Accuracy of positron emission tomography/computed tomography and clinical assessment in the detection of complete rectal tumor regression after neoadjuvant chemoradiation Long-Term Results of a Prospective Trial (National Clinical Trial 00254683)

BACKGROUND: Neoadjuvant chemoradiation (CRT) therapy may result in significant tumor regression in patients with rectal cancer. Patients who develop complete tumor regression have been managed by treatment strategies that are alternatives to standard total mesorectal excision. Therefore, assessment of tumor response with positron emission tomography/computed tomography (PET/CT) after neoadjuvant treatment may offer relevant information for the selection of patients to receive alternative treatment strategies. METHODS: Patients with clinical T2 (cT2) through cT4NxM0 rectal adenocarcinoma were included prospectively. Neoadjuvant therapy consisted of 54 grays of radiation and 5-fluorouracil-based chemotherapy. Baseline PET/CT studies were obtained before CRT followed by PET/CT studies at 6 weeks and 12 weeks after the completion of CRT. Clinical assessment was performed at 12 weeks after CRT completion. PET/CT results were compared with clinical and pathologic data. RESULTS: In total, 99 patients were included in the study. Twenty-three patients were complete responders (16 had a complete clinical response, and 7 had a complete pathologic response). The PET/CT response evaluation at 12 weeks indicated that 18 patients had a complete response, and 81 patients had an incomplete response. There were 5 false-negative and 10 false-positive PET/CT results. PET/CT for the detection of residual cancer had 93% sensitivity, 53% specificity, a 73% negative predictive value, an 87% positive predictive value, and 85% accuracy. Clinical assessment alone resulted in an accuracy of 91%. PET/CT information may have detected misdiagnoses made by clinical assessment alone, improving overall accuracy to 96%. CONCLUSIONS: Assessment of tumor response at 12 weeks after CRT completion with PET/CT imaging may provide a useful additional tool with good overall accuracy for the selection of patients who may avoid unnecessary radical resection after achieving a complete clinical response. Cancer 2012;35013511. (C) 2011 American Cancer Society.

Biochemical control of prostate cancer with iodine-125 brachytherapy alone: experience from a single institution

Brachytherapy is an adequate option as monotherapy for localised prostate cancer. The objective of this study was to evaluate and compare biochemical failure free survival (BFFS) after low-dose-rate brachytherapy (LDRB) alone for patients with prostate cancer using ASTRO and Phoenix criteria, and detect prognostic factors. Data on 220 patients treated between 1998 and 2002 with LDRB were retrospectively analysed. Neoadjuvant hormone therapy was used in 74 (33.6%) patients. Median follow-up was 53.5 months (24-116). Five year BFFS was 83.0% and 83.7% using, respectively, the ASTRO and Phoenix criteria. Low -and intermediate-risk patients presented, respectively, 86.7% and 77.8% 5-year BFFS using the ASTRO definition (p=0.069), and 88.5% and 78.6% considering the Phoenix criteria (p=0.016). Bounce was observed in 66 (30%) patients. Multivariate analysis detected PSA at diagnosis < 10 ng/ml and less than 50% positive biopsy fragments as favourable prognostic factors, regarding BF using both criteria. For the Phoenix criteria, also Gleason score < 7 and low-risk group were identified as independent favourable prognostic factors. LDRB alone should be considered mostly for low-risk patients. PSA level was a strong independent prognostic factor. We support the use of the Phoenix criteria for detection of BF in patients submitted to LDRB alone.

