPT9_v1 could be differently expressed in HNSCC. To determine whether SEPT9_v1 is expressed in HNSCC, tissue microarray immunohistochemical analysis was performed using a SEPT9_v1-specific antibody. Tissue microarrays stained with a polyclonal SEPT9_v1-specific antibody was used to determine protein expression levels in HNSCC tissue samples, some with known clinical outcomes. This analysis showed that SEPT9_v1 is in fact highly expressed in HNSCC compared with normal epithelium, and high expression levels directly correlated with poor clinical outcomes. Specifically, a high SEPT9_v1 expression was associated with decreased disease-specific survival (P = .012), time to indication of surgery at primary site (P = .008), response to induction chemotherapy (P = .0002), and response to chemotherapy (P = .02), as well as advanced tumor stage (P = .012) and N stage (P = .0014). The expression of SEPT9_v1 was also strongly correlated with smoking status (P = .00094). SEPT9_v1 is highly expressed in HNSCC, and a high expression of SEPT9_v1 is associated with poor clinical outcomes. These data indicate that SEPT9_v1 warrants additional investigation as a potential biomarker for HNSCC.

Esophagectomy is indicated occasionally for the treatment of patients with refractory gastroesophageal reflux disease (GERD) or recurrent hiatus hernia. The purpose of this study was to evaluate the impact of previous gastroesophageal operations on outcomes after esophagectomy for recurrent GERD or hiatus hernia.Using a prospectively accumulated database, a retrospective review was performed to identify patients undergoing esophagectomy for complicated GERD or hiatus hernia. Mortality, perioperative and functional outcomes, and need for reoperation were evaluated, assessing esophagectomy patients who had undergone prior operations for GERD or hiatus hernia.Of 258 patients with GERD or hiatus hernia undergoing esophagectomy, 104 had undergone a previous operation, with a median interval to esophagectomy of 28 months. Transhiatal resection was accomplished in fewer patients undergoing reoperation (87 of 104 versus 151 of 154; p0.005). A gastric conduit was used as an esophageal replacement in fewer patients with previous operation(s) (89 of 104 versus 150 of 154; p0.005). Esophagectomy patients with a history of prior gastroesophageal surgery, as compared with those without, sustained more blood loss and were more likely to require reoperation, and fewer reported good to excellent swallowing function (p0.05). There was no difference in the occurrence of anastomotic leak.Esophagectomy in patients who have undergone prior operations for either GERD or hiatus hernia can be accomplished without thoracotomy and with satisfactory intermediate-term quality of life. Such patients should be evaluated and prepared for the use of alternative conduits should the remobilized stomach prove to be an unsatisfactory esophageal substitute at the time of esophagectomy.

Purpose: The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)–positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy. Experimental Design: Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival. Results: One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221). Conclusions: Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users. Clin Cancer Res; 16(4); 1226–35

Background. For patients with advanced laryngeal cancer, a trial was designed to determine if chemotherapy alone, in patients achieving a complete histologic complete response after a single neoadjuvant cycle, was an effective treatment with less morbidity than concurrent chemoradiotherapy. Methods. Thirty-two patients with advanced laryngeal or hypopharyngeal cancer received 1 cycle of induction chemotherapy, and subsequent treatment was decided based on response. Results. A histologic complete response was achieved in 4 patients and were treated with chemotherapy alone. All 4 patients' cancer relapsed in the neck and required surgery and postoperative radiotherapy (RT). Twenty-five patients were treated with concomitant chemoradiation. Three patients were treated with surgery. Overall survival and disease-specific survival at 3 years were 68% and 78%, respectively. Conclusion. Chemotherapy alone is not feasible for long-term control of regional disease in patients with advanced laryngeal cancer even when they achieve a histologic complete response at the primary site.

Although studies differ in their definition of the older patient, increasing age, when considered as a continuum, is associated with greater operative mortality. Complication rates also seem to be significantly higher with advancing age, possibly because of limited physiologic reserve. As the understanding of risk factors for perioperative morbidity and mortality following esophagectomy has improved, investigators have sought to develop models for risk stratification in which patient age is a significant but not the sole determinant of prospective assessment of risk for complication or mortality. Such prognostic indicators, if validated among independent patient cohorts, can serve as useful adjuncts in decision making with appropriate clinical judgment. In addition, reported patient survival differs dramatically between rates reported by single centers and rates observed in population-based studies, with operative mortality rates typically lower in single-center reports. Although such reports usually are issued from groups with higher operative volume that might be a surrogate for surgical experience, it also is possible that the association between operation volume and improved outcomes reflects optimization of institution-specific infrastructure and/or clinical care pathways. As these processes of care evolve, they should be tailored with attention to differences in the care of older patients who have esophageal cancer. Whether widespread application of such processes of care then can lead to less perioperative mortality and fewer complications and to improved long-term survival remains untested.

