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1.
Br J Cancer ; 127(4): 766-775, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35597871

RESUMO

PURPOSE: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a "watch and wait" strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. EXPERIMENTAL DESIGN: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. RESULTS: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76). CONCLUSION: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a "watch and wait" strategy. TRANSLATIONAL RELEVANCE: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for "watch and wait".


Assuntos
Quimiorradioterapia , Neoplasias Retais , Biópsia , Ensaios Clínicos como Assunto , Humanos , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Resultado do Tratamento
2.
Strahlenther Onkol ; 195(6): 544-557, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859254

RESUMO

PURPOSE: Long-term impact of stage-adapted field reduction in a large cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT). PATIENTS AND METHODS: Prospective analysis of paper records of 290 patients with stage IE-IIE gMZL, treated in 78 radiotherapeutic institutions in Germany from 1992-2013. Stage-adapted radiation fields decreased from extended field (EF) to involved field (IF) over the course of three consecutive prospective trials of the German Study Group on Gastrointestinal Lymphoma (DSGL). Treatment results were compared between the three cohorts. RESULTS: Overall collective with median age of 60 years, slight male predominance (m:f = 1.1:1) and ratio of disease stage I:stage II = 2.1:1. Median follow-up 6.4 years in total: 13.0 years in the first gastrointestinal study (GIT 1992), 8.2 years in the second (GIT 1996) and 4.7 years in the third study (DSGL 01/2003). Stage-adapted radiation field decrease together with further technological development led to reduced relative frequencies of acute/chronic adverse effects and until now was accompanied by lower disease recurrence. The third study design with smallest field size (IF in stage I, locoregional EF in stage II) achieved the best survival outcome at the 5­year follow-up (overall survival 92.7%, event-free survival 89.5% and lymphoma-specific survival 100.0%). Disease relapse observed in 10 patients. Cumulative incidence of disease-specific death was 1.7% of the followed patients. Primary disease stage associated with lymphoma-specific survival. CONCLUSION: Stage-adapted reduction towards IF in gMZL resulted in favorable adverse effects, local control and survival rates. These results support further decreases in modern RT of gMZL.


Assuntos
Linfoma de Zona Marginal Tipo Células B/radioterapia , Neoplasias Gástricas/radioterapia , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Estudos Prospectivos , Doses de Radiação , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
3.
Int J Mol Sci ; 17(5)2016 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-27136530

RESUMO

Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to the concave anatomy of the lung recesses, the irradiation field included the upper part of the liver. No rat died due to irradiation. In control tissue, lung immunohistochemistry showed a high constitutive expression of LCN2+ granulocytes. LCN2 mRNA levels in lung tissue increased up to 24 h (9 ± 2.3-fold) after irradiation. However, serum LCN2 levels remained undetectable after lung irradiation. LCN2 expression in the upper part of the liver increased up to 4.2-fold after lung irradiation, but the lower liver showed an early decrease. Acute-phase cytokines (IL-1ß and TNF-α) showed a significant increase on transcript level in both lung and upper liver, whilst the lower liver did not show any considerable increase. In conclusion, constitutive expression of LCN2 in local immune cells demonstrates its local role during stress conditions in the lung. The absence of LCN2 in the serum strengthens our previous findings that the liver is the key player in secreting LCN2 during stress conditions with liver involvement.


Assuntos
Raios gama , Lipocalina-2/sangue , Pulmão/efeitos da radiação , Animais , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Microscopia de Fluorescência , Modelos Animais , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismo
4.
Strahlenther Onkol ; 191(7): 566-72, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25575976