DNA repair gene excision repair cross complementing-group 1 (ERCC1) in head and neck squamous cell carcinoma: analysis of methylation and polymorphism (G19007A), protein expression and association with epidemiological and clinicopathological factors

Aims: To evaluate the associations of excision repair cross complementing-group 1 (ERCC1) (DNA repair protein) (G19007A) polymorphism, methylation and immunohistochemical expression with epidemiological and clinicopathological factors and with overall survival in head and neck squamous cell carcinoma (HNSCC) patients. Methods and results: The study group comprised 84 patients with HNSCC who underwent surgery and adjuvant radiotherapy without chemotherapy. Bivariate and multivariate analyses were used. The allele A genotype variant was observed in 79.8% of the samples, GG in 20.2%, GA in 28.6% and AA in 51.2%. Individuals aged more than 45 years had a higher prevalence of the allelic A variant and a high (83.3%) immunohistochemical expression of ERCC1 protein [odds ratio (OR) = 4.86, 95% confidence interval (CI): 1.2-19.7, P = 0.027], which was also high in patients with advanced stage (OR= 5.04, 95% CI: 1.07-23.7, P = 0.041). Methylated status was found in 51.2% of the samples, and was higher in patients who did not present distant metastasis (OR = 6.67, 95% CI: 1.40-33.33, P = 0.019) and in patients with advanced stage (OR = 5.04, 95% CI: 1.07-23.7, P = 0.041). At 2 and 5 years, overall survival was 55% and 36%, respectively (median = 30 months). Conclusion: Our findings may reflect a high rate of DNA repair due to frequent tissue injury during the lifetime of these individuals, and also more advanced disease presentation in this population with worse prognosis.

Audiological findings in patients treated with radio- and concomitant chemotherapy for head and neck tumors

Abstract Objective To evaluate the functionality of the auditory system in patients who underwent radiotherapy and chemotherapy treatment with cisplatin to treat head and neck tumors. Study Design Case series with planned data collection. Setting From May 2007 to May 2008 by the Department of Otorhinolaryngology and the Department of Oncology/Radiotherapy at Faculdade de Medicina de Marília. Subjects and Methods Audiological evaluation (Pure Tone Audiometry (air and bone conduction), Speech Audiometry, Tympanometry, Acoustic Reflex testing and Distortion Product Otoacoustic Emissions) was performed in 17 patients diagnosed with head and neck neoplasia and treated with chemotherapy, using cisplatin, and radiotherapy. Results 12 left ears (70.5%) and 11 right ears (64.7%) presented bilateral decreased hearing soon after the treatment for the frequency 1 kHz (mild auditory damage) and for the frequency 8 kHz (more significant auditory damage). Conclusion Patients with head and neck cancer submitted to the conventional radiotherapy treatment, combined with the chemotherapy with cisplatin, presented a high incidence of decreased hearing by the end of treatment. Strong evidence was observed linking auditory alteration to the amount of radiotherapy treatment.

Clinical and image findings in bisphosphonate-related osteonecrosis of the jaws

Abstract: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is characterized as exposed bone in the jaws for more than 8 weeks in patients with current or previous history of therapy with bisphosphonates (BPs) and no history of radiotherapy in the head and neck. We report a case series of 7 patients with BRONJ and analyze the variations of clinical and imaging signs, correlating them with the presence or absence of bone exposure. Among the patients, 6 were women and 1 was a man, aged 42–79 years. Five of the patients were using zoledronic acid and the other 2 alendronate. The use of BPs varied from 3 to 13 years. In 5 patients, tooth extraction was the triggering event of injuries. Panoramic radiographs and computed tomography (CT) were evaluated by a radiologist blinded to the cases. There were persistent unremodeled extraction socket even several months after tooth extraction in 3 of the cases that were consistent wit CT findings that also showed areas of osteosclerosis and osteolysis. Patients were treated according to the recommendations of the AAOMS, with surgical debridement and antibiotic coverage with amoxicillin in the symptomatic patients. The follow-up of these patients ranged from 8 to 34 months, with a good response to treatment. The image findings in this case series were not specific and showed no difference between each stages of BRONJ (AAOMS, 2009). The image features were similar in presence or absence of exposed bone.