High rates of overall survival (OS) and laryngeal preservation were achieved in two sequential phase II clinical trials in patients with stage III/IV laryngeal squamous cell carcinoma (SCC). Patients were treated with chemoradiation after a50% primary tumor response to one cycle of neoadjuvant chemotherapy (IC). We analyzed outcomes for T4 patients with cartilage invasion from both studies.Retrospective.Records from 36 patients with T4 SCC of the larynx with cartilage invasion alone (n = 16) or cartilage invasion and extralaryngeal spread (n = 20) were retrospectively reviewed. All were treated with one cycle of cisplatin (100 mg/m(2)) [or carboplatin (AUC 6)] and 5-fluorouracil (1,000 mg/m(2)/d for 5 days) (P+5FU). Those achieving50% response at the primary tumor received chemoradiation (70 Gy; 35 fractions with concurrent cisplatin-100 mg/m(2) [carboplatin (AUC 6)] every 21 days for 3 cycles), followed by adjuvant P+5FU for complete histologic responders (CHR). Patients with50% response after IC underwent total laryngectomy and postoperative radiation.Twenty-nine of 36 patients (81%) had50% response following IC. Of these, 27 received definitive chemoradiation, 23 (85%) obtained CHR, with 58% laryngeal preservation rate. The 3-year OS was 78%, and the disease-specific survival was 80% (median follow-up 69 months). Following chemoradiation, 8/11 (73%) patients with an intact larynx had75% understandable speech, 6/36 (17%) were g-tube dependent and 6/36 (17%) were tracheostomy dependent.Our results suggest that chemo-selection is a feasible organ preservation alternative to total laryngectomy for patients with T4 laryngeal SCC with cartilage invasion.

Transhiatal esophagectomy with cervical esophagogastric anastomosis is a common approach in patients requiring esophagectomy. Factors for developing cervical esophagogastric anastomosis leaks (CEGAL), their presentation, and the value of a routine postoperative screening barium swallow in detecting CEGALs and other complications were analyzed.This single-institution retrospective study used medical records and an esophagectomy database to assess results in 1,133 patients who underwent transhiatal esophagectomy and a cervical esophagogastric anastomosis, 241 for benign disease and 892 for cancer, between January 1996 and December 2006.Esophagectomy patients who experienced CEGALs included 127 (14.2%) with cancer and 23 (9.5%) with benign disease. Logistic regression analysis identified increasing number of preoperative comorbidities (p0.001), active smoking history (p = 0.044), and postoperative arrhythmia (p = 0.002) as risk factors for CEGALs, and a side-to-side stapled cervical esophagogastric anastomosis compared with a manually sewn one as protective (p0.001). For cancer patients, higher pathologic stage disease (p = 0.050) was a risk factor for CEGALs. For patients with benign disease, a higher number of prior esophagogastric operations (p = 0.007) is a risk factor for CEGALs. Of the 90.7% of CEGALs that occurred on or before postoperative day 10, cervical wound drainage (63.3%) was the most common presenting symptom. Screening barium swallow identified postoperative complications and influenced outcome in 39 patients (3.8%).Higher number of preoperative comorbidities, advanced pathologic stage, postoperative arrhythmia, an increased number of prior esophagogastric surgeries, and active smoking history are risk factors for developing CEGAL, and a side-to-side stapled cervical esophagogastric anastomosis is protective. Screening barium swallow identifies few postoperative complications, but provides quality control.

