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Background Breast fibroadenoma (FA) and phyllodes tumour (PT) often have variations of gene mediator complex subunit 12 (MED12) and mutations in the telomerase reverse transcriptase promoter region (TERTp). TERTp mutation is usually tested by Sanger sequencing. In this study, we compared Sanger sequencing and droplet-digital PCR (ddPCR) to measure TERTp mutations in FA and PT samples. Methods FA and PT samples were collected from 82 patients who underwent surgery at our institution from 2005 to 2016. MED12 mutations for all cases and TERTp mutations for 17 tumours were detected by Sanger sequencing. ddPCR was performed to analyse TERTp mutation in all cases. Results A total of 75 samples were eligible for analysis. Sanger sequencing detected MED12 mutations in 19/44 FA (42%) and 21/31 PT (68%). Among 17 Sanger sequencing-tested samples, 2/17 (12%) were TERTp mutation-positive. In ddPCR analyses, a significantly greater percentage of PT (19/31, 61%) was TERTp mutation-positive than was FA (13/44, 30%; P = 0.0046). The mutation positivity of TERTp and MED12 did not correlate, in either FA or PT. Conclusions ddPCR was more sensitive for detecting TERTp mutation than Sanger sequencing, being able to elucidate tumorigenesis in FA and PT.

Recent studies have indicated the potential benefit of intraoperative near-infrared fluorescence imaging (NIR-FI) with indocyanine green in reducing early anastomotic leakage in colorectal surgery. Nonetheless, whether NIR-FI is effective in reducing structural sequelae of anastomotic leakage (SSAL) remains unclear. The aim of the present study was to investigate the impact of NIR-FI on SSAL after laparoscopic intersphincteric resection (ISR) of malignant rectal tumors.This study was a retrospective single-center cohort study. A total of 293 consecutive patients who underwent elective laparoscopic ISR from May 2010 to August 2017 were included. Patients were divided into 2 groups; those who underwent elective laparoscopic ISR with lymphadenectomy for malignant rectal tumors using NIR-F (NIR-FI group) and those who underwent elective laparoscopic ISR with lymphadenectomy for malignant rectal tumors without using NIR-FI (control group). Thirty were excluded from the analyses (13 died, 7 had pelvic recurrence, and 10 were lost to follow-up). The primary endpoint was the rate of SSAL within 2 years after the primary resection, whereas the secondary endpoint was the rate of natural defecation via the anus at 2 years after the primary resection. Using various statistical analyses, such as propensity score matching, the rate of SSAL was compared between groups.A total of 263 patients were analyzed [177 males and 86 females, median age 61 (27-84) years]. Prior to propensity score matching (n = 263), NIR-FI was performed in 70 patients (26.6%) The rates of SSAL were 1.4% (1/70) in the NIR-FI group and 10.4% (20/193) in the control group (p = 0.02). After propensity score matching (n = 163), the rates of SSAL were 1.5% (1/66) in the NIR-FI group and 11.7% (12/103) in the control group (p = 0.02). Propensity score analyses, as well as simple regression analyses, revealed that NIR-FI was associated with a significantly lower risk of SSAL (OR 0.10-0.13; p = 0.03-0.05).NIR-FI is useful in reducing the rate of SSAL after laparoscopic ISR.

We previously reported the usefulness of droplet digital polymerase chain reaction (ddPCR) for the assessment of Human epithelial growth factor receptor 2 (HER2) gene amplification in breast cancer using formalin-fixed and paraffin-embedded sections. In our previous study, we combined HER2/CEP17 ratio (HER2 gene signals to chromosome 17 signals) with ddPCR and tumor content ratio (TCR) of each sample and determined the HER2 status by adopting a two-dimensional chart. This “ddPCR-TCR method” showed a high concordance with conventional HER2 status. In this study, we updated our method to assess the HER2 status of breast cancer in a more quantitative manner. We combined obtained data of the ddPCR ratio [Rx] and TCR [x]; we calculated “(Rx − 1) / x + 1” for 41 samples with primary breast cancer and named the value led by this formula as “eHER2 (estimated HER2/CEP17 ratio of a tumor cell)”. eHER2 was equivalent to conventional ISH HER2/CEP17 ratio in most cases. eHER2 and ISH ratio showed a very strong correlation (Spearman rank correlation; ρ = 0.70, P < 0.0001). The obtained results indicated that eHER2 is a potential tool for HER2 status diagnosis in breast cancer.

Our double-blind, placebo-controlled study evaluated effects of ubiquinol, the reduced form of coenzyme Q10, on mild fatigue in healthy individuals experiencing fatigue in daily life that had continued for more than 1 and less than 6 months. The participants received 100-mg/day (Ubq100, age 44.0 &plusmn, 9.8 years, 14 females and 6 males) or 150-mg/day ubiquinol (Ubq150, age 40.4 &plusmn, 11.8 years, 14 females and 8 males) or placebo (Plc, age 41.3 &plusmn, 13.4 years, 13 females and 7 males) daily for 12 weeks. Measurements of subjective and objective fatigue were conducted by using questionnaires-based fatigue scales/visual analogue scales and autonomic nerve function/biological oxidation index, respectively, prior to the first dosing and every 4 weeks thereafter. Serum ubiquinol level increased three- to four-fold after 4 weeks and remained significantly higher than that after Plc administration throughout the intake period. Although a higher blood level of ubiquinol was observed with Ubq150 than with Ubq100, the difference was not statistically significant. In both Ubq100 and Ubq150 groups, subjective levels of fatigue sensation and sleepiness after cognitive tasks, which consisted of the modified Advanced Trail Making Test, the modified Stroop Color-Word Test, and the Digit Symbol Substitution Test, improved significantly compared with those in the placebo group, suggesting an anti-fatigue effect. The Ubq150 group demonstrated significant improvement compared with the Plc group regarding subjective level of relaxation after task, sleepiness before and after task, motivation for task, and serum level of oxidative stress. Correlation analysis between blood level of ubiquinol and each evaluated effect suggested a positive relationship with relaxation after task, motivation for cognitive task, and parasympathetic activity. The results of the study suggest that ubiquinol intake relieves mild fatigue in healthy individuals.

International audience; Background: Successful application of programmed death 1 (PD1) checkpoint inhibitors in the clinic may ultimately benefit from appropriate patient selection based upon predictive biomarkers. Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while predictive biomarkers for response to PD1 checkpoint inhibitors are lacking. We sought to assess whether overexpression of PD-L1 in CTCs could be detected at baseline and at different timepoints during treatment in a prospective cohort of head and neck squamous cell carcinoma (HNSCC) patients and used to predict clinical outcome after treatment with curative intent. Patients and methods: We developed a highly sensitive, specific and robust RT-qPCR assay for PD-L1 mRNA expression in EpCAM(+) CTCs. In a prospective cohort of 113 locally advanced HNSCC patients treated with curative intent we evaluated PD-L1 expression in the EpCAM(+) CTC fraction at baseline, after 2 cycles of induction chemotherapy (week 6) and at the end of concurrent chemoradiotherapy (week 15). Results: PD-L1 overexpression was found in 24/94 (25.5%) patients at baseline, 8/34 (23.5%) after induction chemotherapy and 12/54 (22.2%) patients at the end of treatment. Patients with CTCs overexpressing PD-L1 at end of treatment had shorter progression-free survival (P = 0.001) and overall survival (P \textless 0.001). Multivariate analysis revealed that PD-L1 overexpression at end of treatment was independent prognostic factor for progression-free survival and overall survival. The absence of PD-L1 overexpression at the end of treatment was strongly associated with complete response with an odds ratio = 16.00 (95% CI = 2.76-92.72, P = 0.002). Conclusions: We demonstrate that detection of CTCs overexpressing PD-L1 is feasible and may provide important prognostic information in HNSCC. Our results suggest that adjuvant PD1 inhibitors deserve evaluation in HNSCC patients in whom PD-L1(+) CTCs are detected at the end of curative treatment.