RESUMO

BACKGROUND: Superior treatment response and survival for patients with human papilloma virus (HPV)-positive head and neck cancer (HNSCC) are documented in clinical studies. However, the relevance of high-grade acute organ toxicity (HGAOT), which has also been correlated with improved prognosis, has attracted scant attention in HPV-positive HNSCC patients. Hence we tested the hypothesis that both parameters, HPV and HGAOT, are positive prognostic factors in patients with HNSCC treated with definite radiotherapy (RT) or radiochemotherapy (RCT). PATIENTS AND METHODS: Pretreatment tumor tissue and clinical records were available from 233 patients receiving definite RT (62 patients) or RCT (171 patients). HPV infection was analysed by means of HPV DNA detection or p16(INK4A) expression; HGAOT was defined as the occurrence of acute organ toxicity >grade 2 according to the Common Toxicity Criteria. Both variables were correlated with overall survival (OS) using Cox proportional hazards regression. RESULTS: Positivity for HPV DNA (44 samples, 18.9 %) and p16(INK4A) expression (102 samples, 43.8 %) were significantly correlated (p < 0.01), and HGAOT occurred in 77 (33 %) patients. Overall, the 5-year OS was 23 %; stratified for p16(INK4A) expression and HGAOT, OS rates were 47 %, 42 %, 20 % and 10 % for patients with p16(INK4A) expression and HGAOT, patients with HGAOT only, patients with p16(INK4A) expression only, and patients without p16(INK4A) expression or HGAOT, respectively. After multivariate testing p16(INK4A) expression (p = 0.003) and HGAOT (p < 0.001) were significantly associated with OS. CONCLUSION: P16(INK4A) expression and HGAOT are independent prognostic factors for OS of patients with HNSCC, whereas p16(INK4A) expression is particularly important for patients without HGAOT.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Otorrinolaringológicas/genética , Neoplasias Otorrinolaringológicas/terapia , Lesões por Radiação/etiologia , Adulto , Idoso , Feminino , Testes de DNA para Papilomavírus Humano , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Dosagem Radioterapêutica
5.
Int J Mol Sci ; 16(3): 4682-97, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25739082

RESUMO

Previously, we reported a radiation-induced inflammation triggering fat-accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36) in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36-expression by anti-tumor necrosis factor-α (anti-TNF-α) (infliximab) was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray) and the effect of anti-TNF-α-therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1-3 h) induction of TNF-α-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6-12 h), compared to sham-irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6-12 h) increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-α. TNF-α-blockage by anti-TNF-α showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with α-smooth muscle actin (α-SMA+) cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-α-therapy prevented early radiation-induced expression of FAT/CD36 in vivo.


Assuntos
Antígenos CD36/metabolismo , Infliximab/farmacologia , Fígado/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Western Blotting , Antígenos CD36/genética , Gorduras/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Infliximab/imunologia , Fígado/metabolismo , Fígado/efeitos da radiação , Masculino , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Modelos Animais , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
Cancer ; 119(18): 3343-53, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23765693

RESUMO

BACKGROUND: In patients with head and neck and esophageal tumors, nutritional status may deteriorate during concurrent chemoradiotherapy (CRT). The aim of this study was to investigate the influence of enteral nutrition enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on body composition and nutritional and functional status. METHODS: In a controlled, randomized, prospective, double-blind, multicenter study, 111 patients with head and neck and esophageal cancer undergoing concurrent CRT received either an enteral standard nutrition (control group) or disease-specific enteral nutrition Supportan®-containing EPA+DHA (experimental group) via percutaneous endoscopic gastrostomy. The primary endpoint was the change of body cell mass (BCM) following CRT at weeks 7 and 14 compared with the baseline value. Secondary endpoints were additional parameters of body composition, anthropometric parameters, and nutritional and functional status. RESULTS: The primary endpoint of the study, improvement in BCM, reached borderline statistical significance. Following CRT, patients with experimental nutrition lost only 0.82 ± 0.64 kg of BCM compared with 2.82 ± 0.77 kg in the control group (P = .055). The objectively measured nutritional parameters, such as body weight and fat-free mass, showed a tendency toward improvement, but the differences were not significant. The subjective parameters, in particular the Kondrup score (P = .0165) and the subjective global assessment score (P = .0065) after follow-up improved significantly in the experimental group, compared with the control group. Both enteral regimens were safe and well tolerated. CONCLUSION: Enteral nutrition with EPA and DHA may be advantageous in patients with head and neck or esophageal cancer by improving parameters of nutritional and functional status during CRT.