Background To evaluate the efficacy of fluorine-18-fluorodeoxyglucose emission tomography (FDG-PET) and CT versus endoscopy with biopsy under general anesthesia for estimating tumor volume reduction among patients treated with induction chemotherapy for advanced squamous cell carcinoma (SCC) of the oropharynx. Methods Twelve patients with oropharyngeal SCC nested in a phase II, induction chemoradiation, organ preservation trial (University of Michigan Cancer Center 9921) underwent tumor volume reduction estimation as assessed by FDG-PET, CT, and endoscopy with biopsy. Results In 9 of 12 patients, FDG-PET, CT, and endoscopy demonstrated agreement in estimation of tumor reduction. Two patients had discordant results, whereas 1 patient was inadequately evaluated with FDG-PET. The kappa value for PET versus endoscopy was 0.62, which is categorized as substantial agreement. The kappa value for CT versus endoscopy was 0.40, which is categorized as fair agreement. Conclusion FDG-PET may be as efficacious as endoscopy with biopsy under general anesthesia for estimating tumor volume reduction with induction chemotherapy. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

BACKGROUND: Atypical Spitz tumors (AST) are rare spitzoid melanocytic proliferations with an uncertain malignant potential. ASTs have overlapping features of both Spitz nevi and spitzoid melanoma, and consequently generate controversy with diagnosis and management. Sentinel lymph node biopsy (SLNB) has been proposed as a possible means to gain additional insight into the true biologic potential of these tumors; however, previous reports on the use of SLNB in ASTs have been limited by small numbers of patients and short durations of follow-up. METHODS: The authors extracted data from their institution’s prospective melanoma database, collected between 1994 and 2007, for all patients with ASTs of uncertain biologic potential. They reviewed the clinical features of these patients, including the sentinel lymph node status, and the histological features of the tumors. RESULTS: A total of 67 patients with ASTs were identified, with a median age of 23.7 years. The mean depth was 2.4 mm. Of these, 57 had a SLNB performed, with 27 (47%) having a positive sentinel lymph node. SLNB-positive cases had a significantly lower mean age than SLNB-negative cases (17.9 vs 28.7 years; P ¼ .013); however, no other significant differences were observed. All 27 patients with a positive SLNB were alive and disease free with median follow-up of 43.8 months. One patient who did not receive a SLNB developed recurrent disease with regional and distant metastases. CONCLUSIONS: ASTs do not appear to behave like conventional melanoma. There is a high incidence of microscopic lymph node deposits in SLNBs, but despite this finding, patients have a favorable prognosis. Our findings raise several questions regarding the malignant potential of ASTs, and the role of SLNB in their management. Cancer 2009;115:631–41. V C 2009 American Cancer Society.

Purpose To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome. Patients and Methods Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m2) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m2/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m2 or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV. Results Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008). Conclusion Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.

The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G1-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P < 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P < 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P < 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P < 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs. [Cancer Res 2008;68(10):3959–69]

In 1978, the senior author reported at the Annual Meeting of the American Association for Thoracic Surgery his experience with 28 “blunt” transhiatal esophagectomies, 4 for benign disease and 22 for esophageal carcinoma.1 The concept of resecting the esophagus without performing a thoracotomy had been proposed initially in 1913 by the German anatomist, Denk, who used an instrument similar to a Mayo vein stripper to mobilize the intrathoracic esophagus.2 In 1933, the British surgeon, Turner, carried out the first successful transhiatal blunt esophagectomy for carcinoma and reestablished continuity of the alimentary tract using an antethoracic skin tube at a second operation.3 But as safe open thoracotomy became a reality with the advent of general endotracheal anesthesia, and it was possible to resect the esophagus under direct vision, transhiatal esophagectomy without thoracotomy (THE) was performed only sporadically, usually as a concomitant procedure with laryngopharyngoesophagectomy for pharyngeal or cervical esophageal carcinomas when the stomach was used to restore continuity of the alimentary tract.4–6 Kirk used this approach for palliation of incurable esophageal carcinoma in 5 patients.7 Thomas and Dedo treated 4 patients with pharyngoesophageal caustic strictures by blunt thoracic esophagectomy without thoracotomy, mobilization of the stomach through the posterior mediastinum, and then a pharyngogastric anastomosis.8 The first transhiatal esophagectomy performed by the senior author (MBO) in 1976 was unplanned and without prior knowledge of the historical precedent for the procedure. Avoidance of (1) combined thoracic and abdominal incisions in debilitated patients with esophageal obstruction and (2) a mediastinal anastomosis with its potential for mediastinitis from a leak formed the basis for advocating this approach. This newly “resurrected” operation was not initially well received, and critics of transhiatal esophagectomy were quick to point out that the operation violated basic surgical principles of adequate hemostasis and exposure and was an inadequate “cancer operation” because it precluded an en bloc mediastinal lymph node dissection. Following our 1978 publication, multiple reports of series of transhiatal esophagectomies amply addressed the initial criticism of transhiatal esophagectomy. The 1999 report of the University of Michigan Section of Thoracic Surgery’s 22 year experience with 1085 transhiatal esophagectomies provided a benchmark standard for the operation.9 Since 2000, mortality after esophageal resection has been shown to be strongly related to the hospital volume of the procedure.10–13 In the subsequent 8.5 years since our 1999 report, an additional 944 of these operations have been performed for diseases of the intrathoracic esophagus bringing our experience with transhiatal esophagectomy to more than 2000. This experience of a high volume esophageal surgery center has resulted in a progressive reduction in the historic morbidity and mortality of esophageal resection. The changing trends and lessons learned in this cumulative experience are the subject of this report.