ObjectivesAn operations leader (OL) takes an important role in occupational health management for radiation decontamination workers in Japan, and candidates for the position must participate in a training session to acquire the necessary knowledge as required by law. However, it has not been clarified whether the candidates for the OL position actually possess accurate knowledge regarding occupational health management for such work after the training session. We, therefore, aimed at examining the current occupational health management knowledge among the candidates and investigating factors related to the knowledge, with hypothesis that possession of accurate knowledge is associated with prior experience of having worked in radiation decontamination.DesignA cross-sectional study.SettingThe training sessions held by Fukushima Prefecture Labor Standard Associations in Fukushima, Japan, in 2017.ParticipantsEighty male candidates participated in the training sessions.OutcomeThe number/proportion of correct answers to the questions regarding occupational health management, such as those on working environment management, control of operations and health management.ResultsThe proportion of those who possessed accurate knowledge regarding working environment management, control of operations and health management was 68.8%, 55.0% and 51.2%, respectively. Experience of radiation decontamination work was associated with the possession of inaccurate knowledge regarding working environment management (OR 0.140 (95% CI 0.042 to 0.464)), and the uncertainty of future radiation decontamination work schedules in difficult-to-return zones was associated with the possession of accurate knowledge regarding health management (OR 4.344 (95% CI 1.509 to 12.50)).ConclusionsPrevious experience in radiation decontamination work may hinder the ability to acquire accurate information regarding working environment management among candidates for an OL position. To promote adequate occupational health management for radiation decontamination workers, it is required to establish an effective instructional method for the OL candidate training sessions with consideration of previous relevant experience.

Background Recent preclinical explorations strongly support the tumorigenic potential of bile on laryngopharyngeal mucosa. Herein, the authors describe, in bile-related human hypopharyngeal squamous cell carcinoma (HSCC), NF-κB-related messenger RNA (mRNA) and microRNA (miRNA) oncogenic phenotypes similar to those previously identified in acidic bile-exposed premalignant murine hypopharyngeal mucosa. Methods In this pilot study, the authors included human HSCC specimens paired with their adjacent normal tissue (ANT) derived from 3 representative patients with documented biliary laryngopharyngeal reflux (bile[+]) compared with 5 control patients without signs of bile reflux disease (bile[-]). Immunohistochemical, quantitative polymerase chain reaction, and miRNA analyses were used to detect the levels of activated NF-κB and expression levels of STAT3, EGFR, BCL2, WNT5A, IL-6, IL-1B, ΔNp63, cREL, TNF-α, TP53, NOTCH1, NOTCH2, NOTCH3, miR-21, miR-155, miR-192, miR-34a, miR-375, miR-451a, miR-489, miR-504, and miR-99a. Results Bile(+) HSCC demonstrated an intense NF-κB activation accompanied by significant overexpression of RELA(p65), EGFR, STAT3, BCL-2, cREL, ΔNp63, WNT5A, IL-6, and IL1B; upregulation of oncomir miR-21; and downregulation of tumor suppressor miR-375 compared with their respective ANTs. Bile(+) HSCC demonstrated significantly higher mRNA levels of all the analyzed genes, particularly RELA(p65), IL-6, EGFR, and TNF-α compared with bile(-) tumors. The miR-21/miR-375 ratio, which previously has been linked to tumor aggressiveness, was found to be >260-fold and >30-fold higher, respectively, in bile(+) HSCCs compared with their ANTs and bile(-) tumors. Conclusions Although limitations apply to this pilot study due to the small number of patients with HSCC, the novel findings suggest that a history of bile as a component of esophageal reflux disease may represent an independent risk factor for hypopharyngeal carcinogenesis.

Objectives: Human papillomavirus (HPV) has emerged as a driving cause of head and neck cancer, but investigations outside the West are limited. A p16 immunohistochemistry is a commonly used biomarker for HPV cancers. We sought to investigate the pathology and rates of HPV head and neck oropharyngeal cancer in Japan via p16 immunohistochemistry at 2 institutions in Japan. Methods: Fifty-nine oropharyngeal specimens from 2 university hospitals in Japan were examined for morphology and p16 immunohistochemistry. The rate of p16 positivity was then determined, and the 2 groups were compared for differences in age, smoking history, gender, and stage of presentation and mortality. Results: The rate of p16 positivity among the oropharyngeal specimens was 29.5%. There were important differences in the pathology compared to morphology usually seen in the US. The patients with p16+ cancer tended to be younger. There was no significant difference in smoking status. Patients with p16+ cancers trended toward better survival. Conclusion: There appears to be a geographical difference in HPV rates of oropharyngeal cancers with persistently lower rates in Asian countries when compared to Western Europe and the US. Conclusions about HPV head and neck squamous cell carcinoma (HNSCC) in Western countries may not be generalizable across the globe at this time.

Summary What is known and objective In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout. Methods We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. Results and discussion One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere–Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was −30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of −32·4% ([95% confidence interval, −38·9% to −25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups. What is new and conclusions A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.

Introduction This study compared complication rates between pedicle flaps and free flaps used for resurfacing of intraoperative brachytherapy (IOBT) implants placed following head and neck tumour extirpation to help clarify the ideal reconstructive procedure for this scenario. Patients and methods A retrospective review of reconstructions with IOBT at our institution was conducted. Patient and treatment details were recorded, as were the number and type of flap complications, including re-operations. Logistic regressions compared complications between flap groups. Results Fifty free flaps and 55 pedicle flaps were included. On multivariate analysis, free flap reconstruction with IOBT was significantly associated with both an increased risk of having any flap complication (OR = 2.9, p = 0.037) and with need for operative revision (OR = 3.5, p = 0.048) compared to pedicle flap reconstruction. Conclusions In the setting of IOBT, free flaps are associated with an increased risk of having complications and requiring operative revisions.

