Disubstituted Dithiolethione ACDT Exerts Neuroprotective Effects Against 6-Hydroxydopamine-Induced Oxidative Stress in SH-SY5Y Cells.

Parkinson's disease (PD) is a prevalent, progressive, neurodegenerative disorder with no known cure. Oxidative stress has been found to play a significant role in its etiology, and the search for novel neuroprotective compounds that actively prevent disease progression is currently ongoing. Dithiolethiones are a group of sulfur-containing heterocyclic compounds found in cruciferous vegetables. Using the 6-hydroxydopamine (6-OHDA) model of PD, we tested a previously identified disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) for its neuroprotective potential. Pretreatment of SH-SY5Y cells with ACDT led to a time- and concentration-dependent induction of the antioxidant glutathione (GSH). ACDT also diminished 6-OHDA-induced cell death, lactate dehydrogenase release, elevation of caspase 3/7 activity, and increase in levels of reactive oxygen species. Inhibition of the GSH-synthesizing enzyme glutamate-cysteine ligase catalytic subunit (GCLC) led a corresponding dissipation of ACDT's neuroprotective effects, hence underlining the importance of GSH in ACDT's neuroprotective response. ACDT caused the stabilization and nuclear translocation of nuclear factor erythroid-2 related factor (Nrf2), resulting in increased protein expression of the phase II enzyme NADPH:quinone oxidoreductase 1 (NQO1), and the excitatory amino acid cysteine membrane transporter (EAAT3). Interestingly, no changes in the levels of other Nrf2-dependent molecules including GCLC were observed, indicating the possible involvement of additional alternate mechanisms behind ACDT's GSH-inducing property. Collectively, the data demonstrated ACDT to be a promising new dithiolethione for the treatment of PD, with two modifiable functional groups offering additional avenues for enhanced pharmacological application.

Dosimetric predictors of acute hematologic toxicity during concurrent intensity-modulated radiotherapy and chemotherapy for anal cancer

Purpose. This study aimed at investigating whether the irradiated volume of pelvic bone marrow (PBM) and specific subsites may predict the occurrence of acute hematologic toxicity (HT) in anal cancer patients undergoing concurrent chemo-radiation. Methods. 50 patients, submitted to IMRT and concurrent chemotherapy, were analyzed. Several bony structures were defined on planning-CT: PBM and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood-cell-count (WBC), absolute-neutrophil-count (ANC), hemoglobin (Hb) and platelet nadirs and acute hematologic toxicity (HT) according to RTOG scoring scale. Generalized linear modeling was used to find correlations between dosimetric variables and blood cell nadirs, while logistic regression analysis was used to test correlation with ≥G3 HT. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the optimal cut-off points for predictive dosimetric variables with the Youden method. Results. Maximum detected acute HT comprised 38 % of ≥G3 leukopenia and 32 % of ≥G3 neutropenia. Grade 2 anemia was observed in 4 % of patients and ≥G3 thrombocytopenia in 10 %. On multivariate analysis a higher PBM-V20 was associated with lower WBC nadir. Increased LSBM-V40 was correlated with a higher likelihood to develop ≥G3 HT. A cut-off point at 41 % for LSBM-V40 was found. Patients with LSBM-V40 ≥41 % were more likely to develop ≥G3 HT (55.3 vs. 32.4 %; p < 0.01). Conclusions. Increased low-dose to pelvic bony structures significantly predicted for WBC decrease. Medium-high dose to specific osseous subsites was associated with a higher probability of HT. LSBM-V40 was a strong predictor of ≥G3 HT. A threshold at 41 % for LSBM-V40 could be used to limit HT (AU)

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Dosimetric predictors of acute hematologic toxicity during concurrent intensity-modulated radiotherapy and chemotherapy for anal cancer.

PURPOSE: This study aimed at investigating whether the irradiated volume of pelvic bone marrow (PBM) and specific subsites may predict the occurrence of acute hematologic toxicity (HT) in anal cancer patients undergoing concurrent chemo-radiation. METHODS: 50 patients, submitted to IMRT and concurrent chemotherapy, were analyzed. Several bony structures were defined on planning-CT: PBM and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood-cell-count (WBC), absolute-neutrophil-count (ANC), hemoglobin (Hb) and platelet nadirs and acute hematologic toxicity (HT) according to RTOG scoring scale. Generalized linear modeling was used to find correlations between dosimetric variables and blood cell nadirs, while logistic regression analysis was used to test correlation with ≥G3 HT. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the optimal cut-off points for predictive dosimetric variables with the Youden method. RESULTS: Maximum detected acute HT comprised 38 % of ≥G3 leukopenia and 32 % of ≥G3 neutropenia. Grade 2 anemia was observed in 4 % of patients and ≥G3 thrombocytopenia in 10 %. On multivariate analysis a higher PBM-V 20 was associated with lower WBC nadir. Increased LSBM-V 40 was correlated with a higher likelihood to develop ≥G3 HT. A cut-off point at 41 % for LSBM-V 40 was found. Patients with LSBM-V 40 ≥41 % were more likely to develop ≥G3 HT (55.3 vs. 32.4 %; p < 0.01). CONCLUSIONS: Increased low-dose to pelvic bony structures significantly predicted for WBC decrease. Medium-high dose to specific osseous subsites was associated with a higher probability of HT. LSBM-V 40 was a strong predictor of ≥G3 HT. A threshold at 41 % for LSBM-V 40 could be used to limit HT.