The efficacy of fluoxetine in the acute management of bulimia nervosa is well established; however, few controlled studies have examined whether continuation of pharmacotherapy provides protection from relapse. This study compared the efficacy and safety of treatment with fluoxetine versus placebo in preventing relapse of bulimia nervosa during a 52-week period after successful acute fluoxetine therapy.Patients who met DSM-IV criteria for bulimia nervosa, purging type, were assigned to single-blind treatment with 60 mg/day of fluoxetine. After 8 weeks of treatment, patients were considered responders if they experienced a decreaseor =50% from baseline in the frequency of vomiting episodes during 1 of the 2 preceding weeks. Responders were randomly assigned to receive 60 mg/day of fluoxetine or placebo and were monitored for relapse for up to 52 weeks. Patients met relapse criteria if they experienced a return to the baseline vomiting frequency that persisted for 2 consecutive weeks.Of the 232 patients who entered the acute phase, 150 patients (65%) met response criteria and were randomly assigned to receive fluoxetine (N=76) or placebo (N=74). Fluoxetine-treated patients exhibited a longer time to relapse than placebo-treated patients. Quantitative analysis of other efficacy measures, including frequency of vomiting episodes, frequency of binge eating episodes, Clinical Global Impression severity and improvement scores, the patient's global impression score, and Yale-Brown-Cornell Eating Disorder Scale score, indicated that the efficacy of fluoxetine treatment was statistically superior, compared to placebo. There were no clinically relevant differences in safety between groups. Attrition in this study was high, especially in the first 3 months after random assignment to treatment groups.Continued treatment with fluoxetine in patients with bulimia nervosa who responded to acute treatment with fluoxetine improved outcome and decreased the likelihood of relapse.

BACKGROUND People with cancer are increasingly turning to the Internet for health-related information. OBJECTIVE To compare the patterns of Internet use of people with skin cancer with previous findings by including people with nonmelanoma skin cancer (NMSC) using a comprehensive survey. To evaluate perceived anxiety levels and overall satisfaction after searching the Internet of people with skin cancer. METHODS & MATERIALS We conducted a survey study and prospectively collected data from people newly diagnosed with melanoma or NMSC. RESULTS Four hundred fifteen participants with melanoma and 400 with NMSC completed the questionnaire. Internet use and overall satisfaction with the Internet search increased more than 50% in participants with melanoma from 2005. One-third of participants with melanoma, but many fewer participants with NMSC, reported higher anxiety after Internet use. Participants who were younger, female, more highly educated, and diagnosed with melanoma were most likely to use the Internet to search for information about their diagnosis. CONCLUSION Internet use is prevalent and increasing sharply in individuals with skin cancer. The majority of individuals describe their use of the Internet as a positive experience. Greater anxiety from searching the Internet is more common in individuals with melanoma than in those with NMSC. The authors have indicated no significant interest with commercial supporters.