Purpose: Programmed death-ligand 1 (PD-L1; also known as CD274 or B7-H1) expression represents a mechanism of immune escape for cancer. Our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in primary laryngeal squamous cell carcinomas (SCC). Experimental Design: A well-annotated cohort of 260 operable primary laryngeal SCCs [formalin-fixed paraffin-embedded (FFPE) specimens] was morphologically characterized for stromal tumor-infiltrating lymphocytes (TIL), on hematoxylin/eosin-stained whole sections and for PD-L1 mRNA expression by qRT-PCR in FFPE specimens. For PD-L1 protein expression, automated quantitative protein analysis (AQUA) was applied on tissue microarrays consisting of two cores from these tumors. In addition, PD-L1 mRNA expression in fresh-frozen tumors and normal adjacent tissue specimens was assessed in a second independent cohort of 89 patients with primary laryngeal SCC. Results: PD-L1 mRNA levels were upregulated in tumors compared with surrounding normal tissue (P = 0.009). TILs density correlated with tumor PD-L1 AQUA levels (P = 0.021). Both high TILs density and high PD-L1 AQUA levels were significantly associated with superior disease-free survival (DFS; TILs: P = 0.009 and PD-L1: P = 0.044) and overall survival (OS; TILs: P = 0.015 and PD-L1: P = 0.059) of the patients and retained significance in multivariate analysis. Conclusions: Increased TILs density and PD-L1 levels are associated with better outcome in laryngeal squamous cell cancer. Assessment of TILs and PD-L1 expression could be useful to predict response to immune checkpoint inhibitors. Clin Cancer Res; 22(3); 704–13. ©2015 AACR.

To design and implement a postoperative clinical care pathway designed to reduce intensive care usage on length of stay, readmission rates, and surgical complications in head and neck free flap patients.A postoperative clinical care pathway detailing timelines for patient care was developed by a multispecialty team. In total, 108 matched patients receiving free tissue transfer for reconstruction of head and neck defects in the year before (prepathway), year after (early pathway), and second year after (late pathway) pathway implementation were compared based on postoperative length of stay, 30-day readmission rate, intensive care unit (ICU) admission, and rates of medical/surgical complications.Median length of stay decreased from 10 to 7.5 and 7 days in the pre-, early, and late-pathway groups, respectively ( P = .012). Readmission rate decreased from 16% in the prepathway group to 0% and 3% in the early and late-pathway groups. The number of patients admitted to the ICU postoperatively decreased from 100% to 36% and 6% in the pre-, early, and late-pathway groups, respectively ( P = .025). The rates of surgical and medical complications were equivalent.This pathway effectively reduced ICU admission, length of stay, and readmission rates, without increasing postoperative complications. These outcomes were sustainable over 2 years.Free flap patients may not require routine ICU admission and may be taken off ventilatory support in the operating room. This effectively reduces costly resource use in this patient population. Similar pathways could be introduced at other institutions.

SummaryObjectiveTo examine whether the detection of osteophytes anywhere in the knee could serve as a pre-radiographic biomarker for osteoarthritis (OA) development.MethodsBaseline magnetic resonance imaging (MRIs) of 132 participants in the Osteoarthritis Initiative (OAI) were studied. Based on radiographs, 66 knees were assessed as osteoarthritis-free (no-osteoarthritis [NOA], or Kellgren/Lawrence [K/L] severity grade 0/1 both at baseline and 48 months), and another 66 knees were assessed as having radiographic OA changes (pre-radiographic osteoarthritis [PROA], or with K/L grade 0/1 at baseline and grade ≥2 at 48 months). Using baseline MRI data, we examined eight sites of osteophyte formation: the medial and lateral femoral condyle (MFC and LFC, respectively); medial and lateral tibial plateau (MTP and LTP, respectively); medial and lateral facets of the patellofemoral joint (PM and PL, respectively); tibial spine (TS); and femoral intercondylar notch (IC). Knee joint osteophyte size was assessed via the 8-point marginal osteophytes item of the whole-organ magnetic resonance imaging score (WORMS). The frequencies and distributions of osteophytes were compared between groups.ResultsMild-size osteophytes (defined as score ≥2) were observed more frequently at the MFC (P = 0.00278), MTP (P = 0.0046), TS (P = 0.0146), PM (P

To characterize treatment delays in oropharyngeal cancer treated with radiation in a national sample, identify factors associated with delays, and associate treatment delays with survival.We included adults in the National Cancer Database treated for oropharyngeal cancer with primary radiation or chemoradiation 2010-2013. We characterized diagnosis-to-treatment initiation, radiation treatment duration, and diagnosis-to-treatment end intervals as medians. We examined delays for association with patient, tumor, and treatment characteristics and with overall survival with multivariable logistic and Cox proportional hazards regression, respectively.4089 patients were included; 12% received radiation alone and 88% chemoradiation. The incidence of human papilloma virus-associated tumors was 64%. Median durations of diagnosis-to-treatment initiation, radiation duration, and diagnosis-to-treatment end were 35, 50, and 87 days, respectively. Human papilloma virus-positive tumors were linked to decreased delays in radiation treatment duration and diagnosis-to-treatment end (OR = 0.72 (0.60-0.85), p 0.001 and OR = 0.79 (0.66-0.95), p = 0.010, respectively). Delays in radiation treatment duration and diagnosis-to-treatment end were negatively associated with overall survival (HR = 1.23 (1.03-1.47), p = 0.024 and 1.24 (1.04-1.48), p = 0.017, respectively). When examined separately, radiation duration remained associated with decreased overall survival in patients with human papilloma virus-negative (HR = 1.29 (1.03-1.63), p = 0.030) but not human papilloma virus-positive tumors (HR = 1.17 (0.89-1.54), p = 0.257).These median durations can serve as national benchmarks. Diagnosis-to-treatment end interval is associated with overall survival in all patients, and radiation treatment duration in patients with human papilloma virus-negative tumors. These intervals could be considered quality indicators for oropharyngeal squamous cell carcinoma treated with primary radiation or chemoradiation.

The 2017 National Comprehensive Cancer Network Clinical Practice Guidelines recommend surgical resection or definitive radiation therapy for early-stage oral cavity malignancies, and surgical resection or multimodality clinical trials for late-stage disease. Few studies have been conducted to identify predictors of choice of treatment modality for oral cavity malignancies.All patients in the National Cancer Data Base (NCDB) diagnosed with oral cavity squamous cell carcinoma (OCSCC) between 1998 and 2011 were identified. Chi-square and binary logistic regression were used to identify factors predictive of surgical or nonsurgical treatment; multiple imputation was used for missing data. Cox proportional hazards models were generated to identify associations between treatment modality and overall survival (OS).Of 23,459 patients, 4139 (17.6%) underwent primary nonsurgical treatment. Among NCDB-registered facilities, there has been a decrease in use of nonsurgical treatment for OCSCC (OR 0.97, p0.001). Older age, non-white race, Medicaid insurance, low income, low education, and later-stage disease were associated with nonsurgical therapy, while patients at academic/research programs were more likely to undergo surgery (OR 0.38, p0.001). Nonsurgical treatment was associated with decreased OS (HR=2.02, p0.001); this was upheld on subgroup analysis of early- and late-stage disease.Use of primary nonsurgical treatment for OCSCC has decreased over time among NCDB-registered facilities and is associated with factors related to access to care. Surgical resection for the primary treatment of oral cavity cancer may be associated with improved OS, though conclusions regarding survival are limited by the non-randomized nature of the data.

