M.P. Gebhard

Prognostic factors (including HPV status) for irradiation of locally advanced squamous cell carcinoma of the head and neck (SCCHN)

Background and PurposeThe prognosis of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) is generally poor. However, prognostic factors can help optimize the care for the individual patient. This study investigated potential prognostic factors, including HPV status, for locoregional control (LRC), metastases-free survival (MFS), and survival (OS).Patients and MethodsTwelve potential prognostic factors were investigated in 170 patients irradiated for stage III or IV SCCHN, including age (≤ 60 vs > 60 years), gender, ECOG performance score (0–1 vs 2), preradiotherapy hemoglobin level (< 12 vs ≥ 12 g/dl), tumor site (oropharynx, oral cavity, hypopharynx, or larynx), histological grade (G1–2 vs G3), T category (T1–T2 vs T3–T4), N category (N0–N1 vs N2–N3), AJCC stage (III vs IV), surgery (no vs yes), and chemotherapy (no vs yes).ResultsOn multivariate analysis, positive HPV status (RR 2.34; p = 0.014), ECOG performance score 0–1 (RR 1.94; p = 0.017), preRT hemoglobin ≥ 12 g/dl (RR 1.88; p = 0.018), T category T1–T2 (RR 2.72; p < 0.001), and surgery (RR 2.29; p = 0.007) were significantly associated with improved LRC. PreRT hemoglobin ≥ 12 g/dl (RR 1.98; p = 0.040) and T category T1–T2 (RR 3.33; p < 0.001) were significantly associated with improved MFS. Positive HPV status (RR 2.19; p = 0.019), pre-RT hemoglobin ≥ 12 g/dl (RR 2.15; p = 0.002), T category T1–T2 (RR 2.31; p = 0.002), and AJCC stage III (RR 1.91; p = 0.034) were significantly associated with improved OS.Conclusion Improved treatment outcomes were significantly associated with positive HPV status, better performance status, lower tumor stage, and pretreatment hemoglobin levels ≥ 12 g/dl. These factors should be considered in future trials.HintergrundDie Prognose von Patienten mit lokal fortgeschrittenem Plattenepithelkarzinom im Kopf-Hals-Bereich (SCCHN) ist häufig schlecht. Prognosefaktoren können dabei helfen, die optimale Behandlung für den individuellen Patienten auszuwählen. Diese Studie untersuchte mögliche Prognosefaktoren inklusive HPV-Status für die lokoregionale Kontrolle (LRC), das metastasen-freie Überleben (MFS) und das Gesamtüberleben (OS).Material und MethodeZwölf mögliche Prognosefaktoren wurden in einer Serie von 170 Patienten, die aufgrund eines SCCHN im Stadium III oder IV eine Strahlentherapie erhielten, untersucht. Diese Faktoren waren Alter (≤ 60 vs > 60 Jahre), Geschlecht, Allgemeinzustand (ECOG 0–1 vs 2), Hämoglobinwert vor Strahlentherapie (< 12 vs ≥ 12 g/dl), Tumorlokalisation (Oropharynx, Mundhöhle, Hypopharynx, Larynx), Grading (G1–2 vs G3), T-Kategorie (T1–T2 vs T3–T4), N-Kategorie (N0–N1 vs N2–N3), AJCC-Stadium (III vs IV), Operation (nein vs ja) und Chemotherapie (nein vs ja).ErgebnisseIn der multivariaten Analyse waren ein positiver HPV-Status (RR 2,34; p = 0,014), ein besserer Allgemeinzustand (RR 1,94; p = 0,017), Hämoglobinwerte ≥ 12 g/dl (RR 1,88; p = 0,018), eine niedrigere T-Kategorie (RR 2,72; p < 0,001) und eine Operation (RR 2,29; p = 0,007) signifikant mit einer besseren LRC assoziiert. Hämoglobinwerte ≥ 12 g/dl (RR 1,98; p = 0,040) und eine niedrigere T-Kategorie (RR 3,33; p < 0,001) waren signifikant mit einem besseren MFS assoziiert. Ein positiver HPV-Status (RR 2,19; p = 0,019), Hämoglobinwerte ≥ 12 g/dl (RR 2,15; p = 0,002), eine niedrigere T-Kategorie (RR 2,31; p = 0,002) und AJCC-Stadium III (RR 1,91; p = 0,034) waren signifikant mit einem besseren OS assoziiert.SchlussfolgerungenEine Verbesserung der Behandlungsergebnisse war signifikant mit positivem HPV-Status, besserem Allgemeinzustand, niedrigerem Tumorstadium und Hämoglobinwerten ≥12 g/dl vor Therapie assoziiert. Diese Faktoren sollten in zukünftigen Studien berücksichtigt werden.