Purpose: In head and neck squamous cell carcinoma (HNSCC) cells, Rap1 shuttles between the nucleus and cytoplasm. Prior findings suggested that Rap1 may modulate the β-catenin–independent Wnt pathway in some settings, but the role of Rap1 in β-catenin–dependent Wnt signaling remains undefined. Experimental Design and Results: We observed that β-catenin bound to active Rap1 in vitro and Rap1 activated β-catenin/T-cell factor (TCF)–dependent transcription. Immunofluorescence studies showed that ectopic expression of Rap1 increased nuclear translocation of β-catenin. Overexpression of active Rap1 facilitated an increase in β-catenin–mediated transcription that was abrogated by dominant-negative TCF4. Conversely, small interfering RNA–mediated inhibition of endogenous Rap1 expression inhibited β-catenin/TCF–mediated transcription as well as invasion of HNSCC. Furthermore, inhibition of Rap1 expression downregulated the expression of matrix metalloproteinase 7, a transcriptional target of β-catenin/TCF. In HNSCC cells stably transfected with β-catenin or treated with lithium chloride or Wnt3A to stabilize endogenous β-catenin, inhibition of Rap1 expression led to decreases in the free pool of β-catenin. Immunohistochemical studies of tissue from HNSCC patients revealed that increased β-catenin intensity correlated with higher tumor stage. Furthermore, the prognostic effect of active Rap1 on tumor N stage was found to depend on cytosolic β-catenin expression (P < 0.013). When β-catenin is high, higher Rap1GTP intensity is associated with more advanced N stage. Conclusions: The findings suggest that Rap1 enhances β-catenin stability and nuclear localization. In addition to indicating that Rap1 has a significant role in regulating β-catenin and β-catenin–dependent progression to more advanced N-stage lesions, these data highlight Rap1 as a potential therapeutic target in HNSCC. Clin Cancer Res; 16(1); 65–76

A quasi-experimental retrospective study was undertaken to evaluate a new concept of free tissue volume restoration combined with bridging reconstruction plate (compartment approach) to reduce plate-related complication rates.We evaluated 40 patients with large lateral mandible defects and associated complex soft tissue defects reconstructed with a revascularized soft tissue flap and titanium hollow screw reconstruction plates. A case-control comparison was performed based on reconstruction type: restoration of soft tissue defect (conventional approach-group 1) versus over-reconstruction of soft tissue defect (compartment approach-group 2).Plate exposure rate was 6 of 16 (38%) in group 1 versus 2 of 24 (8%) in group 2, and the difference was statistically significant (p = .04). The mean time to exposure was 10 months. Plate fracture rate was 6 of 23 (26.1%) in dentulous patients versus 1 of 17 (5.9%) in edentulous patients. Gastrostomy tube dependence was 6 of 16 (38%) in group 1 versus 6 of 24 (25%) in group 2.The "compartment approach" reduces plate exposure rate and gastrostomy tube dependence. Revascularized osseocutaneous reconstruction is still required in dentulous patients.

Induction chemotherapy and concurrent chemoradiation for responders or immediate surgery for non-responders is an effective treatment strategy head and neck squamous cell carcinoma (HNSCC) of the larynx and oropharynx. Biomarkers that predict outcome would be valuable in selecting patients for therapy. In this study, the presence and titer of high risk human papilloma virus (HPV) and expression of epidermal growth factor receptor (EGFR) in pre-treatment biopsies, as well as smoking and gender were examined in oropharynx cancer patients enrolled in an organ sparing trial. HPV16 copy number was positively associated with response to therapy and with overall and disease specific survival, whereas EGFR expression, current or former smoking behavior, and female gender (in this cohort) were associated with poor response and poor survival in multivariate analysis. Smoking cessation and strategies to target EGFR may be useful adjuncts for therapy to improve outcome in the cases with the poorest biomarker profile.

Purpose: The aim of this study was to test the hypothesis that measuring quantitative changes in signal intensity early after radiotherapy (RT) in the contrast-enhancing tumor rim and nonenhancing core may be a noninvasive marker of early treatment response in patients with high-grade gliomas. Methods and Materials: Twenty patients with high-grade gliomas had magnetic resonance imaging (MRI) performed 1 week before RT, during Weeks 1 and 3 of RT, and every 1 to 3 months after RT as part of a clinical prospective study. Regions of interest (ROI) including contrast-enhancing rim, and the nonenhancing core were defined automatically based on a calculated image of post- to precontrast T1-weighted MRI. Pretreatment T1-weighted MRI signal intensity changes were compared with Weeks 1 and 3 RT and 1 and 3 months post-RT MRI. Clinical and MRI parameters were then tested for prediction of overall survival. Results: Regional T1-weighted signal intensity changes in both the contrast-enhancing rim and the nonenhancing core were observed in all patients during Week 1 and Week 3 of RT. Imaging parameters including signal intensity change within the nonenhancing core after Weeks 1 to 2 RT ( p = 0.004), Weeks 3 to 4 RT ( p = 0.002) and 1 month after completion of RT ( p = 0.002) were predictive of overall survival. Using multivariate analysis including RTOG recursive partitioning analysis (RPA) and signal intensity change, only the signal intensity change in the nonenhancing core at 1 month after RT ( p = 0.01) retained significance. Conclusion: Quantitative measurements of T1-weighted MRI signal intensity changes in the nonenhancing tumor core (using ratios of pre–post values) may provide valuable information regarding early response during treatment and improve our ability to predict posttreatment outcome.