Radiation therapy for Graves' ophthalmopathy: a systematic review and meta-analysis of randomized controlled trials

PURPOSE: To evaluate the efficacy of radiotherapy (RT) with total dose of 20 Gy (RT 20 Gy) in the treatment of Graves' ophthalmopathy. METHODS: A systematic review and meta-analysis of randomized controlled trials was performed comparing RT 20 Gy with or without glucocorticoid to clinical treatments for Graves' ophthalmopathy. The MEDLINE, EMBASE, Cochrane Library databases and recent relevant journals were searched. Relevant reports were reviewed by two reviewers. Response to radiotherapy was defined as clinical success according to each trial. We also evaluated the quality of life and whether RT to produce fewer side effects than other treatments. RESULTS: A total of 8 randomized controlled trials (439 patients) were identified. In the subgroup analysis, the overall response to treatment rates was better for: RT 20 Gy plus glucocorticoid vs glucocorticoids alone, OR=17.5 (CI95% 1.85-250, p=0.04), RT 20 Gy vs sham RT, OR= 3.15 (CI95%1.59-6.23, p=0.003) and RT 20Gy plus intravenous glucocorticoid vs RT 20Gy plus oral glucocorticoid, OR=4.15(CI95% 1.34-12.87, p=0.01). There were no differences between RT 20 Gy versus other fractionations and RT 20 Gy versus glucocorticoid alone. RT 20 Gy with or without glucocorticoids showed an improvement in diplopia grade, visual acuity, optic neuropathy, lid width, proptosis and ocular motility. No difference was seen for costs, intraocular pressure and quality of life. CONCLUSION: Our data have shown that RT 20 Gy should be offered as a valid therapeutic option to patients with moderate to severe ophthalmopathy. The effectiveness of orbital radiotherapy can be increased by the synergistic interaction with glucocorticoids. Moreover, RT 20 Gy is useful to improve a lot of ocular symptoms, excluding intraocular pressure, without any difference in quality of life and costs.

Prevention of skin reactions due to teletherapy in women with breast cancer: a comprehensive review

One of the possible courses of cancer treatment is teletherapy, and one of the most important adverse side effects are skin reactions, an ailment more commonly called radiodermatitis. The main purpose of this study is to analyze knowledge of the evidence about topical products used in the prevention of radiodermatitis, to support care delivery to women with breast cancer during teletherapy. The research method used here is the comprehensive literature review. Four databases were used to select the bibliography. The sample consists of 15 articles. The data shows that, among the topical products analyzed here, Calendula, corticosteroids and Xclair have shown significant protective effects, underlining their actions. The lack of articles published in Brazil highlights the need for further research in this area, seeking better care quality through the use of products with scientifically proven efficiency.

Efeitos da oxigenoterapia hiperbárica em lesões actícas da veia cava e aorta infra-renal. Estudo experimental em ratos

Objetivos: Estudar o efeito da Oxigenoterapia Hiperbárica sobre as lesões causadas pela radiação ionizante na veia cava e aorta. Método: Foram utilizados 32 ratos adultos distribuídos aleatoriamente em 4 grupos: 3 no grupo controle; 10 no grupo oxigenoterapia hiperbárica (5 sessões e 3 ATA e após 3 dias, operados), 9 no grupo radioterapia (8 sessões de 5Gy, atingindo 54Gy, sendo operados após 7 dias), 10 no grupo radioterapia e oxigenoterapia hiperbárica (procedimento radioterapia, observação por 7 dias, submetidos a 5 sessões de oxigenoterapia hiperbárica e após 3 dias, são operados. Ressecamos a veia cava e aorta infrarenal para estudo morfológico (integridade endotelial, infiltrado inflamatório e integridade da vasa-vasorum), avaliação do ciclo celular pelo método do AgNOR e índice de apoptose nas distintas camadas dos vasos, através da Caspase-3 (imuno-histoquímica). Resultados: O grupo radioterapia – oxigenoterapia hiperbárica apresentou diminuição estatisticamente significativa das alterações morfológicas em vasa-vasorum, aumento da atividade celular na camada média e também diminuição do índice de apoptose nas camadas íntima e média da aorta infra-renal quando comparados ao grupo apenas submetidos à radiação ionizante. A lesões rádio induzidas na veia cava não apresentaram melhora significativa com a oxigenoterapia hiperbárica Conclusão: A oxigenoterapia hiperbárica é capaz de minimizar as lesões radio-induzidas em fase aguda em aorta.