BACKGROUND Head and neck (HN) defects after tumor extirpation can be challenging to repair. Historically, pedicled flaps were the mainstay for reconstruction, but recently, free tissue transfer has been preferred. This study compares patient characteristics and flap outcomes for HN defects over a 30-year period at the authors' institution. METHODS Head and neck cancer patients receiving flap reconstruction from 1983 to 2013 were included. Records were reviewed for demographic and perioperative data. Flap complications were compared and statistical tests were 2-tailed with a significance level of 0.05. RESULTS Eight hundred sixty-one patients fulfilled inclusion and exclusion criteria. Pedicled reconstruction predominated during early time-points (96.3% pedicled), compared with later years (69.5% free-tissue). Free flaps were associated with significantly longer operative times (643.5 versus 429.7 minutes, P

Background The tall cell variant of papillary thyroid carcinoma is an aggressive subtype that generally present as large tumors in advanced stage. However, little is known about the tall cell variant of microcarcinoma (tumors measuring

Background: This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment. Methods: Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS). Results: Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP. Conclusion: Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.

We used a retrospective chart review to analyze revision endoscopic carbon dioxide (CO2) laser and staple repairs of recurrent Zenker diverticulum (ZD).The medical records of patients with recurrent ZD after primary endoscopic repair were selected. The chart data included method of repair (CO2 laser or stapler), demographics (age and sex), defect size (in centimeters), preoperative and postoperative symptoms, and complications. Patients' dysphagia was graded on a modified Functional Oral Intake Scale from 1 to 4 (1 being normal intake and 4 being severely limited intake or gastrostomy tube dependence). Regurgitation was also graded on a 1-to-4 scale (1 being no regurgitation and 4 being aspiration).A total of 148 consecutive patients with ZD were treated with endoscopic repair between 2000 and 2010. Twelve of these patients had revisions after failed primary endoscopic management procedures, all done with the stapler. Eight revision surgeries were performed by CO2 laser, and 4 by stapler repair. No difference was noted in patient age or defect size (laser, 3.06-cm defects; stapler, 2.75-cm defects). The length of hospital stay and the time to oral intake for the patients who had a revision stapler procedure were significantly greater (p values of 0.029 and 0.009) than those for the patients in the primary stapler procedure group. Better postoperative regurgitation scores were noted for patients who had a CO2 laser procedure.Secondary endoscopic repair for ZD recurrence is an effective treatment method. Better symptom outcomes were observed with secondary CO2 laser repair than with stapler revision. Patients with revision stapling had longer hospital stays and a longer time to oral intake than did patients with primary staple repairs.

Conclusion: P-glycoprotein is abundantly expressed in certain parotid mucoepidermoid carcinoma tissues, known historically to be multidrug resistant. This discovery may be important in incrementally advancing our ability to develop alternative pharmacologic strategies to improve multi-modality tumor control.P-glycoprotein plays a functional role in promoting the efflux of drug metabolites in certain malignant tumors. With this understanding we immunohistochemically investigated the expression of P-glycoprotein in parotid mucoepidermoid carcinoma tissues and examined prognostic factors that contribute to the treatment of parotid cancer.Thirteen patients with mucoepidermoid carcinoma of the parotid gland were included. P-glycoprotein expression was immunohistochemically investigated by a modified avidin-biotin-peroxidase complex method using four different antibodies.P-glycoprotein expression was observed in a higher percentage of patients with higher grade malignancy. The tumor size-related difference in P-glycoprotein expression was only significant for staining with one antibody, and no significant differences were observed with or without induction chemotherapy.

Digital polymerase chain reaction (dPCR) has been used to yield an absolute measure of nucleic acid concentrations. Recently, a new method referred to as droplet digital PCR (ddPCR) has gained attention as a more precise and less subjective assay to quantify DNA amplification. We demonstrated the usefulness of ddPCR to determine HER2 gene amplification of breast cancer. In this study, we used ddPCR to measure the HER2 gene copy number in clinical formalin-fixed paraffin-embedded samples of 41 primary breast cancer patients. To improve the accuracy of ddPCR analysis, we also estimated the tumor content ratio (TCR) for each sample. Our determination method for HER2 gene amplification using the ddPCR ratio (ERBB2:ch17cent copy number ratio) combined with the TCR showed high consistency with the conventionally defined HER2 gene status according to ASCO-CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines (P

Objectives/Hypothesis: To analyze a single surgeon's experience with endoscopic CO2 laser and stapler repair of Zenker diverticulum (ZD) by comparing dysphagia and regurgitation outcomes. Study Design: Retrospective chart review of 148 patient charts. Methods: Medical records of all patients receiving endoscopic repair of ZD with either CO2 laser (61 patients) or stapler (67 patients) were reviewed. Additional data included demographics (age and sex), size (cm), preoperative and postoperative symptoms, need for revision, and complications. Symptoms of dysphagia were graded based on a modified Functional Oral Intake Scale 1 to 4 scale (1 = normal intake; 4 = severely limited/G-tube dependent). Regurgitation was also graded on a 1 to 4 scale (1 = no regurgitation; 4 = aspiration events). Results: We noted no difference in patient age or defect size (laser, 3.26 cm; stapler, 3.53 cm; P .135). Significant differences were noted in return trips to the operating room for failed procedures (laser, 0; stapler, 7; P = .009), length of stay (laser, 3.19 days; stapler, 1.29 days; P < .001), time to oral intake (laser, 3.01 days; stapler, 1.22 days; P < .001). Significant improvement occurred in laser and staple patient symptom scales following surgery (P < .001). Laser dysphagia and regurgitation scores showed greater improvement when compared to stapler scores (P < .001). Conclusions: Endoscopic CO2 laser and staple methods are effective in treating ZD. The laser can have greater efficacy and result in lower recurrence rates. Both methods are analyzed and compared.

Background The use of contrast radiography as a screening test for anastomotic integrity after esophagectomy is unclear. Methods Consecutive patients undergoing either transhiatal esophagectomy (THE) or pharyngolaryngoesophagectomy (PLE) with the cervical anastomosis performed by the same single surgeon were registered into a database. Anastomotic leak rate, modality of detection, and the result of esophagram (if performed) were recorded. Results A total of 132 patients underwent esophagectomy (THE, 93 patients; PLE, 39 patients). Ninety-nine patients (75%) underwent contrast radiography. The overall leak rate was 12.1% (n = 16). Nine of 16 anastomotic leaks (56.3%) were detected without contrast radiography. Seven additional patients with anastomotic leaks underwent contrast radiography, 2 (28.6%) were true positives, 4 (57.1%) were false negatives, and 1 was equivocal (14.3%). Results of contrast esophagography modified patient management in only 2 instances, whereas 4 leaks were missed by this modality. Conclusions Most leaks (56.3%) were diagnosed without contrast esophagography. Contrast studies changed clinical management correctly in only 2 of 132 patients, while failing to diagnose 4 of 7 possible leaks. This study suggests that its routine use after THE or PLE is not indicated.

The purpose of this study was to identify the early predictor of survival for prostate cancer patients with bone metastasis. We reviewed 87 prostate cancer patients with bone metastasis who had received primary androgen deprivation therapy (PADT) at our institution. The medical records of the patients were examined with respect to laboratory data, pathological results, PSA response to PADT and clinical outcome. The overall survival (OS) rates were analyzed with reference to the nadir PSA level and time to PSA nadir (TTN) following PADT by Kaplan-Meier method. In all, 59 patients (67%) had progression to castration-resistant prostate cancer. Nadir PSA0.2 ng ml(-1) (lower PSA nadir) during PADT were observed in 47 patients (54%). Multivariate analysis revealed that the extent of disease on bone scan (P=0.04), lower PSA nadir following PADT (P=0.003), albumin (P=0.04) and lactate dehydrogenase (P=0.01) were independent prognostic factors for survival. OS rates in the patients with lower PSA nadir were significantly higher. Longer TTN (9 months) identified patients with prolonged OS in both lower and higher PSA nadir groups. PSA nadir0.2 ng ml(-1) and prolonged TTN (9 months) following PADT might be the most important early predictors for longer survival in prostate cancer patients with bone metastasis.