Dose-Escalation Study for Cardiac Radiosurgery in a Porcine Model

PURPOSE To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. METHODS AND MATERIALS Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm(3)). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. RESULTS Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. CONCLUSIONS Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

Pulmonary vein isolation by radiosurgery: implications for non-invasive treatment of atrial fibrillation

AIMS Electrical isolation of the pulmonary veins (PVs) has been established in clinical routine as a curative treatment for atrial fibrillation (AF). While catheter ablation carries procedural risks, radiosurgery might be able to non-invasively induce lesions at the PV ostia to block veno-atrial electrical conduction. This porcine feasibility and dose escalation study determined the effect of radiosurgery on electrophysiologic properties of the left atrial-PV junction. METHODS AND RESULTS Eight adult Goettingen mini-pigs underwent electrophysiological voltage mapping in the left atrium and the upper right PV. Radiation was delivered with a conventional linear accelerator. A single homogeneous dose ranging from 22.5 to 40 Gy was applied circumferentially to the target vein antrum. Six months after radiosurgery, electrophysiological mapping was repeated and a histological examination performed. Voltage mapping consistently showed electrical potentials in the upper right PV at baseline. Pacing the target vein prompted atrial excitation, thus proving veno-atrial electrical conduction. After 6 months, radiation had reduced PV electrogram amplitudes. This was dose dependent with a mean interaction effect of -5.8%/Gy. Complete block of atrio-venous electrical conduction occurred after 40 Gy dose application. Histology revealed transmural scarring of the targeted PV musculature with doses >30 Gy. After 40 Gy, it spanned the entire circumference in accordance with pulmonary vein isolation. CONCLUSION Pulmonary vein isolation to treat AF can be achieved by radiosurgery with a conventional linear accelerator. Yet, it requires a high radiation dose which might limit clinical applicability.

Increased Activation and Differentiated Localization of Native and Phosphorylated STAT3 in Nasal Polyps

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disease; the underlying mechanisms of cell signalling are not fully understood. STAT3 (signal transducer and activator of transcription 3) is a phosphokinase and a key signalling molecule implicated in cell cycle regulation. We studied the distribution and expression of STAT3 to examine the role of STAT3 in the pathogenesis of CRSwNP. Methods: We investigated tissue samples of the nasal polyps and inferior turbinate of patients with CRSwNP as well as samples of the inferior turbinate of subjects without chronic sinusitis. The expression levels of STAT3 and its activated form pSTAT3 were analysed using Western blotting, protein array, DNA microarray and immunohistochemistry. Results: No significant differences were found in STAT3-mRNA levels between the samples of nasal polyps and inferior turbinates of the same patient. However, the amount of pSTAT3 was increased in the polyp tissue compared to the inferior turbinates from both CRSwNP patients and control subjects (p < 0.01), indicating an activation of STAT3 in polyps. We identified a varying distribution pattern of pSTAT3; pSTAT3 was primarily found in superficial epithelial cells but not in the basal layer of the epithelium of the turbinate, whereas pSTAT3 was located in all layers of the epithelium of the polyp and mostly noted in the basal layer. Conclusions: Our results of the activation and varying localisation of STAT3 and its phosphorylated form in nasal polyps suggest that pSTAT3 plays a crucial role in the proliferative development of nasal polyps.