MVP and Vaults: a role in the radiation response

[EN] Vaults are evolutionary highly conserved ribonucleoproteins particles with a hollow barrel-like structure. The main component of vaults represents the 110 kDa major vault protein (MVP), whereas two minor vaults proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (vPARP) and the 240 kDa telomerase-associated protein-1 (TEP-1). Additionally, at least one small and untranslated RNA is found as a constitutive component. MVP seems to play an important role in the development of multidrug resistance. This particle has also been implicated in the regulation of several cellular processes including transport mechanisms, signal transmission and immune responses. Vaults are considered a prognostic marker for different cancer types. The level of MVP expression predicts the clinical outcome after chemotherapy in different tumour types. Recently, new roles have been assigned to MVP and vaults including the association with the insulin-like growth factor-1, hypoxia-inducible factor-1alpha, and the two major DNA double-strand break repair machineries: non-homologous endjoining and homologous recombination. Furthermore, MVP has been proposed as a useful prognostic factor associated with radiotherapy resistance. Here, we review these novel actions of vaults and discuss a putative role of MVP and vaults in the response to radiotherapy.

Radiation induced apoptosis and initial DNA damage are inversely related in locally advanced breast cancer patients

[EN] Background: DNA-damage assays, quantifying the initial number of DNA double-strand breaks induced by radiation, have been proposed as a predictive test for radiation-induced toxicity. Determination of radiation-induced apoptosis in peripheral blood lymphocytes by flow cytometry analysis has also been proposed as an approach for predicting normal tissue responses following radiotherapy. The aim of the present study was to explore the association between initial DNA damage, estimated by the number of double-strand breaks induced by a given radiation dose, and the radio-induced apoptosis rates observed. Methods: Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radio-induced apoptosis at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results: Radiation-induced apoptosis increased in order to radiation dose and data fitted to a semi logarithmic mathematical model. A positive correlation was found among radio-induced apoptosis values at different radiation doses: 1, 2 and 8 Gy (p < 0.0001 in all cases). Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). A statistically significant inverse correlation was found between initial damage to DNA and radio-induced apoptosis at 1 Gy (p = 0.034). A trend toward 2 Gy (p = 0.057) and 8 Gy (p = 0.067) was observed after 24 hours of incubation. Conclusions: An inverse association was observed for the first time between these variables, both considered as predictive factors to radiation toxicity.

Prediction of clinical toxicity in locally advanced head and neck cancer patients by radio-induced apoptosis in peripheral blood lymphocytes (PBLs)

[EN] Head and neck cancer is treated mainly by surgery and radiotherapy. Normal tissue toxicity due to x-ray exposure is a limiting factor for treatment success. Many efforts have been employed to develop predictive tests applied to clinical practice. Determination of lymphocyte radio-sensitivity by radio-induced apoptosis arises as a possible method to predict tissue toxicity due to radiotherapy. The aim of the present study was to analyze radio-induced apoptosis of peripheral blood lymphocytes in head and neck cancer patients and to explore their role in predicting radiation induced toxicity. Seventy nine consecutive patients suffering from head and neck cancer, diagnosed and treated in our institution, were included in the study. Toxicity was evaluated using the Radiation Therapy Oncology Group scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Radiation-induced apoptosis increased in order to radiation dose and fitted to a semi logarithmic model defined by two constants: α and β. α, as the origin of the curve in the Y axis determining the percentage of spontaneous cell death, and β, as the slope of the curve determining the percentage of cell death induced at a determined radiation dose, were obtained. β value was statistically associated to normal tissue toxicity in terms of severe xerostomia, as higher levels of apoptosis were observed in patients with low toxicity (p = 0.035; Exp(B) 0.224, I.C.95% (0.060-0.904)). These data agree with our previous results and suggest that it is possible to estimate the radiosensitivity of peripheral blood lymphocytes from patients determining the radiation induced apoptosis with annexin V/propidium iodide staining. β values observed define an individual radiosensitivity profile that could predict late toxicity due to radiotherapy in locally advanced head and neck cancer patients. Anyhow, prospective studies with different cancer types and higher number of patients are needed to validate these results.