Background: The renin–angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth. Methods: We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs). Results: Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis. Conclusions: The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.

Little is known about the pathology and pathogenesis of the rupture of intracranial aneurysms. For a better understanding of the molecular processes involved in intracranial aneurysm (IA) formation we performed a gene expression analysis comparing ruptured and unruptured aneurysm tissue to a control artery. Tissue samples of six ruptured and four unruptured aneurysms, and four cerebral arteries serving as controls, were profiled using oligonucleotide microarrays. Gene ontology classification of the differentially expressed genes was analyzed and regulatory functional networks and canonical pathways were identified with a network-based computational pathway analysis tool. Real time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining were performed as confirmation. Analysis of aneurysmal and control tissue revealed 521 differentially expressed genes. The most significantly associated gene ontology term was antigen processing (P=1.64E-16). Further network-based analysis showed the top scoring regulatory functional network to be built around overexpressed major histocompatibility class (MHC) I and II complex related genes and confirmed the canonical pathway "Antigen Presentation" to have the highest upregulation in IA tissue (P=7.3E-10). Real time RT-PCR showed significant overexpression of MHC class II genes. Immunohistochemical staining showed strong positivity for MHC II molecule specific antibody (HLA II), for CD68 (macrophages, monocytes), for CD45RO (T-cells) and HLA I antibody. Our results offer strong evidence for MHC class II gene overexpression in human IA tissue and that antigen presenting cells (macrophages, monocytes) play a key role in IA formation.

Background. This study investigated the patient's self-report and clinician's confirmation of tracheoesophageal voice prosthesis leakage patterns (through or around) with or without the cough reflex and whether prosthesis diameter affected the leakage route. Methods. Sixty-six consecutive participants with a total of 200 patient-initiated reasons for prosthesis changes were en- rolled prospectively. Patient's self-report of leakage and cough reflex were recorded prior to clinician's confirmation. Results. One-hundred eight (54%) of the 200 patient-initi- ated reasons for prosthesis changes were leakage through or around the voice prosthesis. Leakage was unrecognized in 21 (23%) of 92 instances, even though 15 (71%) of those 21 instan- ces exhibited a cough reflex. Clinician's confirmed leakage in 118 (59%) of 200 patient-initiated reasons for prosthesis changes. Coughing occurred significantly less with leakage around (9 (53%) of 17 instances) than that with leakage through the voice prosthesis (80 (88%) of 91 instances) (v 2 (1, N 5 108), p < .05). Leakage around the voice prosthesis occurred more with 20-Fr diameter prostheses (16 (76%) of 21 instances). Conclusions. Patient education is important for reliable iden- tification of leakage for prompt prosthesis replacement. Leakage around the voice prosthesis can be minimized or avoided by ini- tially fitting and continuing the use of smaller diameter (16 Fr) voice prostheses. V C 2008 Wiley Periodicals, Inc. Head Neck 30: 618-621, 2008

Objective The purpose of this study was to demonstrate the efficacy of arterial coupling. Study Design Retrospective data were collected in a consecutive series of 124 patients undergoing surgical resection of head and neck tumors followed by free tissue transfer (FTT). Methods and Measures The Unilink coupling device was used to perform arterial and venous anastomosis. Flap survival and thrombosis of the arterial anastomoses were determined. Results A total of 124 consecutive patients underwent a total of 127 microvascular FTTs. Reconstruction included 90 radial forearm, 26 fibula, 9 rectus abdominis, and 2 iliac crest myocutaneous free flaps. There were four (3.2%) complications related to arterial insufficiency in our series, three of which were salvageable. There were three (2.4%) flap failures, resulting in an overall free flap survival rate of 97.6 percent. Conclusion The flap survival with the Unilink Microvascular Anastomotic System is similar to that of standard suture techniques. Use of a coupler device is the preferred method in performing microvascular FTT at our institution.

Background: Several lines of laboratory evidence support a role of persistent activation of Akt pathway in oropharyngeal squamous cell carcinoma (OSCC) progression. Loss of phosphatase PTEN is one of the proposed mechanisms of Akt activation. We sought to determine the prognostic significance of Akt activation in a cohort of patients with OSCC as well as the association between phosphorylated (activated) Akt and PTEN levels. Methods: Using a novel system of in situ quantitative protein expression analysis (AQUA), we studied the protein expression levels of phosphorylated Akt (p-Akt) and PTEN on a tissue microarray. The array included 79 OSCCs with a mean follow-up of 36 months. Results: Patients with tumors expressing low tumor p-Akt levels had lower 5-year local recurrence rates (5% versus 38%). Additionally, these patients had improved 5-year overall survival rates (45% versus 27%). This survival effect was likely due to disease recurrence, as there was no difference in death without recurrence between low- and high-expressing groups. In adjusted analysis, tumor p-Akt expression was a strong predictor of local recurrence. A significant inverse relationship was found between nuclear p-Akt and nuclear PTEN: Tumors with high nuclear p-Akt had low nuclear PTEN and vice versa. Conclusions: Akt activation in OSCC is associated with adverse patient outcome, indicating that Akt is a promising molecular target in OSCC. PTEN loss may be one of the mechanisms of Akt activation in OSCC. (Cancer Epidemiol Biomarkers Prev 2007;16(3):553–8)

We present a case of a deep lobe parotid pleomorphic adenoma extending into the parapharyngeal space via an unusual morphology. This is a single patient case report of an unusual morphology with an associated review of the literature. The patient successfully underwent right parotidectomy during which it was seen that the tumor was extending above rather than through the stylomandibular tunnel, an unusual morphology for a pleomorphic adenoma. Despite the classic teaching that deep lobe parotid tumors reach the parapharyngeal space by traveling through, or below, the stylomandibular tunnel, it is possible for tumors to occur outside this tunnel. Recognition that this unusual growth path, although rare, can occur is important when designing an appropriate surgical resection.

The long-term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26-week core + 26-week extension, controlled, open-label, parallel-group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal-time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p

Aims To quantify the effect of the sodium-glucose co-transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic–pharmacodynamic (PK–PD) model. Methods Four phase I/II trials were used for model development. Empagliflozin's PK characteristics were characterized by a two-compartmental model with sequential zero- and first-order absorption. Urinary glucose excretion (UGE) was described as dependent on renal glucose filtration and reabsorption; splay of the glucose reabsorption/excretion curves was considered. The modelling assumed that empagliflozin lowers the maximum renal glucose reabsorption capacity and, thereby, the renal threshold for glucose (RTg). Covariate effects were investigated using a full covariate modelling approach, emphasizing parameter estimation. Results The PK–PD model provided a reasonable description of the PK characteristics of empagliflozin and its effects on UGE across a range of renal function levels. Its parameters are consistent with reported values for renal physiology. Using this model, the effect of empagliflozin on renal glucose reabsorption was quantified. Steady-state empagliflozin doses (1, 5, 10 and 25 mg) reduced RTg from 12.5 mmol/L [95% confidence interval (CI) 12.0, 13.1] to 5.66 (95% CI 4.62, 6.72), 3.01 (95% CI 2.33, 3.69), 2.53 (95% CI 1.83, 3.14) and 2.21 (95% CI 1.47, 2.84) mg/dl, respectively. Covariate analysis showed the effect of empagliflozin on UGE was not influenced, to a clinically relevant extent, by sex, age or race. Conclusions A method for characterizing renal glucose reabsorption was developed that does not require complex glucose clamp experiments. These analyses indicate that empagliflozin provided concentration-dependent RTg reductions, with 10 and 25 mg providing near-maximum RTg-lowering.