Assuntos
Nutrição Enteral/métodos , Neoplasias Esofágicas/dietoterapia , Neoplasias de Cabeça e Pescoço/dietoterapia , Adulto , Idoso , Índice de Massa Corporal , Ácidos Docosa-Hexaenoicos/administração & dosagem , Método Duplo-Cego , Ácido Eicosapentaenoico/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Feminino , Alimentos Formulados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Estudos Prospectivos , Resultado do Tratamento
7.
Basic Res Cardiol ; 108(6): 385, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24068185

RESUMO

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Miócitos Cardíacos/efeitos da radiação , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Animais , Ecocardiografia , Espectroscopia de Ressonância de Spin Eletrônica , Immunoblotting , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Miócitos Cardíacos/metabolismo
8.
Liver Int ; 33(3): 459-68, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23331620

RESUMO

BACKGROUND/AIM: IL-6 - IL-1- lipocalin2 (LCN2) - liver irradiation - oxidative stress - TNF-a Lipocalin2 (LCN2) is an acute phase protein. The source of its increased serum level in oxidative stress conditions (ROS) remains still unknown. We prospectively evaluate the serum LCN2 increase after single dose liver irradiation along with hepatic LCN2 gene and protein expression. METHODS: A single dose of 25 Gray was administered percutaneously to the liver of randomly paired rats after a planning CT scan. Male Wistar rats were sacrificed 1, 3, 6, 12, 24 and 48 h after irradiation along with sham-irradiated controls. ELISA, RT-PCR, Western blot and immunofluorescence staining was performed. Furthermore, hepatocytes, myofibroblasts and Kupffer cells were isolated from the liver of healthy rats and irradiated ex-vivo. RESULTS: After liver irradiation, LCN2 serum levels increased significantly up to 2.7 µg/ml within 6 h and stayed elevated over 24 h. LCN2 specific transcripts increased significantly up to 552 ± 109-fold at 24 h after liver irradiation, which was further confirmed at protein level. α2-macroglobulin and hemoxygenase-1 also showed an increase, but the magnitude was less as compared to LCN2. LCN2+ granulocytes were detected within 1 h after irradiation around central and portal fields and remained high during the course of study. Ex-vivo irradiated hepatocytes (2.4 ± 0.6-fold) showed a higher LCN2 gene expression as compared to myofibroblasts and Kupffer cells. IL-1ß treatment further increased LCN2 gene expression in cultured hepatocytes. CONCLUSIONS: Single dose liver irradiation induces a significant increase in LCN2 serum levels, comparable to the induction of acute phase proteins. We suggest LCN2 as marker for the early phase of radiation-induced tissue damage.


Assuntos
Biomarcadores/sangue , Regulação da Expressão Gênica/fisiologia , Lipocalinas/sangue , Fígado/lesões , Fígado/efeitos da radiação , Lesões por Radiação/diagnóstico , Animais , Western Blotting , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Lipocalina-2 , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
9.
Exp Mol Pathol ; 92(2): 243-58, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22227376

RESUMO

INTRODUCTION: The out-of-field effects on the intestine, caused by radiation treatment of a parenchymatous organ, have not previously been studied. METHODS: A single dose of 25Gy was administered percutaneously to the liver of male Wistar rats after a planning CT-scan. Sham-irradiated animals served as controls. At 1, 6, 24, 96h, 1.5 and 3months the duodenum, jejunum, ileum and distal colon were removed, washed and deep-frozen or prepared for paraffin staining. RESULTS: All animals survived the treatment. Epithelial cell damage occurred in all small-intestinal segments. However, prolonged denudation of the villi together with destruction of the crypt lining was only observed in the ileum, resulting in deficient regeneration. In the colon, changes were minor. Radiation mucositis with granulocyte (MP0+) infiltration was seen from 1 to 24h in the duodenum and jejunum, when ED1+ macrophages, CD3+ T-lymphocytes, and CD34+ hematopoietic precursor cells were recruited, accompanied by an increase in the chemokines MCP-1, MIP-1α, MIP3α and Il-8. In the ileum, early granulocyte infiltration was delayed but continuous. Recruitment of macrophages and lymphocytes was deficient and induction of chemokines as of the adhesion molecules PECAM-1, ICAM-1 was lacking. CONCLUSION: Post-irradiation damage to the ileum was delayed and followed by an altered repair process with structural changes of the villi. The observed changes might result from a higher sensitivity to oxidative stress mechanisms with subsequent damage of the regenerative capacity of the crypt-villus axis, accompanied by a sustained "inflammatory response" and vascular damage with a lack of regeneratory cell recruitment.