Expression of cyclooxygenase-2 in cervical cancer is associated with lymphovascular invasion

Cyclooxygenase-2 (COX-2) is associated with carcinogenesis and tumor progression. The current study analyzed the effect of COX-2 expression in patients with invasive squamous cervical cancer. Tissue samples from 123 cervical cancer patients were collected for a retrospective analysis using immunohistochemistry (IHC) with an antibody against COX-2. The clinical and survival data of the patients were analyzed. Positive staining for COX-2 (defined as an immunoreactivity score of ≥4) was detected in 28 patients (23%), with significantly higher percentages of staining in tumor cells compared with peritumoral stroma cells (P<0.001). COX-2 expression was significantly associated with lymphovascular space invasion (LVSI; P=0.017). The association of COX-2 expression with LVSI suggests a possible effect of COX-2 on tumor progression in cervical cancer. Further studies including larger patient collectives are required in order to perform analyses of clinical subgroups and patient survival.

Nuclear expression of p65 (RelA) in patients receiving post-operative radiotherapy for locally advanced squamous cell carcinoma of the head and neck

BackgroundThis study investigated the prognostic role of nuclear expression of p65 in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) receiving post-operative radio(chemo)therapy.MethodsNuclear p65-expression (H-score ≤50 versus >50) plus twelve characteristics were analyzed in 151 patients for overall survival (OS), metastases-free survival (MFS) and loco-regional control (LRC). Additional characteristics included age, gender, Karnofsky performance score (KPS), pre-radiotherapy hemoglobin levels, tumor site, histological grading, human papilloma virus (HPV)-status, T-classification, N-classification, American Joint Committee on Cancer (AJCC)-stage, extent of resection and concurrent chemotherapy. Univariate analyses were performed with Kaplan-Meier method and log-rank test, multivariate analyses with Cox proportional hazards model.ResultsOn univariate analyses, p65-expression had a significant impact on OS (p < 0.001) and LRC (p < 0.001) but not on MFS (p = 0.29). On multivariate analysis, KPS ≥80 (risk ratio [RR] 2.23; p = 0.012), HPV-positivity (RR 5.83; p = 0.020), T1-T2 (RR 1.38; p = 0.048), N0-N2a (RR 2.72; p = 0.005) and complete resection (RR 2.02; p = 0.049) were positively associated with OS; p65-negativity achieved borderline significance (RR 3.02; p = 0.052). Better MFS was associated with KPS ≥80 (RR 2.49; p = 0.015), T1-T2 (RR: 1.74; p = 0.005), N0-N2a (RR: 6.22; p < 0.001) and complete resection (RR 3.43; p = 0.003). Positive associations with LRC were found for p65-negativity (RR 5.06; p = 0.008), T1-T2 (RR: 1.49; p = 0.022), N0-N2a (RR: 2.97; p = 0.004) and favorable tumor site (RR 1.28; p = 0.025).ConclusionsP65-negativity was significantly associated with improved LRC and achieved borderline significance with respect to improved OS. Thus, p65-expression may be an additional target for novel agents in the treatment of locally advanced SCCHN.

Increased phosphorylation of STAT5b, but not STAT5a, in nasal polyps.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a recurrent, benign, extensively proliferating disease that is triggered by inflammation. The signaling pathways in sinusitis and the regulation by intracellular signaling peptides and proteins are not fully understood. Signal transducer and activator of transcription (STAT) 5a and STAT5b are two closely related phosphokinases involved in the regulation of diverse cellular functions, including proliferation and apoptosis. Objective The objective of the study was to investigate the expression, activation, and distribution of STAT5 Transcription factor in CRSwNP. Methods We studied these transcription factors in tissue samples of nasal polyps and inferior turbinates from a total of 35 patients with CRSwNP and compared them with healthy nasal mucosa. The samples were analyzed by using a DNA microarray, quantitative real-time polymerase chain reaction, a protein array, immunoblot, immunoprecipitation and immunohistochemistry. Results We found equivalent overall expression of STAT5a in all tissue types. We observed an increase in the expression of STAT5b protein in both polyps and turbinates of patients with CRSwNP. In addition, STAT5b, but not STAT5a, was activated by phosphorylation in nasal polyps. Phosphorylated STAT5a/b was not detectable in the epithelium of turbinates from either patients with CRSwNP or patients with healthy mucosa, but it was clearly expressed in the epithelium of nasal polyps. Conclusion Analysis of these data indicates distinct expression and activation of STAT5a and STAT5b in nasal polyps, particularly the activation of STAT5b. It is possible that STAT5b may contribute to the development of nasal polyps.