Background: Several lines of evidence support the epidermal growth factor receptor (EGFR) as a molecular target for therapy in head and neck squamous cell carcinomas (HNSCC). Determination of tumor EGFR levels by conventional immunohistochemistry has not always predicted antitumor efficacy. Quantitative assays may provide more accurate assessment of the level of EGFR receptor in the tumor, which may thus provide more reliable prognostic and predictive information. We studied the prognostic value of quantitative assessment of EGFR in oropharyngeal squamous cell cancers treated with radiotherapy.Experimental Design: We studied EGFR protein expression on a tissue microarray composed of 95 oropharyngeal cancer cases using an in situ molecular-based method of quantitative assessment of protein expression (AQUA) and correlated those with clinical and pathologic data. Automated, quantitative analysis uses cytokeratin to define pixels as cancer (tumor mask) within the array spot and measures intensity of EGFR expression using a Cy5-conjugated antibody within the mask. A continuous index score is generated, which is directly proportional to the number of molecules per unit area, and cases were defined as high expressing if they were above the median expression level.Results: The mean follow-up time for survivors was 44.9 months, and for the entire cohort was 34.8 months. Patients with high tumor EGFR expression levels had a local recurrence rate of 58% compared with 17% for patients with low EGFR tumor expression (P < 0.01). Similarly, patients with high nuclear EGFR expression had a local recurrence rate of 54% compared with 21% for patients with low EGFR nuclear expression (P < 0.05). Additionally, patients with high tumor and nuclear EGFR levels had inferior disease-free survival compared with low expressors (19% versus 43% and 19% versus 45%, respectively. P < 0.05 for each). In multivariate analysis adjusting for well-characterized prognostic variables, high tumor and nuclear EGFR expression levels retained their prognostic significance.Conclusion: The AQUA system provides a continuous measurement of EGFR on paraffin-embedded tissue and was able to reveal the association between EGFR expression and outcome expected from the biological role of EGFR. In the future, EGFR AQUA score may be useful in predicting response to EGFR-targeted therapies.

Background: β-catenin, depending on subcellular localization, plays a dual role in carcinogenesis: as a signaling factor (in the nucleus) and as an adhesion molecule (in cell membrane). In this study, we sought to determine the role of β-catenin in head and neck carcinogenesis.Methods: First, we studied the incidence of mutations of β-catenin in a cohort of 60 head and neck squamous cell cancers (HNSCC). We subsequently evaluated the protein expression levels of β-catenin in a cohort of oropharyngeal squamous cell cancer tissue microarray using a novel in situ method of quantitative protein analysis and correlated those with cyclin D1 levels and clinical and pathologic data.Results: The mean follow-up time for survivors was 45 months and for all patients was 35 months. We found no mutations in the cohort of 60 HNSCC. β-catenin displayed primarily membranous expression pattern. Patients with high tumor-node-metastasis stage were more likely to have high expression of β-catenin (P = 0.040). Patients with low β-catenin expression had a local recurrence rate of 79% compared with 29% for patients with high β-catenin tumors (P = 0.0021). Univariate Cox regression revealed a hazard ratio for low β-catenin tumors of 3.6 (P = 0.004). Kaplan-Meier analysis showed that patients with low β-catenin expressing tumors trended toward worse 5-year disease-free survival (P = 0.06). In multivariate analysis, only β-catenin expression status was an independent prognostic factor (P = 0.044) for local recurrence. Tumors with high β-catenin had low cyclin D1 and vice versa (P = 0.007).Conclusions: The absence of activating β-catenin mutations combined with the inverse correlation between β-catenin levels with cyclin D1 levels and outcome suggest that β-catenin mainly functions as an adhesion and not signaling molecule in HNSCC.

Background: Considerable controversy exists in the literature regarding the clinical course of young patients with oral squamous cell carcinoma (SCC). The purpose of this study was to evaluate the clinico-pathological features of oral SCC among young people. Methods: From a cohort of 529 patients diagnosed with SCC, 35 (6.6%) were under the age of 40 years. This group was compared to a control group of 110 cases aged over 40 to determine if there were any differences in clinicopathological features between the two groups. Results: In the young group there were 20 males and 15 females. The site was most frequently the tongue (51.3%), followed by the floor of the mouth, the buccal mucosa, and the upper and lower alveolus and gingiva. The local and regional control rate was 64.8% which was similar to that of older patients in this series. Conclusions: The prognosis of oral SCC in the young patients does not appear to be different from that of the older population. Univariate analysis showed that clinical stage and the mode of invasion were the most significant prognostic factors in both younger and older patients.

Purpose Previous randomized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C (MC) and radiation (RT) in the management of squamous cell cancer of the head and neck (SCCHN). We conducted a randomized trial comparing MC with porfiromycin (POR) in combination with RT in the management of SCCHN. Methods and materials Between 1992 and 1999, 128 patients with SCCHN were enrolled in this prospective randomized trial. Patients were stratified by management intent, and balanced with respect to stage and site of disease. They were randomized to receive MC (15 mg/M 2 ) or POR (40 mg/M 2 ) on Days 5 and 47 (or last day) of RT. Of 121 evaluable patients, 61 were randomized to MC and 60 to POR. Patients were treated with standard daily RT to a total median dose of 64 Gy over 47 days. Patients were well balanced with respect to management intent, stage, site, age, sex, hemoglobin levels, tumor grade, radiation dose, and days on treatment. Results There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities. As of January 2003 with a median follow-up of 6.3 years, there have been 19 local relapses (4 MC vs. 15 POR), 21 regional relapses (7 MC vs. 14 POR), 24 distant metastases (11 MC vs. 13 POR), and 66 deaths (33 MC vs. 33 POR). MC was superior to POR with respect to 5-year local relapse-free survival (91.6% vs. 72.7%, p = 0.01), local-regional relapse-free survival (82% vs. 65.3%, p = 0.05), and disease-free survival (72.8% vs. 52.9%, p = 0.026). There were no significant differences between the two arms with respect to overall survival (49.2% vs. 54.4%) or distant metastasis–free rate (79.9% vs. 75.9%). Conclusions Despite promising preclinical data, and an acceptable toxicity profile, POR was inferior to MC as an adjunct to RT in the management of SCCHN. This randomized trial emphasizes the need for randomized studies to evaluate new agents in the management of SCCHN.