Prediction of clinical toxicity in localized cervical carcinoma by radio-induced apoptosis study in peripheral blood lymphocytes (PBLs)

[EN] Background: Cervical cancer is treated mainly by surgery and radiotherapy. Toxicity due to radiation is a limiting factor for treatment success. Determination of lymphocyte radiosensitivity by radio-induced apoptosis arises as a possible method for predictive test development. The aim of this study was to analyze radio-induced apoptosis of peripheral blood lymphocytes. Methods: Ninety four consecutive patients suffering from cervical carcinoma, diagnosed and treated in our institution, and four healthy controls were included in the study. Toxicity was evaluated using the Lent-Soma scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24, 48 and 72 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide to determine early and late apoptosis. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Results: Radiation-induced apoptosis (RIA) increased with radiation dose and time of incubation. Data strongly fitted to a semi logarithmic model as follows: RIA = βln(Gy) + α. This mathematical model was defined by two constants: α, is the origin of the curve in the Y axis and determines the percentage of spontaneous cell death and β, is the slope of the curve and determines the percentage of cell death induced at a determined radiation dose (β = ΔRIA/Δln(Gy)). Higher β values (increased rate of RIA at given radiation doses) were observed in patients with low sexual toxicity (Exp(B) = 0.83, C.I. 95% (0.73-0.95), p = 0.007; Exp(B) = 0.88, C.I. 95% (0.82-0.94), p = 0.001; Exp(B) = 0.93, C.I. 95% (0.88-0.99), p = 0.026 for 24, 48 and 72 hours respectively). This relation was also found with rectal (Exp(B) = 0.89, C.I. 95% (0.81-0.98), p = 0.026; Exp(B) = 0.95, C.I. 95% (0.91-0.98), p = 0.013 for 48 and 72 hours respectively) and urinary (Exp(B) = 0.83, C.I. 95% (0.71-0.97), p = 0.021 for 24 hours) toxicity. Conclusion: Radiation induced apoptosis at different time points and radiation doses fitted to a semi logarithmic model defined by a mathematical equation that gives an individual value of radiosensitivity and could predict late toxicity due to radiotherapy. Other prospective studies with higher number of patients are needed to validate these results.

Il craniofaringioma nel bambino e nell'adolescente. Luci ed ombre durante il follow-up

