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Objective Relatively little attention has been devoted to the role of communication between physicians as a mechanism for individual and organisational learning about diagnostic delays. This study’s objective was to elicit physicians’ perceptions about and experiences with communication among physicians regarding diagnostic delays in cancer. Design, setting, participants Qualitative analysis based on seven focus groups. Fifty-one physicians affiliated with three New York-based academic medical centres participated, with six to nine subjects per group. We used content analysis to identify commonalities among primary care physicians and specialists (ie, medical and surgical oncologists). Primary outcome measure Perceptions and experiences with physician-to-physician communication about delays in cancer diagnosis. Results Our analysis identified five major themes: openness to communication, benefits of communication, fears about giving and receiving feedback, infrastructure barriers to communication and overcoming barriers to communication. Subjects valued communication about cancer diagnostic delays, but they had many concerns and fears about providing and receiving feedback in practice. Subjects expressed reluctance to communicate if there was insufficient information to attribute responsibility, if it would have no direct benefit or if it would jeopardise their existing relationships. They supported sensitive approaches to conveying information, as they feared eliciting or being subject to feelings of incompetence or shame. Subjects also cited organisational barriers. They offered suggestions that might facilitate communication about delays. Conclusions Addressing the barriers to communication among physicians about diagnostic delays is needed to promote a culture of learning across specialties and institutions. Supporting open and honest discussions about diagnostic delays may help build safer health systems.

Importance Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. Objective To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. Design, setting, and participants After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. Interventions Next-generation sequencing of tumors and matched normal DNA. Main outcomes and measures Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. Results Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]). Conclusions and relevance These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.

Obesity is associated with increased adipose tissue in the tongue. Chronic white adipose tissue (WAT) inflammation commonly occurs in the obese. We investigated whether WAT inflammation in the tongue impacts survival in patients with squamous cell carcinoma (SCC) of the oral tongue.In a retrospective cohort study, patients with T1 and T2 SCC of the oral tongue who underwent curative-intent resection were included. Tongue WAT inflammation was defined by the presence of dead or dying adipocytes surrounded by macrophages forming crown-like structures. The primary and secondary endpoints were disease-specific survival (DSS) and overall survival (OS), respectively. Subgroup analyses were carried out in patients without lymph node involvement for whom adjuvant therapies were not indicated.Archived tissue was available from 125 patients. The median follow-up was 55 months (range, 3-156 months). Overall, 49 of 125 patients (39%) had tongue WAT inflammation, which was associated with higher body mass index, increased tumor thickness, and vascular invasion (P .05). The 3-year DSS rate for patients with tongue WAT inflammation was 59% (95% confidence interval [CI], 46%-76%) versus 82% (95% CI, 73%-92%) for those without inflammation. For patients without lymph node involvement for whom adjuvant therapy was not indicated (N = 70), tongue WAT inflammation was associated with shortened DSS and OS (P .05). When adjusted for body mass index and potential prognostic covariates, the hazard ratio for DSS and OS was 5.40 (95% CI, 1.20-24.26) and 2.97 (95% CI, 1.02-8.65), respectively.Tongue WAT inflammation is associated with worse DSS and OS in patients who have early stage SCC of the oral tongue. Cancer 2016;122:3794-3802. © 2016 American Cancer Society.

The mammalian target of rapamycin complex 1 (mTORC1) is aberrantly activated in many head and neck squamous cell carcinomas (HNSCCs). This phase I study combines the mTORC1 inhibitor temsirolimus with carboplatin and paclitaxel.This was a single institution phase I study for patients with R/M HNSCC with a standard 3 + 3 design. Three doses of temsirolimus were planned: 15, 20, and 25 mg. Due to excessive toxicity with the original study regimen, the protocol was amended to carboplatin AUC 1.5, paclitaxel 80 mg/m(2), and temsirolimus (according to dose escalation plan), all on days 1 and 8 of a 21-day cycle.18 patients (14 male, 4 female) enrolled, with median age 56 years (range 33-78). The most common toxicities were anemia, leukopenia, thrombocytopenia, and hyperglycemia. Among all patients treated, the confirmed objective partial response (cPR) rate was 22 %. DLT was not exceeded among 6 patients treated at dose level 3 of the revised protocol, and 4 of 6 subjects treated at this dose level had cPRs.The phase II recommended regimen is temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m(2), all on days 1 and 8 of a 21-day cycle. A phase II study of this regimen in R/M HNSCC is ongoing.

BACKGROUND: For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high-dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation. METHODS: Planned treatment consisted of definitive intensity-modulated radiation therapy (IMRT) (total, 70 grays) with concurrent cisplatin (50 mg/m2 on days 1, 2, 22, 23, 43, and 44) and bevacizumab (15 mg/kg on days 1, 22, and 43). The primary endpoint was 2-year progression-free survival (PFS), and overall survival (OS) was a secondary endpoint. RESULTS: Forty-two previously untreated patients (34 men and 8 women; median age, 55 years; range, 27-75 years) with stage III through IV HNSCC without distant metastasis (oropharyngeal carcinoma, 39 patients; laryngeal carcinoma, 3 patients) were treated. Human papillomavirus (HPV) status by was determined by in situ hybridization (HPV positive, 16 patients; HPV negative, 14 patients, unknown HPV status, 12 patients). The toxicities (determined according to version 3.0 of Common Terminology Criteria for Adverse Events Common) that were experienced by all patients (any grade) were mucositis, lymphopenia, leukopenia, throat pain, fatigue, and anemia. There were 2 treatment-related deaths, including 1 sudden death and 1 death from aspiration pneumonia. The median follow-up was approximately 31.8 months (range

Objectives/Hypothesis: To develop and validate a simple prognostic tool that would help predict larynx preservation outcome. Study Design: A retrospective review of 3 prospective studies. Methods: We reviewed consecutive chemotherapy/radiation protocols for patients (n = 170) with advanced, resectable, squamous cell, larynx, or pharynx cancer treated at Memorial Sloan-Kettering Cancer Center from 1988 to 1995 with larynx preservation intent. The outcome was successful larynx preservation. Model validation used data from U. S. Department of Veterans Affairs larynx preservation study. Results: The developed model added one point for each poor prognostic covariate present (show in parentheses) and was given the acronym TALK: T stage (T4), albumin (

Summary Background We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy. Methods We enrolled patients older than 18 years with stage IIB–IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m 2 ) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m 2 ), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m 2 per day), given on days 64–67, 85–88, and 106–109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694. Findings From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3–4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1–2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3–4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1–2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6–94·9), the 2 year distant metastasis-free interval was 90·8% (82·2–99·5), the 2 year progression-free survival was 74·7% (61·8–87·6), and 2 year overall survival was 90·9% (82·3–99·4). Interpretation The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease. Funding National Cancer Institute, USA.