Assuntos
Intestinos/efeitos da radiação , Fígado/efeitos da radiação , Lesões Experimentais por Radiação/metabolismo , Animais , Antígenos CD34/análise , Complexo CD3/análise , Quimiocinas/biossíntese , Granulócitos/metabolismo , Granulócitos/patologia , Granulócitos/efeitos da radiação , Mucosa Intestinal/metabolismo , Intestinos/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/efeitos da radiação , Masculino , Mucosite/etiologia , Mucosite/metabolismo , Mucosite/patologia , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Wistar , Linfócitos T/metabolismo , Linfócitos T/patologia , Linfócitos T/efeitos da radiação
10.
Oncologist ; 16(5): 621-31, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21558132

RESUMO

Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil-based (5-FU-based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity. All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5-FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade ≥3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone. Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5-FU+oxaliplatin. A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity. These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity.


Assuntos
Fluoruracila/efeitos adversos , Compostos Organoplatínicos/efeitos adversos , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Índice de Massa Corporal , Terapia Combinada , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Cuidados Pré-Operatórios , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Fatores Sexuais
11.
Radiology ; 258(3): 864-71, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21339350

RESUMO

PURPOSE: To test for an association between high-grade acute organ toxicity during adjuvant radiation and chemotherapy and treatment outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. From September 1994 to October 2008, 294 HNSCC patients were treated with adjuvant radiation and chemotherapy at the authors' department. They received normofractionated (2 Gy per fraction) irradiation to include associated nodal drainage sites, for a cumulative dose of 60-64 Gy. From January 2002 to December 2009, 91 patients received additional concomitant cisplatin-based chemotherapy. Toxicity during treatment was monitored weekly according to the common toxicity criteria (CTC); any CTC toxicity grade 3 or higher, including mucositis, dysphagia, or skin reaction, was considered high-grade acute organ toxicity. The influence of possible prognostic factors on overall survival and locoregional control was studied by means of uni- and multivariate Cox regression. RESULTS: A statistically significant association was found between high-grade acute organ toxicity and both overall survival and locoregional control. Patients with CTC grade 3 or greater acute organ toxicity had a 5-year overall survival and locoregional control rate of 90% and 97%, respectively, as compared with 24% and 74%, respectively, in patients without such toxicity (P < .01). Multivariate analyses revealed that this association was independent from other factors that may influence treatment toxicity, especially concomitant chemotherapy and/or radiation therapy. CONCLUSION: The data suggest that normal tissue and tumor tissue may behave similarly with respect to treatment response, as high-grade acute organ toxicity during radiation and chemotherapy was associated with better outcomes in the patient population; therefore, the hypothesis should be further analyzed on the biomolecular and clinical level and with other tumor entities in prospective clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Doença Aguda , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida
12.
Radiat Environ Biophys ; 50(1): 145-54, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21085979

RESUMO

The purpose of this work was to analyze chemokine and chemokine receptor expression in untreated and in irradiated squamous cell carcinoma of the head and neck (SCCHN) tumor cell lines, aiming at the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy. Five low passage and 10 established SCCHN lines, as well as two normal cell lines, were irradiated at 2 Gy or sham-irradiated, and harvested between 1 and 48 h after treatment. For chemokines with CC and CXC structural motifs and their receptors, transcript levels of target and reference genes were quantified relatively by real-time PCR. In addition, CXCL1 and CXCL12 protein expression was analyzed by ELISA. A substantial variation in chemokine and chemokine receptor expression between SCCHN was detected. Practically, all cell lines expressed CCL5 and CCL20, while CCL2 was expressed in normal cells and in some of the tumor cell lines. CXCL1, CXCL2, CXCL3, CXCL10, and CXCL11 were expressed in the vast majority of the cell lines, while the expression of CXCL9 and CXCL12 was restricted to fibroblasts and few tumor cell lines. None of the analyzed cell lines expressed the chemokines CCL3, CCL4, or CCL19. Of the receptors, transcript expression of CCR1, CCR2, CCR3, CCR5, CCR7, CCXR2, and CCXR3 was not detected, and CCR6, CXCR1, and CXCR4 expression was restricted to few tumor cells. Radiation caused up- and down-regulation with respect to chemokine expressions, while for chemokine receptor expressions down-regulations were prevailing. CXCL1 and CXCL12 protein expression corresponded well with the mRNA expression. We conclude that the substantial variation in chemokine and chemokine receptor expression between SCCHN offer opportunities for the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy.