Introduction. Craniopharyngioma (CF) is a malformation of the hypothalamicpituitary region and it is the most common nonglial cerebral tumor in children with an high overall survival rate. In some case severe endocrinologic and metabolic sequelae may occur during follow up. 50% of patients (pts), in particular those with radical removal of suprasellar lesions, develop intractable hyperphagia and morbid obesity, with dyslypidemia and high cardiovascular risk. We studied the auxological and metabolic features of a series of 29 patients (18 males) treated at a mean age of 7,6 years, followed up in our Centre from 1973 to 2008 with a mean follow up of 8,3 years. Patients features at the onset. 62% of pts showed as first symptoms of disease visual impairment and neurological disturbancies (headache); 34% growth arrest; 24% signs of raised intracranial pressure and 7% diabetes insipidus. Diagnosis. Diagnosis of CF was reached finally by TC or MRI scans which showed endo-suprasellar lesion in 23 cases and endosellar tumour in 6 cases. Treatment and outcome. 25/29 pts underwent surgical removal of CF (19 by transcranial approach and 6 by endoscopic surgery); 4 pts underwent stereotactic surgery as first line therapy. 3 pts underwent local irradiation with yttrium-90, 5 pts post surgery radiotherapy. 45% of pts needed more than one treatment procedure. Results. After CF treatment all patients suffered from 3 or more pituitary hormone deficiencies and diabetes insipidus. They underwent promptly substitutive therapy with corticosteroids, l-thyroxine and desmopressin. In 28/29 pts we found growth hormone (GH) deficiency. 20/28 pts started GH substitutive therapy and 15 pts reached final height(FH) near target height(TH). 8 pts were not GH treated for good growth velocity, even without GH, or for tumour residual. They reached in 2 cases FH over TH showing the already known phenomenon of growth without GH. 38% of patients showed BMI SDS >2 SDS at last assessment, in particular pts not GH treated (BMI 2,5 SDS) are more obese than GH treated (BMI 1,2 SDS). Lipid panel of 16 examined pts showed significative differencies among GH treated (9 pts) and not treated (7 pts) with better profile in GH treated ones for Total Cholesterol/C-HDL and C-LDL/C-HDL. We examined intima media thickness of common carotid arteries in 11 pts. 3/4 not GH treated pts showed ultrasonographic abnormalities: calcifications in 2 and plaque in 1 case. Of them 1 pt was only 12,6 years old and already showed hypothalamic obesity with hyperphagia, high HOMA index and dyslipidemia. In the GH treated group (7) we found calcifications in 1 case and a plaque in another one. GH therapy was started in the young pt with carotid calcifications, with good improvement within 6 months of treatment. 5/29 pts showed hypothalamic obesity, related to hypothalamic damage (type of surgical treatment, endo-suprasellar primitive lesion, recurrences). 48% of patients recurred during follow up ( mean time from treatment: 3 years) and underwent, in some cases up to 4 transcranial surgical treatments. GH seems not to increase recurrence rate since 40% of GH treated recurred vs 66,6% of not GH treated pts. Discussion. Our data show the extereme difficulties that occur during follow up of craniopharyngioma treated patients. GH therapy should be offered to all patients even with good growth velocity after CF treatment, to avoid dislypidemia and reduce cardiovascular risk. The optimal therapy is not completely understood and whether gross tumor removal or partial surgery is the best option remains to be decided only on one patient tumour features and hypothalamic involvement. In conclusion the gold standard treatment of CF remains complete tumour removal, when feasible, or partial resection to preserve hypothalamic function in endosuprasellar large neoplasms.

Attivazione del sistema Wnt in linee cellulari di medulloblastoma umano: valutazione della risposta biologica e della risposta alle radiazioni ionizzanti

Medulloblastoma (MB) is a paediatric malignant brain tumour, sensitive to ionizing radiations (IR). However radiotherapy has detrimental effects on long-term survivors and the tumour is incurable in a third of patients, due to intrinsic radioresistance. Alterations of the Wnt pathway distinguish a molecular subgroup of MBs and nuclear beta-catenin, indicative of activated Wnt, is associated with good outcome in MB. Therefore there are increasing evidences about Wnt involvement in radio-response: IR induce activation of Wnt signalling with nuclear translocation of beta-catenin in MB cell lines. We studied effects of Wnt pathway activation in a MB cell line with p53 wild-type: UW228-1. Cells were stably transfected with a beta-catenin constitutively active and assessed for growth curves, mortality rate, invasiveness and differentiation. Firstly, activation of Wnt pathway by itself induced a slower cell growth and a higher mortality. After IR treatment, nuclear beta-catenin further inhibited cell growth, increasing mortality. Cell invasiveness was strongly inhibited by Wnt activation. Furthermore, Wnt cell population was characterized by club shaped cells with long cytoplasmic extensions containing neurofilaments, suggesting a neural differentiation of this cell line. These findings suggest that nuclear beta-catenin may leads to a less aggressive phenotype and increases radio-sensitivity in MB, accounting for its favourable prognostic value. In the future, Wnt/beta-catenin signalling will be considered as a molecular therapeutic target to develop new drugs for the treatment of MB.