Purpose To correlate proton magnetic resonance spectroscopy ( 1 H-MRS), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and 18 F-labeled fluorodeoxyglucose positron emission tomography ([ 18 F]FDG PET) of nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) for assessment of tumor biology. Additionally, pretreatment multimodality imaging was evaluated for its efficacy in predicting short-term response to treatment. Methods and Materials Metastatic neck nodes were imaged with 1 H-MRS, DCE-MRI, and [ 18 F]FDG PET in 16 patients with newly diagnosed HNSCC, before treatment. Short-term patient radiological response was evaluated at 3 to 4 months. Correlations among 1 H-MRS (choline concentration relative to water [Cho/W]), DCE-MRI (volume transfer constant [ K trans ]; volume fraction of the extravascular extracellular space [ v e ]; and redistribution rate constant [ k ep ]), and [ 18 F]FDG PET (standard uptake value [SUV] and total lesion glycolysis [TLG]) were calculated using nonparametric Spearman rank correlation. To predict short-term responses, logistic regression analysis was performed. Results A significant positive correlation was found between Cho/W and TLG (ρ = 0.599; p = 0.031). Cho/W correlated negatively with heterogeneity measures of standard deviation std( v e ) (ρ = −0.691; p = 0.004) and std( k ep ) (ρ = −0.704; p = 0.003). Maximum SUV (SUVmax) values correlated strongly with MRI tumor volume (ρ = 0.643; p = 0.007). Logistic regression indicated that std( K trans ) and SUVmean were significant predictors of short-term response ( p Conclusion Pretreatment multimodality imaging using 1 H-MRS, DCE-MRI, and [ 18 F]FDG PET is feasible in HNSCC patients with nodal metastases. Additionally, combined DCE-MRI and [ 18 F]FDG PET parameters were predictive of short-term response to treatment.

In der Entwicklung des Prostatakarzinoms spielen Androgene und der Androgenrezeptor eine zentrale Rolle. Über Jahrzehnte war die konventionelle Androgendeprivationstherapie (ADT) die wichtigste Behandlungsoption im metastasierten Stadium. Trotz initialen Ansprechens auf eine ADT entwickelt sich im Verlauf in der Regel ein metastasiertes kastrationsresistentes Prostatakarzinom (mCRPC). Für dieses Stadium gab es jahrelang keine Therapie, für die eine Verlängerung des Überlebens gezeigt werden konnte. Dies änderte sich erst 2004 mit der Studie TAX 327 zur Wirksamkeit von Docetaxel. Seither ist eine Reihe weiterer Wirkstoffe entwickelt und zugelassen worden, die das Überleben der mCRPC-Patienten verlängern können. Doch auch hierunter entwickeln sich Resistenzen. Diese könnten künftig einen Einfluss auf die Therapiesteuerung beim mCRPC haben.

Background and purpose Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy. The potential for pathologic misclassification complicates interpretation of published data. One standard treatment option for locoregionally advanced disease is weekly low-dose doxorubicin with concurrent radiation therapy, and was previously developed at our institution. We evaluated our more recent experience with this approach, which included pathologic confirmation of all cases. Materials and methods A retrospective review was performed on patients identified through the Memorial Sloan-Kettering Cancer Center (MSKCC) Cancer Database. Inclusion criteria: pathologically confirmed ATC; locoregional disease encompassable within a radiation portal; treatment with curative intent at MSKCC with planned weekly doxorubicin (10 mg/m2) and concurrent radiation. Principle outcomes assessed were locoregional progression-free survival (LR-PFS) and overall survival (OS). Results Thirty-seven patients were included. Median radiotherapy dose was 57.6 Gy, and was ⩾50 Gy in 29 (78%), administered through hyperfractionated or once-daily schedules. One-year outcomes were LR-PFS, 45%; OS, 28%. Conclusion The prognosis of patients with ATC remains grim and our current results appear inferior to those reported previously by our institution. More accurate histologic diagnoses and patient selection in the present series compared to the prior one may be responsible in part. Better therapy is desperately needed for this aggressive disease.

Background: The assessment of a clinical significance of certain quality of life score changes is often controversially discussed. Materials and Methods: The Expa

Preclinical studies demonstrate synergistic anti-tumor activity with the combination of everolimus and cisplatin. We conducted a phase I study to establish the recommended phase II of oral everolimus to be given with low-dose weekly intravenous cisplatin.Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels of everolimus: 2.5, 5, 7.5, and 10 mg/day. Subjects received oral everolimus during days 1-21 and cisplatin 20 mg/m(2) intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetic (PK) blood samples were collected on day 1 and day 8 of cycle 1 in Part A. After the phase II recommended dose was established (Part A), 6 additional subjects were enrolled in an expansion cohort (Part B). Response was assessed by RECIST q 2 cycles for all subjects.Thirty patients were enrolled (18 male, 12 female) and 29 were treated. Median age was 61 years (31-79) and the median number of prior cytotoxic chemotherapy regimens was 2 (0-3). Eighty-three percent of subjects had received prior RT. DLTs occurred at dose level 1 (sudden death of unclear cause in a patient with melanoma metastatic to liver) and dose level 2 (bowel obstruction). No DLTs occurred at dose levels 3 and 4. The most common adverse events (≥grade 3) among 28 patients evaluable for toxicity were lymphopenia (36%), hyperglycemia (11%), fatigue (11%), and venous thrombosis (11%). PK analysis of everolimus demonstrated dose-proportional increases in C (max) (mean 91.9 ng/ml) and AUC(0-INF) (mean 680.5 h*ng/ml) at dose level 4. Three partial responses were seen (metastatic pulmonary carcinoid, n = 2; metastatic sinus carcinoma, n = 1). Prolonged stable disease ≥6 cycles occurred in subjects with pulmonary carcinoid, oropharyngeal squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma, and esthesioneuroblastoma (n = 1 each).The phase II recommended dose is everolimus 10 mg/day (days 1-21) + cisplatin 20 mg/m(2) (days 1, 8, and 15) of a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for everolimus monotherapy. Anti-tumor activity was observed in several tumor types.