The MEK1/2-ERK1/2 Pathway is Activated in Chronic Rhinosinusitis with Nasal Polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common disease that has a considerable impact on the quality of life. Alterations in signalling pathways may contribute to the ongoing inflammation and proliferation in CRSwNP. The MEK1/2–ERK1/2 pathway transmits signals from many extracellular molecules to regulate cellular processes. We examined tissue samples from nasal polyps and the inferior turbinate of patients with CRSwNP and the inferior turbinate from subjects with healthy mucosa. The expressions of MEK1/2, ERK1/2, and their active phosphorylated forms pMEK1/2 and pERK1/2 were analysed using DNA microarray, quantitative real-time PCR, protein array, Western hybridisation, and immunohistochemistry. We detected increased MEK1/2 protein expression in nasal polyps compared to the inferior turbinates of patients with CRSwNP or healthy mucosa. We also found a higher amount of MEK1/2 in the inferior turbinates of patients with CRSwNP compared to those with healthy mucosa. Most importantly, we observed a significant increase in the phosphorylation of MEK1/2 and ERK1/2 in nasal polyps compared to both types of controls. We observed activation of the MEK1/2–ERK1/2 pathway in nasal polyps. Interestingly, we did not see the same activation pattern in different tiers of the MEK1/2–ERK1/2 signalling cascade. One explanation for this result is that the components enhance the complex MEK–ERK cascade in a distinct manner, enabling a wide variety of functions. The MEK1/2–ERK1/2 pathway appears to play a pivotal role in the pathogenesis of CRSwNP.

Contents Vol. 162, 2013

W. Aberer, Graz M. Akdis, Davos I.J. Ansotegui, Belfast L.K. Arruda, Ribeirão Preto C.E. Baena-Cagnani, Cordoba T. Biedermann, Tübingen S.C. Bischoff , Stuttgart H. Breiteneder, Vienna G.W. Canonica, Genova M. Capron, Lille M.D. Chapman, Charlottesville, Va. K.Y. Chua, Singapore M. Ebisawa, Kanagawa E. Fernández-Caldas, Seefeld F. Ferreira, Salzburg H. Grönlund, Stockholm K.T. HayGlass, Winnipeg, Man. K. Hoff mann-Sommergruber, Vienna P.G. Holt, Perth F. Horak, Vienna E. Jensen-Jarolim, Vienna M. Jutel, Wroclaw D. Kabelitz, Kiel A. Kapp, Hannover D. Kraft , Vienna M. Larché, Hamilton, Ont. E. Maggi, Florence R.N. Maini, London A. Mari, Latina S.F. Martin, Freiburg M. Maurer, Berlin F. Melchers, Basel N.G. Papadopoulos, Athens O. Pérez, Havana City W.J. Pichler, Bern T.A.E. Platts-Mills, Charlottesville, Va. H. Renz, Marburg/Lahn N. Rezaei, Teheran L.J. Rosenwasser, Kansas City, Mo. K. Roux, Tallahassee, Fla. J.-M. Saint-Rémy, Leuven H.A. Sampson, New York, N.Y. R. Sepiashvili, Moscow Y. Shoenfeld, Tel Hashomer H.-U. Simon, Bern J. Smolen, Vienna Z. Szépfalusi, Vienna E. Toubi, Haifa P. Valent, Vienna M. van Hage, Stockholm D.V. Wallace, Fort Lauderdale, Fla. H. Wekerle, Martinsried T. Werfel, Hannover G. Wick, Innsbruck M. Wickman, Stockholm U. Wiedermann, Vienna S. Wöhrl, Vienna H. Yssel, Montpellier Founded 1950 by D. Harley, P. Kallós, W. Löffl er and F.W. Wittich Continued by E.A. Brown (1952–1954), W. Kaufman (1955–1967), F. Hahn (1961–1972), H.C. Goodman (1963–1975), R.R.A. Coombs (1955–1984), Z. Trnka (1972–1987), P. Kallós (1950–1988), G.B. West (1959–1991), J. Bienenstock (1990–1991), L.Å. Hanson (1981–1991), K. Kano (1982–1991), F. Milgrom (1965–1991), K. Rother (1982–1991), G. Wick (1991–1997), B. Grubeck-Loebenstein (1991–1997), D. Kraft (1998–2002) Official Journal of the