To evaluate the ability of a well-known normal tissue complication probability (NTCP) model to predict radiation esophagitis by determining updated model parameters and then comparing these results with the predictive value of other dosimetric parameters.Clinical and dosimetric data regarding esophagitis were analyzed in 101 inoperable/unresectable non-small-cell lung cancer patients treated by external beam irradiation. Grade 2 or higher esophagitis counted as events. Parameters (TD50, n, and m) of the Lyman normal tissue complication probability (NTCP) model were determined using maximum likelihood analysis, and compared to other dose/volume threshold values including: percentage of esophagus receiving40 Gy (V40) to75 Gy (V75), and maximum esophageal doses.Sixteen patients developed grade 2-3 acute esophagitis (no G4 or 5). The maximum likelihood analysis produced new Lyman model parameters of: TD50 = 51 Gy, n = 0.44 and m = 0.32. The mean NTCP value is significantly lower (P0.001) in the group of patients without esophagitis (13.5%) than with esophagitis (27.2%). The rates of esophagitis are 2.5, 7, 9 and 13.4%, respectively, when the NTCP values are10%,15%,20% and25%. A significant association is found between esophagitis and dose/volume parameters V40 (P = 0.001) to V70 (P = 0.024).New values of TD50, n and m offer a good description of the esophagitis distribution in our population. Compared to the use of this model with previously published parameters (associated with late toxicity) predictions of the model for acute esophagitis using the new parameters would indicate that, for a population of patients, the distribution of events as a function of uniform dose would occur with a lower mean uniform dose value (smaller TD50), over a wider range of uniform doses (larger m), while also exhibiting a bigger volume effect (larger n). These new parameter values are supported in essence by the correlations found for the dose/volume threshold parameters.

Purpose: To determine the relationship between the radiation dose to the inner ear and long-term hearing loss. Methods and Materials: Eligible patients included those receiving curative radiotherapy (RT) for head-and-neck cancer. After enrollment, patients underwent three-dimensional conformal RT planning and delivery (180–200 cGy/fraction) appropriate for their disease site and stage. The inner ear was contoured on axial CT planning images. Dose-volume histograms, as well as the mean and maximal dose for each structure, were calculated. Patients underwent pure tone audiometry at baseline (before treatment) and 1, 6, 12, 24, and 36 months after RT. The threshold level (the greater the value, the more hearing loss) in decibels was recorded for 250, 500, 1000, 2000, 4000, and 8000 Hz. For patients receiving predominantly unilateral RT, the contralateral ear served as the de facto control. The differences in threshold level between the ipsilateral and contralateral ears were calculated, and the temporal pattern and dose-response relation of hearing loss were analyzed using statistical methods that take into account the correlation between two ears in the same subject and repeated, sequential measurements of each subject. Results: Of the 40 patients enrolled in this study, 35 qualified for analysis. Four patients who received concurrent chemotherapy and RT were analyzed separately. The 31 unilaterally treated patients received a median dose of 47.4 Gy (range, 14.1–68.8 Gy) to the ipsilateral inner ear and 4.2 Gy (range, 0.5–31.3 Gy) to the contralateral inner ear. Hearing loss was associated with the radiation dose received by the inner ear (loss of 210dB was observed in ears receiving ≥45 Gy) and was most appreciable in the higher frequencies (≥2000 Hz). For a 60-year-old patient with no previous hearing loss in either ear, after receiving 45 Gy, the ipsilateral ear, according to our clinical model, would have a 19.3-dB (95% confidence interval [CI], 15.5–23.0) and 5.4-dB (95% CI, 3.5–7.5) hearing decrement compared with the contralateral ear for 8000 Hz and 1000 Hz, respectively. Age and an initial hearing difference within an ear pair also affected hearing loss. The baseline hearing threshold was inversely related to radiation-induced hearing loss. The degree of hearing loss was dependent on the frequency tested, age, baseline hearing, and baseline difference in hearing between a patient's two ears. Conclusion: High-frequency (≥2000 Hz) hearing acuity worsens significantly after RT in a dose-dependent fashion. A larger number of patients needs to be studied to validate these results. This knowledge can be applied to create guidelines regarding future dose limits to the auditory apparatus for patients undergoing head-and-neck RT.