Adenoid cystic carcinomas (ACC) are rare cancers usually arising in the salivary glands. Once metastatic, the natural history can vary; some patients with indolent cancer remain asymptomatic for long periods, whereas others have rapidly progressive disease. Chemotherapy is generally reserved for the palliative treatment of symptomatic locally recurrent or metastatic disease that is not amenable to further surgery or radiation. Prospective trials of chemotherapy in advanced ACC are limited, and the optimum regimen is unclear. The aim of this systematic review is to summarise and rate the quality of trials assessing chemotherapy for treatment of ACC, by use of the European Lung Cancer Working Party scoring system. Endpoints evaluated include tumour response and rates of symptomatic improvement. 34 trials involving 441 patients are included. We give evidence-based recommendations for management of ACC with chemotherapy, along with considerations for the design of future clinical trials in this disease.

Purpose XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article. Patients and Methods A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses. Results Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC. Conclusion Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing ( ClinicalTrials.gov number NCT00215605).

Background. Expression of p16 is a marker for human papillomavirus (HPV)-related carcinogenesis in head and neck cancer. The purpose of this study is to determine if p16 immunoreactivity is associated with aberrant expression of components of the PI3 kinase pathway. Methods. A tissue microarray (TMA) was constructed for 46 archived tonsillar squamous cell carcinoma specimens. Clinical demographics of these patients were analyzed, and the TMA was interrogated with antibodies directed against p16, phosphorylated AktSer473, phosphorylated S6Ser240/244, phosphorylated S6Ser235/236, phosphorylated 4E-BP1Thr37/46, phosphorylated eIF4ESer209, PTEN, p21, and p53. Results. There was a significant correlation between history of tobacco abuse (>10 pack/years) and absence of p16 expression (p = .01). Expression of p16 was significantly associated with immunoreactivity of p21 (p = .02), PTEN (p = .02), and phosphorylated eIF4E (p = .03). There was no evidence of association between p16 status and expression of phosphorylated S6, phosphorylated 4E-BP1, or p53. Conclusion. p16 positive tonsillar squamous cell carcinoma is characterized by expression of phosphorylated eIF4E that may occur via a mammalian target of rapamycin (mTOR)-independent mechanism. © 2010 Wiley Periodicals, Inc. Head Neck, 2010

Management of the neck in patients treated with primary chemoradiation for cancer of the laryngopharynx with a clinically positive neck remains an area of controversy. The neck may be managed in 1 of 3 ways: by observation, by planned neck dissection, or by salvage neck dissection. Observation of the neck can be done in patients who have a complete or near-complete response to treatment and have a negative positron emission tomography (PET) scan result. Evidence for this approach comes from recent studies that have reported low regional recurrence rates.1–6 Planned neck dissection was carried out in the past in patients with N2 and N3 neck disease irrespective of the response to chemoradiation. The neck dissection was carried out 6 weeks after completion of chemoradiation; this approach had the advantage of carrying out the neck dissection before the onset of fibrosis, thereby making the neck dissection technically similar in complexity to a nonchemoradiation neck dissection. Evidence for a policy of planned neck dissection comes from studies that have shown the presence of tumor in neck dissection specimens in patients who have complete or near-complete radiologic and clinical response in the neck.4,7–10 Before the introduction of fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning, planned neck dissection was a common method for managing the neck after chemoradiation. Some groups still practice this policy because of limitations or unavailability of PET. However, in general, most centers now reserve neck dissection for salvage for residual or recurrent neck disease. Salvage neck dissection is normally carried out if there is clinical or radiologic evidence of neck disease after completion of chemoradiation. Before 2005, our policy was to assess response by clinical examination and CT imaging at 6 to 12 weeks after completion of chemoradiation. However, since 2005, we have been using 18FDG-PET for the assessment of tumor response. The 18FDG-PET is usually carried out at 12 weeks after completion of chemoradiation to minimize any false-positive results from residual inflammation from chemoradiation. Salvage neck dissection in patients who have neck disease as detected by PET is therefore carried out 12 weeks after chemoradiation. This has the disadvantage of making the operation technically more difficult because of the onset of fibrosis. As a consequence, some have advocated the use of selective and superselective salvage neck dissections in these patients.11–14 Clearly there is evidence in the literature to support the practice of planned, as well as salvage neck dissection. However, there is little in the literature that describes what the impact of viable tumor in such neck dissection specimen has on prognosis. In this study, we have examined our own experience of patients undergoing comprehensive neck dissection either as a planned procedure or salvage procedure in the time period before our routine use of PET. The objective was to determine whether viable tumor had a negative impact on prognosis, even after removal of residual tumor by neck dissection.

BACKGROUND: Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC). METHODS: This was an open-label, single-institution, single-arm, phase 2 study for patients who had received no more than 2 cytotoxic regimens for recurrent and/or metastatic HNSCC. All patients received pemetrexed 500 mg/m2 intravenously plus gemcitabine 1250 mg/m2 intravenously every 2 weeks with vitamin B12 and folate support. The primary endpoint was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints were to estimate overall survival and to evaluate safety and tolerability. RESULTS: Twenty-five patients received therapy. All patients had received prior radiotherapy, and half had received prior cytotoxic chemotherapy for recurrent and/or metastatic disease. Neutropenia (grade ≥3) occurred in 24% of patients. Four patients (16%) had a partial response (PR) according to RECIST, and 5 additional patients (20%) had objective tumor reductions of >20 but

Dans le cadre d'une etude experimentale et theorique des heterocycles sulfures, nous avons aborde l'examen de derives du dithiole-1,3 et du dithiole-1,2 en utilisant la methode C. N. D. O. A notre connaissance, aucun de ces composes n'a fait l'objet d'une approche theorique incluant tous les electrons de valence. Les donnees experimentales les plus completes que nous possedions etant les spectres d'absorption de ces composes dans l'ultra-violet et le visible, nous nous sommes attaches en premier lieu a l'interpretation des spectres electroniques de ces heterocycles.