Value of staging squamous cell carcinoma of the anal margin and canal using the sentinel lymph node procedure: an update of the series and a review of the literature.

BACKGROUND: Inguinal metastases in patients affected by anal cancer are an independent prognostic factor for local failure and overall mortality. Since 2001, sentinel lymph node biopsy was applied in these patients. This original study reports an update of personal and previous published series, which were compared with Literature to value the incidence of inguinal metastases T-stage related and the overall incidence of false negative inguinal metastases at sentinel node. METHODS: In all, 63 patients diagnosed with anal cancer submitted to inguinal sentinel node. Furthermore a research in the Pub Med database was performed to find papers regarding this technique. RESULTS: In our series, detection rate was 98.4%. Inguinal metastases were evidentiated in 13 patients (20.6%). Our median follow-up was 35 months. In our series, no false negative nodes were observed. CONCLUSION: Sentinel node technique in the detection of inguinal metastases in patients affected by anal cancer should be considered as a standard of care. It is indicated for all T stages in order to select patients to be submitted to inguinal radiotherapy, avoiding related morbidity in negative ones. An overall 3.7% rate of false negative must be considered acceptable.

Tracking target position variability using intraprostatic fiducial markers and electronic portal imaging in prostate cancer radiotherapy.

PURPOSE: Modern radiotherapy has achieved substantial improvement in tumour control and toxicity rates by escalating the total dose to the target volume while sparing surrounding normal tissues. It has therefore become necessary to precisely track tumour position in order to minimise geometrical uncertainties due to setup errors and organ motion. We conducted this prospective evaluation of prostate cancer patients treated with image-guided conformal radiation therapy at our institution. We implanted three fiducial markers (gold seeds) within the prostatic gland in order to quantify daily target displacements and to generate specific margins around the clinical target volume (CTV) to create an appropriate planned target volume (PTV). MATERIALS AND METHODS: Between April and December 2009, ten patients affected with localised prostate cancer were transrectally implanted with three radio-opaque markers. Each patient underwent a computed tomography (CT) scan for planning purposes following proper bladder and rectum preparation. During treatment two orthogonal images were acquired daily and compared with previously generated digitally reconstructed radiographs. After manual localisation, comparison between the position of the gold seeds on the portal and reference images was carried out, and a set of extrapolated lateral-lateral (LL), anterior-posterior (AP) and cranial-caudal (CC) shift corrections was calculated and recorded. Couch corrections were applied with a threshold of 3 mm displacement. RESULTS: Systematic and random errors for each direction were calculated either as measured according to displacement of the gold seeds prior to any couch movement and after couch position correction according to the radio-opaque markers. For skin marks, mean systematic and random errors were 0.12+2.94 mm for LL, 1.04+3.37 mm for AP, -1.14+2.71 mm for CC, whereas for seed markers, mean and systematic errors were 0.6+1.5 mm for LL, 0.51+2.45 mm for AP and -0.25+2.51 mm for CC. A scatter plot generated on all measurements after couch repositioning according to gold-seed displacement suggested a confidence range of shift distributions within 5 mm for LL, 8 mm for CC, and 7 mm for AP. The total systematic and random components were then used to calculate proper PTV in patients receiving conventional treatment (7 mm for LL and 9 mm for both AP and CC). CONCLUSIONS: Prostate positional variability during a course of radiation treatment is strongly influenced by setup and organ motion. Organ tracking through fiducial markers and electronic portal imaging is able to reduce the spread of displacements, significantly contributing to improve the ballistic precision of radiation delivery.

[Prognostic factors in the treatment of advanced cervical cancer. A retrospective study]. / Fattori prognostici nel trattamento del cervicocarcinoma in stadio localmente avanzato. Studio retrospettivo.

BACKGROUND: The value of prognostic factors in patients with advanced cervix carcinoma treated by radiotherapy was assessed in a retrospective study. METHODS: From January 1977 through December 1990, 261 patients (average age 60 years) were treated at the Radiotherapy Department of the University of Turin. Distribution by stage was: 142 T2b (54%), 8 T3a (3%), 98 T3b (38%) and 13 T4 (5%). 83% of the patients underwent radiotherapy alone; the total dose was 45-88 Gy in 91 patients (42%) with poor clinical conditions, 60-75 Gy in 121 (56%) and 75-80 Gy in 5 cases. 17% of the patients was treated by surgery combined with radiotherapy. The median follow-up was 50 months (minimum 2, maximum 177 months). RESULTS: The 5-year NED survival and local control were 42% (52% for T2b, 33% for T3 and 15% for T4). The severe (G3-G4) complication rate was very low (1.9%). CONCLUSION: In our series, the prognostic factors which significantly influenced survival in the uni-variate analysis were: advanced T stage, contemporary infiltration of parametrium and vagina, nodal status, non squamous neoplasm, younger age and the absence of brachytherapy in the radiotherapy alone protocol.