Purpose We sought to determine whether African American men diagnosed with prostate cancer in the prostate-specific antigen (PSA) era differed in initial presenting serum PSA levels ( i PSA) compared to white men. Recent retrospective studies have demonstrated higher i PSA within the African American men than in white men at the time of diagnosis, suggestive of more advanced disease in African American men. Both biologic differences and/or sociologic factors have been postulated as explaining the noted differences in i PSA. We reviewed our institution's PSA-era experience to determine any association between race and i PSA. Methods and materials Between January 1990 and September 2001, 4519 patients representing a broad demographic sample were seen in the radiation oncology department of a university hospital or one of its four community affiliates. A total of 2332 eligible patients, with data on race, age, year of diagnosis, Gleason score, T stage, and i PSA, were analyzed. The patients were separated into the two following time periods for analysis, based on the new American Cancer Society screening guidelines: ( 1 ) 1991 to 1996 and ( 2 ) 1997 to 2001. The relationships between race and i PSA, T stage, Gleason score, and age are explored. Results Of the 2332 patients analyzed, there were 1968 white men and 364 African American men. For the time period 1990 through 1996, the expected average (median) i PSA level was 10.5 (10.2) and 14.6 (15.8) for white men and African American men, respectively. For 1997 to 2001, the expected average i PSA level was 9.5 (8.4) and 10.8 (9.8), respectively. T stage distributions improved, independent of race, toward earlier stage at presentation. Gleason score distribution remained unchanged. African American men are 2.5–3.1 years younger than white men at diagnosis. Conclusion An overall decline in i PSA has occurred in both racial groups over time. More importantly, racial differences in i PSA among men diagnosed in the later time period (1997 to 2001) are less pronounced compared to men diagnosed in the earlier time period (1990 to 1996). This racial convergence in i PSA over time suggests improved penetrance of PSA screening in the African American population. Our findings also suggest that studies comparing racial differences in i PSA should consider time period of diagnosis and possible sociologic changes during that period (i.e., access to medical care, socioeconomic status, and educational level). The American Cancer Society guideline to begin screening African Americans at an earlier age is appropriate.

Detailed clinical, ophthalmological, and molecular studies were performed on a multigeneration family in which there were many subjects with type 1 neurofibromatosis, a common autosomal dominant disorder. Affected family members displayed a wide range of clinical findings including, in two subjects, features seen in Noonan syndrome (triangular facies, downward slanting palpebral fissures, micrognathia, short stature, and learning disability). Subjects have been described previously whose features have overlapped with neurofibromatosis and Noonan syndrome, and it has been suggested that these persons might represent a separate condition. DNA haplotype analysis showed linkage of the neurofibromatosis phenotype seen in this family to the proximal long arm of chromosome 17 in the region where the type 1 neurofibromatosis gene has been mapped. These results imply that the Noonan phenotype seen in some patients with type 1 neurofibromatosis might be the result of variable or variant expression of the neurofibromatosis gene on chromosome 17. The possible role of non-specific factors, such as fetal hypotonia, in producing the neurofibromatosis-Noonan phenotype needs further investigation. The availability of closely linked and intragenic molecular markers for neurofibromatosis could potentially be useful in the diagnosis and characterisation of patients and families with atypical forms of neurofibromatosis.

The deterioration from outdoor weathering of experimental wool fabrics differing in fiber fineness was measured by breaking strength, elongation at break, and crease recovery. With the amount of solar energy held approximately constant for each sampling period of each of the three consecutive sets of exposures, ambient temperature seemed to control the rate of deterioration. Differences in strength and elongation among the fabrics were non-significant. The fine wools recovered from creasing significantly more than the medium wool.

Experimental cotton fabries made from four lots of Acala 1517C cotton fiber selected for strength and fineness were used for constructing 192 gingham dresses. One dress of each fabric was assigned to each of 48 wearers. A schedule for regular wear and care was established. Over a series of 16 wear periods, dresses were withdrawn in replicates of three according to a random sampling plan. The worn fabries were tested at each of the wear periods for qualities pertaining to durability and appearance. Regression equations were calculated and trends of change plotted. Properties of the fabries from the four fiber lots were compared. Fiber fine ness was of greater importance than strength in maintaining desirable wearing qualities of the fabries.