PURPOSE: To assess noninvasively the tumor microenvironment of neck nodal metastases in patients with head-and-neck cancer by investigating the relationship between tumor perfusion measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and hypoxia measured by (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET).METHODS AND MATERIALS: Thirteen newly diagnosed head-and-neck cancer patients with metastatic neck nodes underwent DCE-MRI and (18)F-FMISO PET imaging before chemotherapy and radiotherapy. The matched regions of interests from both modalities were analyzed. To examine the correlations between DCE-MRI parameters and standard uptake value (SUV) measurements from (18)F-FMISO PET, the nonparametric Spearman correlation coefficient was calculated. Furthermore, DCE-MRI parameters were compared between nodes with (18)F-FMISO uptake and nodes with no (18)F-FMISO uptake using Mann-Whitney U tests.RESULTS: For the 13 patients, a total of 18 nodes were analyzed. The nodal size strongly correlated with the (18)F-FMISO SUV (rho = 0.74, p < 0.001). There was a strong negative correlation between the median k(ep) (redistribution rate constant) value (rho = -0.58, p = 0.042) and the (18)F-FMISO SUV. Hypoxic nodes (moderate to severe (18)F-FMISO uptake) had significantly lower median K(trans) (volume transfer constant) (p = 0.049) and median k(ep) (p = 0.027) values than did nonhypoxic nodes (no (18)F-FMISO uptake).CONCLUSION: This initial evaluation of the preliminary results support the hypothesis that in metastatic neck lymph nodes, hypoxic nodes are poorly perfused (i.e., have significantly lower K(trans) and k(ep) values) compared with nonhypoxic nodes.

Background: Biomarkers predictive of response to anti-PD-1 therapy include tumor mutational burden (TMB) and inflammatory biomarkers such as PD-L1 expression and T-cell activated gene expression profile (GEP). This study evaluated relationships between TMB, PD-L1 expression, and GEP and response to pembrolizumab in HNSCC patients in the KEYNOTE (KN)-012 and KN-55 trials. Methods: Data were combined from 261 HNSCC patients in KN-012 (NCT01848834, subsets of B1 [PD-L1+, ≥1%, modified proportion score or interface pattern, QualTek IHC; n=34] and B2 [n=73] cohorts) and KN-055 (NCT02255097, platinum/cetuximab resistant, n=154) who had TMB data available by whole exome sequencing. Of these, 258 patients had PD-L1 data (PD-L1 IHC using 22C3 pharmDx, CPS readout) and 240 patients had GEP score (RNA analyzed on NanoString nCounter). HPV+/- status was assessed by p16 IHC and WES methods. Statistical testing of relationships between biomarkers and best overall response (BOR) by logistic regression and progression free survival (PFS) by Cox regression was prespecified and performed in a blinded manner. Results: TMB, PD-L1 CPS and GEP were each significantly associated with BOR in the overall population (p Conclusion: TMB, PD-L1 and T-cell inflamed GEP were independently predictive of response to pembrolizumab in HNSCC patients, in general regardless of HPV status. When used alone or jointly, these biomarkers may have utility in characterizing responses to anti PD-1 therapies and novel cancer regimens in HNSCC. Citation Format: Tanguy Y. Seiwert, Robert Haddad, Joshua Bauml, Jared Weiss, David G. Pfister, Shilpa Gupta, Ranee Mehra, Iris Gluck, Hyunseok Kang, Francis Worden, J. Paul Eder, Makoto Tahara, Barbara Burtness, Stephen V. Liu, Andrea Webber, Lingkang Huang, Robin Mogg, Razvan Cristescu, Jonathan Cheng, Laura Q. Chow. Biomarkers predictive of response to pembrolizumab in head and neck cancer (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-339.

A pproximately 37,000 new cases of thyroid cancer are diagnosed annually in the United States, and of these, about 10–20% present with or ultimately develop distant metastases (1). The prognosis of patients with distant metastases from non-medullary thyroid cancer (non-MTC) remains favorable when these are responsive to radioactive iodine (RAI). By contrast, the 10-yr survival after discovery of distant metastases is only 10% if these have lost the ability to trap or retain iodine. Patients with metastatic RAI-refractory lesions that are also positive on fluoro-deoxyglucose-positron emission tomography (FDG-PET) have a particularly poor prognosis. In addition to patients with distant metastatic disease, those with unresectable local recurrences also have a higher mortality. Palliative external beam irradiation plays an important role in local disease control; however, conventional chemotherapeutic agents are relatively ineffective in thyroid cancer (2). Recent clinical trials with several kinase inhibitors have shown promising evidence of activity in thyroid cancer of follicular origin (3,4,5,6) as well as in MTC (7,8).

6087Background: mutations (BRAFm) are the most common mutations in thyroid cancer. BRAF inhibitors (DAB) are active in BRAFm melanoma, but there is less activity noted in BRAFm thyroid cancer. Prec...

6009Background: A minority of patients with metastatic HNSCC respond to the anti-programmed death (PD-1) monoclonal antibody, Nivolumab (Nivo). We sought to determine whether targeted radiation to a single lesion combined with Nivo would enhance tumor regression in non-irradiated lesions (abscopal response) and improve outcomes. Methods: Patients with M1 HNSCC (including nasopharynx) with at least two RECIST 1.1 measurable lesions were randomized with stratification for viral status (EBV/HPV pos vs. neg) 1:1 to either Nivo alone q 2 weeks or Nivo with SBRT to a single lesion (9 Gy x 3) between the 1st and 2nd doses of Nivo. The primary end-point was objective response rate (ORR) in non-irradiated lesions using RECIST 1.1. Secondary analyses included overall survival (OS), progression free-survival (PFS), and duration-of-response (DOR). We hypothesized that SBRT added to Nivo would increase ORR from 15% to 45%. Enrolling 53 patients thus provides a one-sided alpha of 0.10 and a power of 0.80. Results: 53 p...

TPS6090Background: Although the EXTREME regimen is a Category 1 evidence-supported combination recommended by NCCN guidelines as first-line (1L) treatment for patients with R/M SCCHN, it is associa...