Assuntos
Carcinoma de Células Escamosas/patologia , Quimiocinas/genética , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Receptores de Quimiocinas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
13.
Strahlenther Onkol ; 186(5): 262-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20437012

RESUMO

PURPOSE: To test for a possible correlation between high-grade acute organ toxicity during primary radio(chemo)therapy and treatment outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: From 05/1994 to 01/2009, 216 HNSCC patients were treated with radio(chemo)therapy in primary approach. They received normofractionated (2 Gy/fraction) irradiation including associated nodal drainage sites to a cumulative dose of 70 Gy. 151 patients received additional concomitant chemotherapy (111 patients 5-fluorouracil/mitomycin C, 40 patients cisplatin-based). Toxicity during treatment was monitored weekly according to the Common Toxicity Criteria (CTC), and any toxicity grade CTC >or= 3 of mucositis, dysphagia or skin reaction was assessed as high-grade acute organ toxicity for later analysis. RESULTS: A statistically significant coherency between high-grade acute organ toxicity and overall survival as well as locoregional control was found: patients with CTC >or= 3 acute organ toxicity had a 5-year overall survival rate of 44% compared to 8% in patients without (p < 0.01). Thereby, multivariate analyses revealed that the correlation was independent of other possible prognostic factors or factors that may influence treatment toxicity, especially concomitant chemotherapy and radiotherapy technique or treatment-planning procedure. CONCLUSION: These data indicate that normal tissue and tumor tissue may behave similarly with respect to treatment response, as high-grade acute organ toxicity during radio(chemo)therapy showed to be an independent prognostic marker in the own patient population. However, the authors are aware of the fact that a multivariate analysis in a retrospective study generally has statistical limitations. Therefore, their hypothesis should be further analyzed on biomolecular and clinical levels and other tumor entities in prospective trials.


Assuntos
Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Radioterapia/efeitos adversos , Radioterapia/métodos , Terapia Combinada , Progressão da Doença , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Mitomicina/efeitos adversos , Mitomicina/uso terapêutico , Estadiamento de Neoplasias , Prognóstico , Dosagem Radioterapêutica , Estudos Retrospectivos , Sobreviventes , Fatores de Tempo , Resultado do Tratamento
14.
Brachytherapy ; 19(2): 168-175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31883803

RESUMO

PURPOSE: The impact of rectal filling and bladder volume on in vivo rectal dosimetry (IVD) in vaginal cuff brachytherapy (VCBT) is unknown. The purpose of this study was to compare rectal doses from IVD with those calculated from treatment planning and to identify influencing factors. MATERIALS AND METHODS: We collected data of 80 VCBT sessions, four for each of 20 patients. Each was retrospectively compared with doses determined by the treatment planning system. Factors potentially predicting the IVD rectum dose were analyzed. RESULTS: For a series of 80 brachytherapy applications, the calculated mean dose to the rectum was 2.52 Gy. The mean difference between all calculated and measured doses for the 80 applications with five probe positions each was 0.09 Gy (p = 0.952) proving high overall accordance between IVD and calculated doses at the rectum. The mean volume of the rectum was 119 ± 57 cm³. The rectal volume was not statistically significantly associated with the IVD or the calculated rectum doses. At the third and fourth rectal probe position in craniocaudal ordering, increased filling of the urinary bladder resulted in decreased measured and calculated doses (p < 0.05 for both). A rectum pointing position of the applicator significantly increased the maximum rectum dose compared with a bladder-oriented position (p < 0.05). CONCLUSIONS: IVD provided valuable data for rectal exposure in VCBT. Increased bladder filling and vaginal applicator positioning off the rectum elicited related with less rectal radiation exposure, whereas rectal filling did not. Further confirmation including assessment of IVD in bladder is pending to define optimal dosimetric conditions in VCBT.