Objective: The purpose of this analysis is to determine whether a significant correlation exists between cyclooxygenase-2 (COX-2) expression and local relapse in a large cohort of patients with T1 to 2N0 laryngeal cancer treated with primary radiation therapy. Methods and Materials: Clinical and molecular analyses were conducted on 123 patients with biopsy-proven T1 to 2N0 laryngeal cancer. Clinical prognostic factors included pretreatment hemoglobin, age, sex, race, T stage, tumor subsite, beam energy, biologically equivalent dose, therapy duration, and treatment date. Molecular prognostic factors included COX-2, p53, and Ki-67 expression. Expression levels were determined by immunohistochemistry on paraffin-embedded tissues arrayed on tissue microarrays. Multivariate analysis was done with the Cox proportional hazards model. Results: Thirty-two patients have locally relapsed, for an actuarial 5-year local relapse-free rate of 70.4%. On multivariate analysis, positive COX-2 expression predicted local relapse after radiation therapy. The relative risk (RR) for local relapse with COX-2 positivity was 2.57 (95% CI, 1.21–5.47; P = .01). Other prognostic factors for local relapse included negative Ki-67 expression (RR = 5.72; 95% CI, 2.04–16.1; P < .001), T2 stage (RR = 2.98; 95% CI, 1.39–6.38; P = .005), and therapy duration greater than 43 days (RR = 6.04; 95% CI, 1.37–26.7; P = .02). Conclusions: Positive COX-2 expression predicts for local relapse in T1 to 2N0 larynx cancer in a multivariate model. This relationship may have potential therapeutic implications regarding the use of COX-2 inhibitors during radiation therapy for optimal outcome.

Purpose: Functional inactivation of p16 is an early and frequent event in head and neck squamous cell cancers. In this study, we sought to determine whether p16 expression is of prognostic importance in oropharyngeal squamous cell carcinoma. Experimental Design: p16 protein expression was evaluated by immunohistochemistry in a tissue microarray composed of 123 oropharyngeal squamous cell cancers with a mean patient follow-up time of 33 months. Results: p16 overexpression was associated with more advanced Tumor-Node-Metastasis stage and higher histologic grade. Despite this association with unfavorable features, p16 overexpression was associated with decreased 5-year local recurrence rates (11 versus 53%) and increased 5-year disease-free survival (62 versus 19%) and overall survival (60 versus 21%). In multivariate analysis, p16 expression status remained an independent prognostic factor for local recurrence, disease-free survival, and overall survival. Conclusions: In patients with oropharyngeal squamous cell carcinoma, overexpression of p16 as determined by immunohistochemistry is associated with significantly improved prognosis and lower local recurrence rates.

We present a rare case of a lateral dislocation of the proximal interphalangeal joint that required open reduction. During an operation, we found the collateral ligament and the capsule interposing into the joint space. After reducing the soft tissue and reproducing the collateral ligament with a suture anchor, sufficient joint stability and full range of motion was achieved.

Objectives: The management of recurrent or persistent head and neck cancer poses a challenging problem. Salvage surgery for these individuals consists of ablative surgery, interstitial brachytherapy, and microsurgical free flap reconstruction. This study reviews complications after such reconstruction. Methods: We reviewed 139 consecutive head and neck cancer patients undergoing free flap reconstruction from January 1994 to May 2002. These included 66 patients with recurrent head and neck cancer undergoing intraoperative brachytherapy (IOBT) and free flap reconstruction and 73 undergoing free flap reconstructions only. A total of 142 reconstructions were performed, with three patients in IOBT group receiving two free flap reconstructions per patient, giving us a total of 69 reconstructions in the IOBT group versus 73 in the non-IOBT group. Nine patients were excluded from the IOBT group because of non-synchronous use of brachytherapy and reconstruction, and 10 patients were excluded from the other group because they had prior radiotherapy or surgical treatment, leaving us with a total of 123 reconstructions, 60 in the IOBT group and 63 in the non-IOBT group. The IOBT group patients received 125 iodine Vicryl seed implants, 103 palladium seed implants, or both, to deliver an average dose of 79.3 ± 31.8 Gy (mean ± 1SD) to the surgical bed. Results: All patients were followed for evidence of local wound complications. The IOBT group showed multiple complications in 23 (38.33%) of 60 reconstructions, the most common being wound dehiscence in 11. This, when compared with the non-IOBT group complications (15.87%), was found to be statistically significant (X 2 test, P

Purpose To elucidate a relationship between pretreatment hemoglobin and local control in patients with T1-T2N0 larynx cancer treated with radiotherapy. Methods and materials A total of 246 patients with T1-T2N0 cancer of the larynx were included in this analysis. Patients were treated using a median daily fraction of 200 cGy to a total median dose of 66 Gy within 47 days. Prognostic factors included pretreatment hemoglobin, age, gender, race, T stage, tumor subsite, beam energy, biologically equivalent dose, and therapy duration. Results Fifty patients developed local relapse, for an actuarial 5-year relapse-free rate of 77.3%. The actuarial 5-year survival rate was 69.8%. The pretreatment hemoglobin levels were assessed using the following hemoglobin quartiles: 10.1–13.3, 13.4–14.1, 14.2–14.9, and 15.0–18.3 g/dL. On Cox multivariate analysis, the pretreatment hemoglobin level predicted for local failure and poorer overall survival. The relative risk for 5-year local relapse by hemoglobin quartile was 2.70, 2.33, 1.91, and 1.00 ( p = 0.034). The relative risk for poorer 5-year overall survival by hemoglobin quartile was 2.23 1.30, 0.80, and 1.00 ( p Conclusion Pretreatment hemoglobin levels predicted for local control and overall survival for larynx cancer in a multivariate model. This relationship has potential therapeutic implications regarding correcting anemia before the initiation of radiotherapy for optimal outcome.

Objectives: To evaluate the significance of maxillary bone invasion by gingival carcinoma as an indicator of cervical metastasis. Methods: Twenty-one patients with squamous cell carcinoma of the upper gingiva were included in the study. The extent of bone invasion was assessed by dental CT. Six patients had cervical metastases at the initial examination and eight more developed them during the 2-year follow-up period. The relationship of cervical metastases with age and gender of these patients, as well as with the size of the lesion and extent of bone invasion, was examined by logistic multivariate regression analysis. Results: There was a significant relationship between the presence of bone invasion and the presence of cervical metastasis (P

MRI studies using the manual tracing method have shown a smaller-than-normal hippocampal volume in patients with posttraumatic stress disorder (PTSD). However, these studies have yielded inconsistent results, and brain structures other than the hippocampus have not been well investigated. A recently developed, fully automated method called voxel-based morphometry enables an exploration of structural changes throughout the brain by applying statistical parametric mapping to high-resolution MRI. Here we first used this technology in patients with PTSD. Participants were 9 victims of the Tokyo subway sarin attack with PTSD and 16 matched victims of the same traumatic event without PTSD. The voxel-based morphometry showed a significant gray-matter volume reduction in the left anterior cingulate cortex (ACC) in trauma survivors with PTSD compared with those without PTSD. The severity of the disorder was negatively correlated with the gray-matter volume of the left ACC in PTSD subjects. There were no significant differences in other gray-matter regions or any of the white-matter regions between two groups. The present study demonstrates evidence for structural abnormalities of ACC in patients with PTSD. Together with previous functional neuroimaging studies showing a dysfunction of this region, the present findings provide further support for the important role of ACC, which is pivotally involved in attention, emotional regulation, and conditioned fear, in the pathology of PTSD.