Context The rationale for locoregional staging lymphadenectomy in bladder cancer lies in the accurate diagnosis of occult micrometastases to stratify patients who might benefit from adjuvant therapeutic measures. In bladder cancer, pelvic lymphadenectomy (PLA) as a common procedure of radical cystectomy has not been standardized, although evidence supports a relationship between the extent of lymph node dissection and therapeutic outcome. Evidence acquisition Recent retrospective and prospective clinical trials have carefully analyzed the distribution of lymph node metastases at time of radical cystectomy, thereby identifying those regions that should be included in a standard pelvic lymph node dissection. Evidence synthesis Dissecting all lymphatic tissue along the common iliac region—with the aortic bifurcation as cranial margin—along the external, internal iliac region, and the obturator fossae bilaterally will completely clear 80% of all positive nodes. Only if frozen section examination will demonstrate micrometastases at these regions will extending lymphadenectomy further cranially be worthwhile. Conclusions Currently, extended PLA in bladder cancer has been shown to improve progression-free survival if >14 lymph nodes are removed. For the future, prospective trials have to demonstrate a benefit with regard to cancer-specific and overall survival and in terms of regional versus distant recurrences.

213 Background: For planning salvage procedures in recurrent prostate cancer accurate diagnostic tools are needed. Till now in patients suspicious for isolated local recurrent cancer invasive biopsy was needed. 68-Ga-PSMA-PET is frequently used to identify even small metastatic deposits. We analyzed the diagnostic value to identify local recurrence in patients after radiotherapy undergoing salvage radical prostatectomy, sRPE. Methods: We retrospectively reviewed patients undergoing sRPE with 68-Ga-PSMA-PET as preoperative staging. All patients underwent sRPE and extended lymph node dissection. Sensitivity, Specificity, pos and neg predictive value had been calculated per patient and per prostate lobe. Results: 37 patients with preoperative 68-Ga-PSMA-PEt could be identified. In all but one at least in one lobe PSMA staining could be identified. Mean tumor volume per prostate lobe was 6.22 (0.1-24)ml. Sensitivity, Specificity, neg and pos predictive value per lobe is 80%, 75%, 32% and 96%. Sensitivity to identify cancer recurrence per person irrespective of the side is 95% with a pos predictive value of 100%. Conclusions: 68-Ga-PSMA-PET seems to have a very high diagnistic value to identify local recurrence after radiotherapy. After validation of our experience an invasive biopsy to proof cancer recurrence might be spared.

32 Background: Risk stratification for patients diagnosed with prostate cancer (PCa) through MR-TRUS fusion biopsy still relies on Gleason (GL) grading of the biopsy specimens. GL grading of the same sample can differ between pathologists. In our tertiary high-volume center GL grading of the biopsy specimens is crucial for further therapy planning. Methods: Reference pathology of 42 patients after transperineal MR-TURS fusion plus saturation biopsy was assessed by one specialized genitourinary pathologist. GL grading of the original pathology and the reference pathology for the saturation and targeted biopsy cores were compared. Risk groups for this study were set as GL 6 for low, GL 7a and GL 7b for intermediate and GL 8, GL 9 and GL 10 for high-risk. Results: In 42 patients 49 lesions were identified by mpMRI (PI-RADS 3-5) in which 150 biopsy cores were taken. In addition, 709 cores were taken as saturation biopsies. The highest GL grading per patient differed in 18 (43 %) of the cases. In 16 cases, there was a difference within the targeted biopsies but only in 8 cases there was a difference in the saturation biopsies. In 6 cases both saturation and fusion biopsies were different. Taking risk stratification into account there was a misclassification with low- and intermediate risk in 9 (21 %) cases, an intermediate- and high risk in 2 cases and a misclassification within the same risk group in 6 (14 %) cases. In 16 of the 18 differences there was an upgrading of the Gleason score by the reference pathologist whereas only in 2 cases there was a downgrading. Conclusions: The data shows that in times of mpMRIs and transperineal MRI-TRUS fusion biopsies it still is the GL score graded by the pathologist who accounts for many potential therapy plan mistakes. In this study 21 % of the patients were misclassified as GL 6 while reference pathology graded for GL 7a or GL 7b. The demonstrated data suggests that there should be a reference pathology at least for every GL 6 cancer and that the quality of GL grading should be monitored. Also this data again addresses the need for a better risk stratification irrespective of the GL score that can be done in a more objective way with less potential for misclassification.

349 Background: An upregulation of vimentin 3, a truncated version of the full length vimentin, with an unknown function, was previously described by our group, in a direct dependency of increased ET-1 levels. We analyzed now vimentin 3 in further genitourinary cancers. Here, we describe our findings how vimentin 3 is part of the signaling pathways from Endothelin-1 (ET-1) and the Endothelin-A-Receptor (ETAR) and how it correlates with aggressive tumor behavior in a PCa cell culture and in human tissue and serum samples from PCa patients. Methods: DU145 cells were cultured. We stimulated with ET-1 with and without artificial downregulation of the ETAR, the ETBR or both receptors. A scratch assay was performed to demonstrate the influence of ET-1. Proteins were then extracted and WB for vimentin full length and vimentin 3 was performed. Additionally we analyzed ET-1 and vimentin 3 in serum from prostate cancer patients using ELISA and we did IF and IHC staining for vimentin 3 in human prostate cancer tissue. Results: Treatment with ET-1 and downregulation of the ETBR lead to a significant increased migration of DU145 cells after 3 and 6 h. The corresponding WB showed increased vimentin 3. ELISA showed increased levels of ET-1 in samples of prostate cancer patients compared to patients with no cancer history. ELISA could also demonstrate elevated levels of vimentin 3 in serum of patients with local disease and significantly elevated values in metastatic prostate cancer patients compared to patients with no cancer history. Conclusions: The data presented shows that ET-1 stimulation leads to overexpression of vimentin 3 in prostate cancer cell cultures and a concomitant aggressive biological behavior. Here we previously described the direct interaction of Vimentin 3 in prostate cancer and the activation mechanism via ET-1 and the ETAR. IHC, IF show an upregulation of the truncated variant Vimentin3 in tissue samples. In an Vimentin 3 ELISA we could show that this truncated variant is increased and therefore represents a potential biomarker. Highest values of vimentin 3 were measured using ELISA in serum of patients with recurrent and metastatic disease also suggesting that vimentin 3 correlates with aggressive tumor behavior.