Assuntos
Braquiterapia/métodos , Neoplasias do Endométrio/radioterapia , Doses de Radiação , Reto , Idoso , Feminino , Humanos , Dosimetria in Vivo , Pessoa de Meia-Idade , Planejamento da Radioterapia Assistida por Computador , Estudos Retrospectivos , Bexiga Urinária , Vagina
16.
Strahlenther Onkol ; 185(12): 821-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20013092

RESUMO

PURPOSE: To analyze different control-system limitations on the measured dose distributions in low-dose regions of simplified intensity fields with an electronic portal imaging device to ascertain the optimal settings for the control-system limitations in the planning system. MATERIAL AND METHODS: The authors created one field with an "optimal fluence" of intensity 1.0 (full dose) and one field with intensity 0.0 (no dose) in the central part of the field. The influence of different dose rates (DRs) and maximum leaf speeds (LS) on the calculated and measured dose and dose profiles were analyzed. RESULTS: Good agreement between calculated and measured dose in the case of a field of intensity 1.0 was found. For the field with intensity 0.0, the measured dose was 20-60% lower than the dose calculated by the "actual fluence". The results were found dependent on the DR and LS. CONCLUSION: The overestimation in regions of optimal intensity 0.0 by the planning system cannot be resolved by the user. Taking the measured dose in the region of desired intensity 1.0 and other technical limitations (like beam hold interrupts or spikes in the cross and longitudinal profiles) into consideration, the application of an LS of 2.5 cm/s and a DR of 500 MU/min is recommended in order to minimize radiation dose applied to organs at risk, which are located in regions of low intensity, like, for example, the spinal cord.


Assuntos
Planejamento da Radioterapia Assistida por Computador/instrumentação , Radioterapia de Intensidade Modulada/instrumentação , Algoritmos , Humanos , Lesões por Radiação/prevenção & controle , Radiometria , Dosagem Radioterapêutica , Espalhamento de Radiação
17.
Strahlenther Onkol ; 185(5): 303-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19440669

RESUMO

BACKGROUND AND PURPOSE: Transoral laser microsurgery (TLM) and adjuvant radiotherapy are an established therapy regimen for locally advanced laryngeal cancer at our institution. Aim of the present study was to assess value of quality of life (QoL) data with special regard to organ function under consideration of treatment efficacy in patients with locally advanced laryngeal cancer treated with larynx-preserving TLM and adjuvant radiotherapy. PATIENTS AND METHODS: From 1994 to 2006, 39 patients (ten UICC stage III, 29 UICC stage IVA/B) with locally advanced laryngeal carcinomas were treated with TLM and adjuvant radiotherapy. Data concerning treatment efficacy, QoL (using the VHI [Voice Handicap Index], the EORTC QLQ-C30 and QLQ-H&N35 questionnaires) and organ function (respiration, deglutition, voice quality) were obtained for ten patients still alive after long-term follow-up. Correlations were determined using the Spearman rank test. RESULTS: After a median follow-up of 80.8 months, the 5-year overall survival rate was 46.8% and the locoregional control rate 76.5%, respectively. The larynx preservation rate was 89.7% for all patients and 100% for patients still alive after follow-up. Despite some verifiable problems in respiration, speech and swallowing, patients showed a subjectively good QoL. CONCLUSION: TLM and adjuvant radiotherapy is a curative option for patients with locally advanced laryngeal cancer and an alternative to radical surgery. Even if functional deficits are unavoidable in the treatment of locally advanced laryngeal carcinomas, larynx preservation is associated with a subjectively good QoL.


Assuntos
Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/terapia , Terapia a Laser/métodos , Microcirurgia/métodos , Qualidade de Vida , Radioterapia Conformacional/métodos , Recuperação de Função Fisiológica , Adulto , Idoso , Feminino , Humanos , Masculino , Radioterapia Adjuvante/métodos , Resultado do Tratamento
18.
Strahlenther Onkol ; 185(9): 596-602, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19756426

