Oscar Matzinger

Fish oil prevents the adrenal activation elicited by mental stress in healthy men

OBJECTIVES A diet rich in n-3 fatty acids (fish oils) is associated with reduced risks of cardiovascular and metabolic diseases, but the mechanisms remain incompletely understood. Sympathoadrenal activation is postulated to be involved in the pathogenesis of these diseases, and may be inhibited by n-3 fatty acids. We therefore evaluated the effects of a diet supplemented with n-3 fatty acids on the stimulation of the sympathetic nervous system and of stress hormones elicited by a mental stress. METHODS Seven human volunteers were studied on two occasions, before and after 3 weeks of supplementation with 7.2 g/day fish oil. On each occasion, the concentrations of plasma cortisol, and catecholamines, energy expenditure (indirect calorimetry), and adipose tissue lipolysis (plasma non esterified fatty acid concentrations) were monitored in basal conditions followed by a 30 min mental stress (mental arithmetics and Stroops test) and a 30 min recovery period. RESULTS In control conditions, mental stress significantly increased heart rate, mean blood pressure, and energy expenditure. It increased plasma epinephrine from 60.9 +/- 6.2 to 89.3 +/- 16.1 pg/ml (p<0.05), plasma cortisol from 291 +/- 32 to 372 +/- 37 micromol/l (p<0.05) and plasma non esterified fatty acids from 409 +/- 113 to 544 +/- 89 micromol/l (p<0.05). After 3 weeks of a diet supplemented with n-3 fatty acids, the stimulation by mental stress of plasma epinephrine, cortisol, energy expenditure, and plasma non esterified fatty acids concentrations, were all significantly blunted. CONCLUSION Supplementation with n-3 fatty acids inhibits the adrenal activation elicited by a mental stress, presumably through effects exerted at the level of the central nervous system.

Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study.

PURPOSE To assess the outcome in patients with olfactory neuroblastoma (ONB). METHODS AND MATERIALS Seventy-seven patients treated for nonmetastatic ONB between 1971 and 2004 were included. According to Kadish classification, there were 11 patients with Stage A, 29 with Stage B, and 37 with Stage C. T-classification included 9 patients with T1, 26 with T2, 16 with T3, 15 with T4a, and 11 with T4b tumors. Sixty-eight patients presented with N0 (88%) disease. RESULTS Most of the patients (n = 56, 73%) benefited from surgery (S), and total excision was possible in 44 patients (R0 in 32, R1 in 13, R2 in 11). All but five patients benefited from RT, and chemotherapy was given in 21 (27%). Median follow-up period was 72 months (range, 6-315). The 5-year overall survival (OS), disease-free survival (DFS), locoregional control, and local control were 64%, 57%, 62%, and 70%, respectively. In univariate analyses, favorable factors were Kadish A or B disease, T1-T3 tumors, no nodal involvement, curative surgery, R0/R1 resection, and RT-dose 54 Gy or higher. Multivariate analysis revealed that the best independent factors predicting the outcome were T1-T3, N0, R0/R1 resection, and total RT dose (54 Gy or higher). CONCLUSION In this multicenter retrospective study, patients with ONB treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT had the best outcome. Novel strategies including concomitant chemotherapy and/or higher dose RT should be prospectively investigated in this rare disease for which local failure remains a problem.

Decreased Local Control Following Radiation Therapy Alone in Early-Stage Glottic Carcinoma with Anterior Commissure Extension*

Purpose:To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx.Patients and Methods:Between 1983–2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35–92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60–74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21–79 days). Median follow-up period was 85 months.Results:The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5–58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control.Conclusion:For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.Ziel:Ergründung der Versagensmechanismen bei der Therapie des Larynxkarzinoms im Frühstadium.Patienten und Methodik:Zwischen 1983 und 2000 wurden 122 konsekutive Patienten, die wegen eines Larynxkarzinoms (UICC T1N0 und T2N0) eine Strahlentherapie erhielten, retrospektiv untersucht. Das Verhältnis von Frauen zu Männern betrug 106 : 16, das mittlere Alter lag bei 62 Jahren. Es handelte sich um 68 Patienten mit T1a-, 18 mit T1b- und 36 mit T2-Tumoren. Die Diagnose wurde bei 104 Patienten mit Hilfe einer Biopsie und bei 18 Patienten mit Laservaporisation oder Stripping gestellt. Bei 49 Patienten (40%) bestand die Behandlungsplanung aus einer dreidimensionalen konformalen Strahlentherapie, einschließlich neun Patienten, die unter Arytänoidprotektion bestrahlt wurden. Die mittlere Dosis von 70 Gy (60–74 GT) wurde über einen mittleren Zeitraum von 46 Tagen verabreicht. Die mittlere Nachbehandlungszeit erstreckte sich über 85 Monate.Ergebnisse:Das 5-Jahres-Überleben betrug 80%. Das tumorspezifische 5-Jahres-Überleben lag bei 94%, und 70% der Patienten blieben während dieses Zeitraums erkrankungsfrei. 83% wiesen nach 5 Jahren kein Lokalrezidiv auf. Der mittlere Zeitraum bis zum Auftreten eines lokalen Rückfalls belief sich bei 19 Patienten auf 13 Monate (5–58 Monate). Die Rezidivbehandlung bestand bei 17 Patienten aus einem chirurgischen Eingriff (ein Patient lehnte die Rezidivbehandlung ab, ein anderer war inoperabel; totale Laryngektomie bei elf und partielle Laryngektomie bzw. Kordektomie bei sechs Patienten). Sechs Patienten starben an ihrem Larynxkarzinom. Eine einseitige Varianzanalyse zeigte, dass die Ausbreitung auf die vordere Kommissur, die Arytänoidprotektion oder eine Strahlendosis < 66 Gy die Prognose der Lokalrezidive verschlechterte. Eine Multivarianzanalyse (Cox-Modell) belegte, dass unter den berücksichtigten Faktoren die Ausbreitung auf die vordere Kommissur, die Protektion des Aryknorpels und männliches Geschlecht die schlechtesten unabhängigen Prognosefaktoren im Hinblick auf Lokalrezidive sind.Schlussfolgerung:Beim Larynxkarzinom im Frühstadium erbringt die Strahlentherapie hervorragende Ergebnisse. Im Fall einer Ausbreitung auf die vordere Kommissur ist ein chirurgischer Eingriff oder eine höhere Strahlendosis erforderlich. Wegen des hohen Rezidivrisikos sollte keine Protektion des Aryknorpels vorgenommen werden.

Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: Implications for secondary cancer risk assessment

BACKGROUND AND PURPOSE To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). MATERIALS AND METHODS Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. RESULTS Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. CONCLUSIONS In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart).

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer

INTRODUCTION To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years. RESULTS Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving > or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late > or = grade 2 GU toxicities (P=.049). CONCLUSIONS Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anterior commissure extension.

Purpose:To assess the patterns of failure in the treatment of early-stage squamous cell carcinoma of the glottic larynx.Patients and Methods:Between 1983–2000, 122 consecutive patients treated for early laryngeal cancer (UICC T1N0 and T2N0) by radical radiation therapy (RT) were retrospectively studied. Male-to-female ratio was 106 : 16, and median age 62 years (35–92 years). There were 68 patients with T1a, 18 with T1b, and 36 with T2 tumors. Diagnosis was made by biopsy in 104 patients, and by laser vaporization or stripping in 18. Treatment planning consisted of three-dimensional (3-D) conformal RT in 49 (40%) patients including nine patients irradiated using arytenoid protection. A median dose of 70 Gy (60–74 Gy) was given (2 Gy/fraction) over a median period of 46 days (21–79 days). Median follow-up period was 85 months.Results:The 5-year overall, cancer-specific, and disease-free survival amounted to 80%, 94%, and 70%, respectively. 5-year local control was 83%. Median time to local recurrence in 19 patients was 13 months (5–58 months). Salvage treatment consisted of surgery in 17 patients (one patient refused salvage and one was inoperable; total laryngectomy in eleven, and partial laryngectomy or cordectomy in six patients). Six patients died because of laryngeal cancer. Univariate analyses revealed that prognostic factors negatively influencing local control were anterior commissure extension, arytenoid protection, and total RT dose < 66 Gy. Among the factors analyzed, multivariate analysis (Cox model) demonstrated that anterior commissure extension, arytenoid protection, and male gender were the worst independent prognostic factors in terms of local control.Conclusion:For early-stage laryngeal cancer, outcome after RT is excellent. In case of anterior commissure extension, surgery or higher RT doses are warranted. Because of a high relapse risk, arytenoid protection should not be attempted.Ziel:Ergründung der Versagensmechanismen bei der Therapie des Larynxkarzinoms im Frühstadium.Patienten und Methodik:Zwischen 1983 und 2000 wurden 122 konsekutive Patienten, die wegen eines Larynxkarzinoms (UICC T1N0 und T2N0) eine Strahlentherapie erhielten, retrospektiv untersucht. Das Verhältnis von Frauen zu Männern betrug 106 : 16, das mittlere Alter lag bei 62 Jahren. Es handelte sich um 68 Patienten mit T1a-, 18 mit T1b- und 36 mit T2-Tumoren. Die Diagnose wurde bei 104 Patienten mit Hilfe einer Biopsie und bei 18 Patienten mit Laservaporisation oder Stripping gestellt. Bei 49 Patienten (40%) bestand die Behandlungsplanung aus einer dreidimensionalen konformalen Strahlentherapie, einschließlich neun Patienten, die unter Arytänoidprotektion bestrahlt wurden. Die mittlere Dosis von 70 Gy (60–74 GT) wurde über einen mittleren Zeitraum von 46 Tagen verabreicht. Die mittlere Nachbehandlungszeit erstreckte sich über 85 Monate.Ergebnisse:Das 5-Jahres-Überleben betrug 80%. Das tumorspezifische 5-Jahres-Überleben lag bei 94%, und 70% der Patienten blieben während dieses Zeitraums erkrankungsfrei. 83% wiesen nach 5 Jahren kein Lokalrezidiv auf. Der mittlere Zeitraum bis zum Auftreten eines lokalen Rückfalls belief sich bei 19 Patienten auf 13 Monate (5–58 Monate). Die Rezidivbehandlung bestand bei 17 Patienten aus einem chirurgischen Eingriff (ein Patient lehnte die Rezidivbehandlung ab, ein anderer war inoperabel; totale Laryngektomie bei elf und partielle Laryngektomie bzw. Kordektomie bei sechs Patienten). Sechs Patienten starben an ihrem Larynxkarzinom. Eine einseitige Varianzanalyse zeigte, dass die Ausbreitung auf die vordere Kommissur, die Arytänoidprotektion oder eine Strahlendosis < 66 Gy die Prognose der Lokalrezidive verschlechterte. Eine Multivarianzanalyse (Cox-Modell) belegte, dass unter den berücksichtigten Faktoren die Ausbreitung auf die vordere Kommissur, die Protektion des Aryknorpels und männliches Geschlecht die schlechtesten unabhängigen Prognosefaktoren im Hinblick auf Lokalrezidive sind.Schlussfolgerung:Beim Larynxkarzinom im Frühstadium erbringt die Strahlentherapie hervorragende Ergebnisse. Im Fall einer Ausbreitung auf die vordere Kommissur ist ein chirurgischer Eingriff oder eine höhere Strahlendosis erforderlich. Wegen des hohen Rezidivrisikos sollte keine Protektion des Aryknorpels vorgenommen werden.