212 Background: Salvage radical prostatectomy is one option for patients with locally recurrent disease with proven long term oncologic control. There are concerns about worse functional results due to fibrotic tissue after radiotherapy and patients are treated with palliative systemic androgendreptivation. We retrospectively analyzed continence and quality of life in patients undergoing SRPE. Methods: After biopsy proven local recurrent prostate cancer 138 patients were offered SRPE and extended lymphadenectomy. Continence and quality of life had been collected before 6 and 12 months after surgery. Validated questionaires with ICIQ and EORTC qlq 30 had been used. Results: Präoperatively at 6 monts and 12 months the feed back was available in 93, 84 and 82 patients respectively. Präoperatively there was no or mild incontinence in 38(40.8%), moderate in 33 (35.5%) and strong incontinence in 22 (23.7%) of the patients. There is a significant decrease in the rate of continence after 6 and 12 months to no or mild in 19 (23.1%), moderate in 19 (23.2%) and strong incontinence in 44 (53.7%) of the patients. In 5 patients an artifitial sphinkter was implanted. Quality of life did not change significantly before and 12 months after surgery. Median value of Question 30 was 6 and five respectively. Conclusions: Patients need to be informed about a worse functional outcome and the potential need for further surgical interventions as artificial sphinkter implantion compared to primary radical prostatectomy. Quality of life seems to be affected only moderatly. Nevertheless there is already a rather high rate of any incontinence before surgery that needs to be taken into account.

566 Background: Growing teratoma syndrome (GTS) is an infrequent clinical phenomenon constituting only about 2 to 8% of all testis cancer patients. Data in the literature on the therapy of GTS are sparse, reflecting the rarity of the disease. The objective of was to determine the diagnostic, surgical and oncological outcome of patients with GTS treated in the 21st century. Methods: Between 01/2000 and 01/2010 post-chemotherapeutic retroperitoneal lymph node dissections (PCRLND) were performed in 296 patients with advanced NSGCT. We analysed the peri- and postoperative outcome of 16 patients (5.4%) that fulfilled the criteria of a GTS: enlarging metastatic mass in the retroperitoneum or visceral organs during systemic chemotherapy with normalized or decreasing tumour markers. Results: Mean patient age was 31 years (17-57). Initially, all patients had NSGCT with a good or intermediate prognosis according to IGCCCG; one patient had a poor prognosis. In all cases the primary tumour predominantly contained mature teratoma; two patients had a clinical stage IIb, nine and three presented with clinical stage IIc and III respectively. Median tumour diameter at time of surgery was 8.1 cm (1.5-32). Tumour markers were plateauing or normalized in all patients. Tumour masses were localized in the retroperitoneum in 15 patients; one patient demonstrated a pulmonary mass. After a median follow-up of 4.2 years, 2 patients developed outfield recurrences; all but one patients are alive. Conclusions: GTS is a rare disease among patients with advanced NSGCT and necessitates complete surgical resection of the masses with curative intention. Surgery should be considered at time of progression to facilitate complete removal of the growing teratoma and be performed in tertiary referral centers only.

We analyze the transport of pollution across the Pacific during the NASA INTEX-B (Intercontinental Chemical Transport Experiment Part B) campaign in spring 2006 and examine how this year compares to the time period for 2000 through 2006. In addition to aircraft measurements of carbon monoxide (CO) collected during INTEX-B, we include in this study multi-year satellite retrievals of CO from the Measurements of Pollution in the Troposphere (MOPITT) instrument and simulations from the chemistry transport model MOZART-4. Model tracers are used to examine the contributions of different source regions and source types to pollution levels over the Pacific. Additional modeling studies are performed to separate the impacts of inter-annual variability in meteorology and dynamics from changes in source strength. Interannual variability in the tropospheric CO burden over the Pacific and the US as estimated from the MOPITT data range up to 7% and a somewhat smaller estimate (5%) is derived from the model. When keeping the emissions in the model constant between years, the year-to-year changes are reduced (2%), but show that in addition to changes in emissions, variable meteorological conditions also impact transpacific pollution transport. We estimate that about 1/3 of the variability in the tropospheric CO loading over the contiguous US is explained by changes in emissions and about 2/3 by changes in meteorology and transport. Biomass burning sources are found to be a larger driver for inter-annual variability in the CO loading compared to fossil and biofuel sources or photochemical CO production even though their absolute contributions are smaller. Source contribution analysis shows that the aircraft sampling during INTEX-B was fairly representative of the larger scale region, but with a slight bias towards higher influence from Asian contributions.

Purpose To determine survival rates of patients with locally recurrent nasopharynx cancer (LRNPC) treated with modern therapeutic modalities. Methods and Materials From July 1996 to March 2008, 29 patients were reirradiated for LRNPC. Thirteen patients received combined-modality treatment (CMT), consisting of external beam radiotherapy (EBRT) followed by intracavitary brachytherapy, whereas 16 received EBRT alone. The median age was 50 years, 59% were male, 38% were Asian, 69% had World Health Organization Class III histology, and 86% were treated for their first recurrence. Nine, 6, 8, and 6 patients had recurrent Stage I, II, III, and IV disease, respectively. Patients in the EBRT-alone group had more advanced disease. Median time to reirradiation was 3.9 years. In total, 93% underwent imaging with positron emission tomography and/or magnetic resonance imaging before reirradiation, 83% received intensity-modulated radiotherapy, and 93% received chemotherapy, which was platinum-based in 85% of cases. Results The median follow-up for all patients was 45 months and for surviving patients was 54 months. Five-year actuarial local control, event-free survival, and overall survival rates were 52%, 44%, and 60%, respectively. No difference was observed between patients treated with EBRT or CMT. Overall survival was superior in patients who achieved local control (p = 0.0003). The incidence of late Grade ≥3 events in patients re-treated with EBRT alone was significantly increased compared with those receiving CMT (73% vs. 8%; p = 0.005). Conclusions In this modern reirradiation series of patients with LRNPC, favorable overall survival compared with historical series was achieved. Patients treated with CMT experienced significantly fewer severe late effects compared with those treated with EBRT.

The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy. © 2009 by American Society of Clinical Oncology.