RESUMO

BACKGROUND AND PURPOSE: To assess the late effect of a prostaglandin, given rectally during irradiation, on late rectal toxicity. In the acute treatment setting no significant differences in reducing the incidence of acute proctitis symptoms in patients receiving misoprostol, however, significantly more rectal bleeding had been reported. PATIENTS AND METHODS: A total of 100 patients who had undergone radiotherapy for prostate cancer had been entered into this phase III randomized, placebo-controlled, double-blind study with misoprostol or placebo suppositories. The toxicity was evaluated yearly after cessation of irradiation by the RTOG/LENT-SOMA scale. RESULTS: The median follow-up was 50 months. 20 patients suffered from grade 1, four patients from grade 2 as well, and three patients only from grade 2 toxicity. Frequency, bleeding and urgency were the most commonly reported symptoms. In keeping with other studies and clinical experience, the symptoms peaked within the first 2 years with a median for grade 1 of 13 months and for grade 2 of 15 months. The presence of acute toxicity grade 2 showed a correlation with the development of any late toxicity (p = 0.03). Any acute rectal bleeding was significant correlated with any late rectal bleeding (p = 0.017). CONCLUSION: Misoprostol given as once-daily suppository for prevention of acute radiation-induced proctitis does neither influence the incidence and severity of radiation-induced acute nor late rectal toxicity. Misoprostol has no negative impact on the incidence and severity of late rectal bleeding, in contrast to acute rectal bleeding. The routine clinical use of misoprostol suppositories cannot be recommended.


Assuntos
Misoprostol/uso terapêutico , Proctite/prevenção & controle , Neoplasias da Próstata/radioterapia , Radioterapia/efeitos adversos , Administração Retal , Idoso , Antiulcerosos/administração & dosagem , Antiulcerosos/uso terapêutico , Método Duplo-Cego , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Misoprostol/administração & dosagem , Proctite/etiologia , Fatores de Tempo
19.
Scand J Gastroenterol ; 44(8): 939-46, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19504404

RESUMO

OBJECTIVE: Acute proctitis and chronic radiation proctitis are relevant complications of pelvic radiation. The purpose of this study was to investigate two markers of gut inflammation during and after irradiation for prostate cancer to evaluate a correlation between acute and chronic proctitis. MATERIAL AND METHODS: Two patient groups were analysed. In group 1, stool samples from 20 patients were collected before therapy, every week during therapy, at the end of therapy, and 13 and 27 months after therapy. Group 2 comprised 47 patients who had undergone irradiation 40 months earlier. Toxicity was determined by common toxicity criteria (CTC) and the LENT soma scale. Calprotectin and lactoferrin values were determined by ELISA. RESULTS: In group 1, acute values for both faecal markers were significantly correlated with chronic proctitis symptoms and all patients with chronic toxicity had acute proctitis symptoms with elevated faecal values. In group 2, where stool samples were solely collected 40 months after irradiation, the Pearson square test showed both a significant correlation between calprotectin and lactoferrin values and toxicity after 40 months. CONCLUSIONS: Within a group of 19 patients followed for two years after irradiation for prostate cancer, and 47 patients tested 40 months after irradiation, increased faecal values of calprotectin and lactoferrin were significantly correlated with the occurrence of chronic proctitis. This observation should be confirmed in an expanded study.


Assuntos
Fezes/química , Proctite/etiologia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/diagnóstico , Idoso , Biomarcadores/análise , Humanos , Lactoferrina/análise , Complexo Antígeno L1 Leucocitário/análise , Masculino , Estudos Prospectivos
20.
Radiat Environ Biophys ; 48(1): 85-94, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18956207

RESUMO

This study aimed to reveal the pathophysiological signalling responsible for radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis. IkappaB was upregulated in irradiated hepatocytes. Administration of IkappaB antisense oligonucleotides prior to irradiation inhibited occurrence of apoptosis after TNF-alpha administration. Caspases-8, -9 and -3 activities were increased in irradiated hepatocytes and downregulation of apoptosis by IkappaB antisense oligonucleotides was mediated by suppression of caspases-9 and -3 activation but not of caspase-8 activation, suggesting that radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis additionally requires changes upstream of caspase-8 activation. Herein, upregulation of FLIP may play a crucial role. Cleavage of bid, upregulation of bax, downregulation of bcl-2 and release of cytochrome c after TNF-alpha-administration depend on radiation-induced upregulation of IkappaB, thus demonstrating an apoptosis permitting effect of IkappaB.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Hepatócitos/efeitos dos fármacos , Hepatócitos/efeitos da radiação , Proteínas I-kappa B/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos da radiação , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Citocromos c/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Hepatócitos/metabolismo , Proteínas I-kappa B/genética , Masculino , Camundongos , NF-kappa B/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/farmacologia , Doses de Radiação , Ratos , Fator de Necrose Tumoral alfa/administração & dosagem
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