Objectives: To evaluate the significance of mandibular bone invasion by gingival carcinoma revealed by reformatted dental CT images as a prognostic indicator of cervical metastasis. Methods: Thirty-two patients with squamous cell carcinoma of the lower gingiva were examined by dental CT. Cervical metastases and survival rates of these patients were analysed in relation to their clinical characteristics, histologic grading based on gingival biopsy, and mandibular bone invasion using reformatted dental CT imaging diagnoses prior to surgery. The dental CT images were classified into four types: Class I, no bone invasion; Class II, invasion confined to the alveolus; Class III, invasion extending between the alveolus and the mandibular canal; and Class IV, invasion beyond the mandibular canal. Results: Logistic multivariate regression analysis showed that bony invasion identified on dental CT images was a significant prognostic factor in cervical metastases (P=0.028). The 5year overall survival rates of Classes I, II, III, and IV were 100% (n=9), 76.2% (n=9), 71.4% (n=7), and 28.6% (n=7), respectively. Conclusions: The evaluation of mandibular bone invasion using dental CT images is useful as a prognostic indicator of cervical metastasis for patients with gingival carcinoma. Dentomaxillofacial Radiology (2002) 31, 339‐343. doi:10.1038/sj.dmfr.4600726

Objectives Over past decades, function-preserving surgery has been oncologically effective for specific types of laryngeal cancer. Although safe short-term swallow function has been reported, swallow safety during long-term survival has received less attention. The purpose of this report is to highlight potential consequences of late dysphagia and chronic aspiration after partial laryngectomy. Methods A retrospective case series was performed. The head and neck cancer database from Yale–New Haven Hospital identified 3 patients requiring completion laryngectomy due to chronic aspiration 11–15 years after oncologically successful partial laryngectomy. Demographics, presentation, treatment, and course are included. Results Primary treatment was open supraglottic laryngectomy with adjuvant radiation therapy ( n = 2) and vertical hemilaryngectomy ( n = 1). All patients demonstrated locoregional control and preservation of swallow function for > 10 years postoperatively. Due to late dysphagia and chronic aspiration, two patients required completion laryngectomy 11 and 15 years postoperatively and the third patient will require this 14 years postoperatively. Conclusions Successful swallowing after function-preserving laryngeal surgery may not last forever despite adequate control of cancer. Three patients presented with aspiration 11–15 years after partial laryngectomy and required definitive completion laryngectomy. This observation may affect preoperative counseling and consideration for longer post-operative follow-up. The data encourage a larger sample size.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4–8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

In order to predict the prognosis of patients with oral squamous cell carcinomas, volume-corrected mitotic index (M/V index), as well as histopathological and clinical indices were estimated in 50 oral squamous cell carcinoma tumors. Histological malignancy (P = 0.0005), mode of invasion (P = 0.0168) and M/V index (P = 0.0093) showed a significant correlation with survival according to univariate survival analysis. According to multivariate survival analysis (Cox's regression model), the M/V index was the best predictor of the techniques studied of patient prognosis. The M/V index also showed significant correlation with DNA ploidy. The present results suggest that the M/V index is an important prognostic factor for oral carcinoma. Furthermore, the M/V index and DNA ploidy appear to provide similar prognostic information.

Hepatic veno-occlusive disease (VOD) is a major complication after hematopoietic stem cell transplantation (HSCT). Aetiological determinants, diagnosis and treatment remain unclear. Changes in coagulation-fibrinolysis parameters and N-terminal propeptide for type III procollagen (P-III-P) have been studied in patients with or without VOD after HSCT. We prospectively measured protein C activity, tissue plasminogen activator (t-PA), antithrombin III (AT-III), plasminogen activity (PLG), thrombin-antithrombin III (TAT), alpha2-plasmin inhibitor (alpha2-PI),fibrinogen (Fbg) and P-III-P in 44 consecutive adult patients undergoing allogeneic HSCT. Each parameter was determined before conditioning, on day 0 of HSCT and weekly for 5 weeks. Five of the 44 patients developed VOD at a median post HSCT of day 3 (range, day 3 to 12). On repeated analysis of variance (ANOVA), there were significant differences between patients with and without VOD in P-III-P (P < 0.0001), protein C (P < 0.0001), t-PA (P < 0.0001), PLG (P < 0.0001), AT-III(P < 0.0001), Fbg (P < 0.0001), alpha2-PI (P = 0.0002). Levels of P-III-P were significantly higher in patients with VOD than without VOD, before preparative chemotherapy (P < 0.005) and on days 0 and 7 (P < 0.001). On day 0, levels of t-PA were significantly higher in patients with VOD than without VOD (P < 0.05). On day 7, levels of protein C were significantly lower in patients with VOD than without VOD (P < 0.01). On day 0, there were trends of differences (P = 0.0515) between patients with and without VOD in the levels of protein C. These results suggest P-III-P, t-PA and protein C are predictive markers for VOD after HSCT in adults. Moreover, the serum P-III-P level before start of conditioning might indicate patients at risk for developing VOD.

PurposeTo identify PAX6 mutations in patients from four Japanese families with aniridia.MethodsPolymerase chain reaction (PCR)-single stand conformational polymorphism (SSCP) analysis (SSCA) was performed in probands of the families, and restriction analysis using MaeIII or AvaI was carried out in other affected family members.ResultsPCR-SSCA demonstrated in the proband from one family an extra-band in the PCR product for PAX6 exon 8. Base sequence analysis revealed that the patient is a heterozygote for a C to T transition mutation at codon 203. DNAs from the patient and another affected member in the same family were cut with MaeIII into two fragments, while non-affected members in the family showed only one MaeIII fragment, the result confirmed the mutation. In another family, PCR-SSCA revealed an extra-band in the PCR product for exon 9. Sequencing detected a C→T substitution at codon 240 in the patient, the mutation resulted in loss of an AvaI site. AvaI cleavage analysis confirmed the mutation in the patient. The two transition mutations observed in the two families also predict the conversion of arginine to a stop codon (R203X and R240X, respectively) around the homeodomain (HD), leading to the truncation of the PAX6 protein within its glycine-rich region. No abnormal SSCP bands or abnormal restriction fragments were detected in patients from the other two families.ConclusionsThe two mutations sites identified in the two families, one at codon 203 and the other at codon 240, are those most frequently observed among 118 previously reported PAX6 mutations. This indicates that the two mutations are two hot-spots in the gene.

Spontaneous vertebral artery dissection (VAD) has been recognized as being more common than was first thought, with the growing use of magnetic resonance imaging (MRI). However, simple MRI alone is not always satisfactory for making an accurate diagnosis. We experienced two cases of VAD in our clinic, in which three-dimensional computed tomographic angiography (3D-CTA) was performed. Our scanner has the capability of examining a slice of 1mm thick, 0.5mm reconstruction pitch, and a scan time of 1s/rotation. 3D-CTA clearly demonstrated the stenotic change concomitant with the surrounding thrombus and was thought to be useful for making an accurate diagnosis.