Background. The objective of this study was to report our experience in the management of patients with advanced-stage supraglottic laryngeal carcinoma and to identify factors predictive of outcome. Methods. In total, 181 patients with advanced-stage supraglottic laryngeal carcinoma were treated at Memorial Sloan-Kettering Cancer Center between 1984 and 1998. Sixty-nine (38%) patients were treated by surgery ± postoperative radiotherapy (SRT), 93 (52%) by chemoradiotherapy (CTRT), and 19 (10%) by radiotherapy alone (RT). Survival outcomes were calculated using the Kaplan-Meier method. Predictors of outcome were identified using multivariate analysis. Results. The-5 year overall survival (OS) and disease-specific survival (DSS) were 53% and 71%, respectively. Patients treated with SRT and CTRT had comparable outcomes. The main independent predictors of OS and DSS were age greater than 60 years and stage of the neck at presentation. Conclusion. Regardless of index treatment, age over 60 years and clinical stage of the neck at presentation were the main independent predictors of OS and DSS. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

As new guidelines on the use of 5-alpha-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention produced by the American Society of Clinical Oncology (ASCO) and American Urological Association (AUA) have recently been published, the use of 5-ARIs is becoming of increasing interest. We analyzed the current evidence to support the use of 5-ARIs in the prevention of prostate cancer. We therefore compared the new guidelines of the ASCO and AUA with the current data concerning the use of 5-ARIs in the prevention of prostate cancer. At present, there is still an open debate going on whether or not it is advisable to incorporate the use of 5-ARIs as chemopreventive agents in daily practice.

Purpose To present our single-institution experience of intensity-modulated radiotherapy (IMRT) for oral cavity cancer. Methods and Materials Between September 2000 and December 2006, 35 patients with histologically confirmed squamous cell carcinoma of the oral cavity underwent surgery followed by postoperative IMRT. The sites included were buccal mucosa in 8, oral tongue in 11, floor of the mouth in 9, gingiva in 4, hard palate in 2, and retromolar trigone in 1. Most patients had Stage III-IV disease (80%). Ten patients (29%) also received concurrent postoperative chemotherapy with IMRT. The median prescribed radiation dose was 60 Gy. Results The median follow-up for surviving patients was 28.1 months (range, 11.9–85.1). Treatment failure occurred in 11 cases as follows: local in 4, regional in 2, and distant metastases in 5. Of the 5 patients with distant metastases, 2 presented with dermal metastases. The 2- and 3-year estimates of locoregional progression-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 84% and 77%, 85% and 85%, 70% and 64%, and 74% and 74%, respectively. Acute Grade 2 or greater dermatitis, mucositis, and esophageal reactions were experienced by 54%, 66%, and 40% of the patients, respectively. Documented late complications included trismus (17%) and osteoradionecrosis (5%). Conclusion IMRT as an adjuvant treatment after surgical resection for oral cavity tumors is feasible and effective, with promising results and acceptable toxicity.

Background The hemodynamic characteristics of different heart valve prostheses have been investigated in vitro with a novel pulse duplicator. A novel valved stent for transapical or percutaneous valve implantation has been compared with a native heart valve and mechanical heart valves. Methods All experiments were designed to imitate both physiologic pressure ratios and flow characteristics in diastole and systole. After calibrating the system using a human aortic valve (primary orifice diameter: 22.0 mm), the following valves were studied under aortic pulsatile flow conditions: Hall-Kaster (Medtronic-Hall, 20.0 mm), St. Jude Medical (20.0 mm), a newly developed tricuspid valved stent (Tricumed TM4, 20.7 mm) and a newly developed biomechanical valve (Engage aortic valve Model 6000, 21.0 mm). All valves including the human aortic valve were assessed by videotape observation under pulsatile flow conditions. Measured flow-related parameters include in vitro mean transvalvular pressure, regurgitant volume, effective orifice area and performance index. Results The optical assessment of all five valves demonstrated a complete opening during systole and closing at the beginning of diastole. All valves were optically sufficient during diastole. Engage aortic valve Model 6000 showed the highest maximum transvalvular pressure (27.5 +/- 8.2 mmHg), whereas both Hall-Kaster (17.9 +/- 1.5 mmHg) and St. Jude Medical (16.7 +/- 0.7 mmHg) had a lower gradient than the native aortic valve (24.0 +/- 0.2 mmHg) and Tricumed TM4 (21.8 +/- 3.8 mmHg). The maximum effective orifice area of St. Jude Medical amounted to 258.7 +/- 3.4 mm(2), followed by Tricumed TM4 with an area of 222.1 +/- 1.9 mm(2) and the human aortic valve with 160.4 +/- 2.9 mm(2). Hall-Kaster and Engage aortic valve Model 6000 had an area of 198.9 +/- 1.6 mm(2) and 176.7 +/- 3.1 mm(2), respectively. Conclusions The pulse duplicator proved to be highly accurate and yielded reproducible results. Since it has been calibrated with a human aortic valve, the hemodynamics of any heart valve prosthesis can be compared with the human valve. This system can evaluate and promote the development of new biological and mechanical heart valve prostheses.

BACKGROUND: Perfluorocarbon liquids (PFCL) cause retinal damage when used as long-term ocular endotamponades. Whether these changes are related to the mechanical or to the chemical properties of PFCL is unclear. The purpose of this study was to evaluate pressure spikes or shearing forces during endotamponade with PFCL and standardised eye movements. MATERIAL AND METHODS: Part 1: In an eye model the resulting pressure forces of 6 PFCL were measured at four different sites during standardised eye movements. Part 2: Shearing forces were determined in a plexiglass eye model and the resulting tangential forces at the PFCL-retina interface were calculated. Part 3: Rabbit eyes were vitrectomised and filled with light and heavy fluorocarbons for 6 weeks. Subsequently, the retina were examined histologically and by immunohistochemistry. RESULTS: With increasing filling of the eye model, the maximum of the pressure peaks moved from the inferior wall of the eye model to the lateral eye walls. For perfluorodecalin (PFD) the highest pressure peak was 407 Pa with a 75 % filling of the vitreous cavity. The lowest pressure peak was 314 Pa with a 50 % filling of hexafluoropropene oxide. Shearing forces for standardised accelerations were dependent on viscosity and ranged between 0.87 mN/m 2 (perfluorohexyloctane) and 8055 mN/m 2 (hexafluoropropene oxide). Part 3: Histological and immunohistochemical analyses did not reveal pressure-related damage or any difference between the effects of the different tamponades in vivo. CONCLUSION: In comparison with physiological dynamic and static pressure peaks, the measured mechanical forces induced by intraocular PFCL tamponades are low. Specific gravity and mechanical damage by intraocular PFCL as a cause of retinal damage seem unlikely. Animal studies underline these findings.