EORTC Radiation Oncology Group quality assurance platform: Establishment of a digital central review facility

OBJECTIVE Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT. METHODS The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers. RESULTS The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results. CONCLUSIONS This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes.

Radiochemotherapy in Locally Advanced Squamous Cell Carcinomas of the Head and Neck

Squamous cell carcinoma of the head and neck (SCCHN) is a common disease that develops in the upper aerodigestive epithelium. The most important risk factors are tobacco and alcohol consumption. There is also increasing evidence that human papillomavirus plays an important role in the cause of SCCHN. The complex anatomy, the vital functions of the upper aerodigestive tract and the close proximity to vital structures, explain that the goal of treatment is not only to improve survival outcomes, but also to preserve organ function. Radiotherapy and surgery are the standard modalities of treatment, reflecting the locoregional predominance of SCCHN. Chemotherapy plays an important role in the treatment of patients with locoregionally advanced disease, in conjunction with radiotherapy and surgery. Indeed, standard therapy for resectable locoregionally advanced (stage III or IV) SCCHN cancers consists either of surgery and adjuvant chemoradiotherapy or definitive concomitant chemoradiotherapy, depending upon disease site, stage and resectability of the tumour, or institutional experience. Concomitant chemoradiotherapy has been shown in several randomised trials to improve disease-free and overall survival in the postoperative setting for resected disease with poor prognostic factors. Furthermore, multiple randomised studies and meta-analyses have shown that definitive chemoradiotherapy, as well anti-epidermal growth factor receptor treatment in one randomised study, improved disease-free and overall survival when compared with radiotherapy alone. This overview reviews the most relevant published studies on the multidisciplinary management of SCCHN and discusses future strategies to reduce locoregional failures.

Impact of induction therapy on airway complications after sleeve lobectomy for lung cancer.

BACKGROUND Sleeve lobectomy is a valid alternative to pneumonectomy for the treatment of centrally located operable non-small cell lung cancer (NSCLC), but concern has been evoked regarding a potentially increased risk of bronchial anastomosis complications after induction therapy. This study examined the impact of induction therapy on airway healing after sleeve lobectomy for NSCLC. METHODS Bronchial anastomosis complications were recorded with respect to the induction regimen applied (neoadjuvant chemotherapy vs chemoradiotherapy) in a consecutive series of patients with sleeve lobectomy for NSCLC. RESULTS Ninety-nine patients underwent sleeve resection, 28 of them after induction therapy. Twelve patients received chemotherapy alone, and 16 patients had radiochemotherapy. There were no significant differences in postoperative 90-day mortality (3.6% vs 2.8%) and morbidity (54% vs 49%) for patients with and without induction therapy. Bronchial anastomosis complications occurred in 3 patients (10.8%) with neoadjuvant therapy and in 2 (2.8%) without (p = 0.3). In the induction therapy group, two bronchial stenoses occurred after radiochemotherapy and one bronchopleural fistula after chemotherapy alone. In patients without induction therapy, one bronchial stenosis and one bronchopleural fistula were observed. All bronchial stenoses were successfully treated by dilatation, and both bronchopleural fistulas occurring after right lower lobectomy were successfully treated by reoperation and completion sleeve bilobectomy with preservation of the upper lobe. CONCLUSIONS Sleeve lobectomy for NSCLC can be safely performed after induction chemotherapy and radiochemotherapy with mortality and incidence of airway complications similar to that observed in nonpretreated patients. The treatment of airway complications does not differ for patients with and without induction therapy.

Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients.

Background. The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. Methods. Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP) concentrations were compared after intravenous and oral glucose. Results. After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P <0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P <0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. Conclusions. First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the &bgr;-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.