Purpose Unknown primary head and neck cancers often require comprehensive mucosal and bilateral neck irradiation. With conventional techniques, significant toxicity can develop. Intensity-modulated radiotherapy (IMRT) has the potential to minimize the toxicity. Methods and Materials Between 2000 and 2005, 21 patients underwent IMRT for unknown primary head and neck cancer at our center. Of the 21 patients, 5 received IMRT with definitive intent and 16 as postoperative therapy; 14 received concurrent chemotherapy and 7 IMRT alone. The target volumes included the bilateral neck and mucosal surface. The median dose was 66 Gy. Acute and chronic toxicities, esophageal strictures, and percutaneous endoscopic gastrostomy tube dependence were evaluated. Progression-free survival, regional progression-free survival, distant metastasis-free survival, and overall survival were estimated with Kaplan-Meier curves. Results With a median follow-up of 24 months, the 2-year regional progression-free survival, distant metastasis-free survival, and overall survival rate was 90%, 90%, and 85%, respectively. Acute grade 1 and 2 xerostomia was seen in 57% and 43% of patients, respectively. Salivary function improved with time. Percutaneous endoscopic gastrostomy tube placement was required in 72% with combined modality treatment and 43% with IMRT alone. Only 1 patient required percutaneous endoscopic gastrostomy support at the last follow-up visit. Two patients treated with combined modality and one treated with IMRT alone developed esophageal strictures, but all had improvement or resolution with dilation. Conclusion The preliminary analysis of IMRT for unknown primary head and neck cancer has shown acceptable toxicity and encouraging efficacy. The analysis of the dosimetric variables showed excellent tumor coverage and acceptable doses to critical normal structures. Esophageal strictures developed but were effectively treated with dilation. Techniques to limit the esophageal dose could help further minimize this complication.

To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center.From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT).With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT.Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted.

MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor (FcgammaRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the tumor cytotoxicity of bispecific antibodies.In group 1, patients received MDX-447 intravenously (i.v.) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5, 7, 10, 15, 20, 30, and 40 mg/m(2). In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days -3 to +2, 5-9, 12-16, etc.). Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m(2).Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups, with seven patients experiencingor= grade 3 events. MDX-447 half-life (T(1/2)) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and peak levels of circulating tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447 alone was 30 mg/m(2). When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns, with the last patient being treated at the 7 mg/m(2) dose level. There were no objective complete or partial responses in either group.MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m(2) weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation.

Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) analogues or antagonists represents the treatment of choice in men with metastatic prostate cancer (PCA). Depending on the serum concentration of the prostate-specific antigen (PSA) nadir, the survival might vary between 11 and 78 months. In castration-resistant PCA (CRPC), all new medical treatment options can induce complete and partial remissions in metastatic foci, but they have no profound effect on the prostate itself, as has been shown recently. About one-third of all patients without local treatment of the primary will develop significant complications of the lower and upper urinary tract due to local progression of the PCA. In men with CRPC and lower urinary tract symptoms, palliative transurethral resection of the prostate (TURP) can be performed with a 60-70% success rate. Infiltration of the pelvic floor, the bladder neck and trigone, and the external urethral sphincter can make palliative radical surgery necessary. Bladder neck closure with continent vesicostomy, radical cystoprostatectomy with an incontinent urinary diversion, and anterior and posterior exenteration are individual therapeutic options in men with a good performance status and a considerable life expectancy. Symptomatic involvement of the upper urinary tract can be managed by the placement of endoluminal stents or a percutaneous nephrostomy in men with poor performance. In men with a good response to ADT and a good performance status, reconstructive ureteral surgery might be considered and the options of ureteral reimplantation, ureter ileal replacement, and a subcutaneous pyelovesical bypass have to be discussed. The indication to perform one of the above-mentioned surgical approaches needs to be discussed in a multidisciplinary tumor board.

Introduction: Published results of HistoScanning™ (HS) for prostate cancer (PCa) diagnostics are inconsistent and their value remains unclear. We prospectively analyzed the detection rate and tumor volume concordance in PCa patients. Material and Methods: Two hundred and eighty-two patients with biopsy-proven PCa scheduled for radical prostatectomy (RP) were included. All patients underwent ultrasonographical examination by HS prior to surgery. HS was evaluated compared to RP specimen as to (1) the prediction of overall tumor volume and (2) accuracy of HS in detection of PCa lesions larger than 0.2/0.5 ml, separated for each sextant. For each sextant, receiver operating characteristic (ROC)-analysis and area under the curve were determined. Sensitivity and specificity were calculated and visualized in ROC-curves. Results: HS tends to underestimate volume of cancerous lesions, particularly larger lesions >8 ml. Using a 0.2 ml detection threshold, specificity and sensitivity of HS were between 29-68% and 46-78%. For a 0.5 ml detection threshold, sextant-specific specificity increased to 59-92% and sensitivity decreased to 16-54%. Stratification according to pre-operational PSA values did not improve performance characteristics of HS. Conclusions: Our results do not support a significant contribution of HS to PCa diagnostics.

The purpose of this study was to evaluate the efficacy and tolerability of the addition of 2 monoclonal antibodies, bevacizumab and cetuximab, to 2 cycles of high-dose cisplatin administered concurrently with intensity-modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC).Patients with newly diagnosed stage III/IVB (M0) HNSCC received cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2) weekly), bevacizumab (15 mg/kg, days 1 and 22), and cisplatin (50 mg/m(2) , days 1, 2, 22, and 23) concurrently with IMRT (70 Gy). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety and tolerability.Among 30 patients enrolled in this study, the primary tumor site was the oropharynx in 24 patients (p16 immunohistochemistry was positive in 17, negative in 1, and not done in 6 of the oropharyngeal tumors). Median age was 57 years (range, 38-77 years) and 27 patients had clinical stage IVA disease. All patients completed the full planned dose of radiation therapy. The most common ≥ grade 3 adverse events were lymphopenia, mucositis (functional), and dysphagia. With a median follow-up of 33.8 months, 2-year PFS was 88.5% (95% confidence interval [CI] = 68.1-96.1) and 2-year OS was 92.8% (95% CI = 74.2-98.1).The addition of bevacizumab and cetuximab to 2 cycles of cisplatin, given concurrently with IMRT, was well-tolerated and was associated with favorable efficacy outcomes in this patient population. © 2015 Wiley Periodicals, Inc. Head Neck 38: E566-E570, 2016.