Mask dependency of the lacrimal gland dose under whole brain radiotherapy when the six-degrees of freedom couch is not available.

BACKGROUND: Dry eye syndrome has been recently reported in patients who underwent whole brain radiotherapy (WBRT). WBRT based on a couch with three-degrees of freedom (3D) can occasionally be performed in which the rotational head motion is not corrected. This study assessed the dependency of the rotational errors on the mask and the dose variation of the lens and lacrimal gland in WBRT patients. METHODS: Translational and rotational setup errors were obtained at the first treatment with cone-beam CT (CBCT) for patients under WBRT and frameless stereotactic radiosurgery (SRS) (n = 20 each) immobilized using a conventional WB mask and an SRS mask with a bite block, respectively. For the CT sets of SRS cases, WBRT plans were generated for the study. To simulate the rotational error, rotated CT images were created with each rotational error, on which initial WBRT plans were copied and doses were recalculated. The lens and lacrimal gland doses with and without rotation errors were compared. RESULTS: Despite similar translational setup errors for the two masks, the SRS mask showed a dramatic reduction in rotational errors compared to those of the WB mask. The errors varied within -2.9° to 2.9° and -1.2° to 0.7° for the WB and SRS masks, respectively. Accordingly, the SRS mask confined the change in the maximum lens dose, mean dose of the lacrimal gland, and lacrimal volume receiving 15 Gy to one-third of those using the WB mask. CONCLUSION: When the six-degrees of freedom (6D) couch is not available, the frameless SRS mask is beneficial to WBRT for the faithful treatment as it was planned.

Combined effect of dose gradient and rotational error on prescribed dose coverage for single isocenter multiple brain metastases in frameless stereotactic radiotherapy.

BACKGROUND: To evaluate the combined effect of rotational error and dose gradient on target dose coverage in frameless stereotactic radiotherapy. METHODS: Three spherical targets of different diameters (1, 1.5, and 2 cm) were drawn and placed equidistantly on the same axial brain computed tomography (CT) images. To test the different isocenter-target distances, 2.5- and 5-cm configurations were prepared. Volumetric modulated arc therapy plans were created for different dose gradients from the target, in which the dose gradients were modified using the maximum dose inside the target. To simulate the rotational error, CT images and targets were rotated in two ways by 0.5°, 1°, and 2°, in which one rotation was in the axial plane and the other was in three dimensions. The initial optimized plan parameters were copied to the rotated CT sets, and the doses were recalculated. The coverage degradation after rotation was analyzed according to the target dislocation and 12-Gy volume. RESULTS: A shallower dose gradient reduced the loss of target coverage under target dislocation, and the effect was clearer for small targets. For example, the coverage of the 1-cm target under 1-mm dislocation increased from 93 to 95% by increasing the Paddick gradient index from 5.0 to 7.9. At the same time, the widely accepted necrosis indicator, the 12-Gy volume, increased from 1.2 to 3.5 cm3, which remained in the tolerable range. From the differential dose volume histogram (DVH) analysis, the shallower dose gradient ensured that the dose-deficient under-covered target volume received a higher dose similar to that in the prescription. CONCLUSIONS: For frameless stereotactic brain radiotherapy, the gradient, alongside the margin addition, can be adjusted as an ancillary parameter for small targets to increase target coverage or at least limit coverage reduction in conditions with probable positioning error.

Enhancement of megavoltage electronic portal images for markerless tumor tracking.

PURPOSE: The poor quality of megavoltage (MV) images from electronic portal imaging device (EPID) hinders visual verification of tumor targeting accuracy particularly during markerless tumor tracking. The aim of this study was to investigate the effect of a few representative image processing treatments on visual verification and detection capability of tumors under auto tracking. METHODS: Images of QC-3 quality phantom, a single patient's setup image, and cine images of two-lung cancer patients were acquired. Three image processing methods were individually employed to the same original images. For each deblurring, contrast enhancement, and denoising, a total variation deconvolution, contrast-limited adaptive histogram equalization (CLAHE), and median filter were adopted, respectively. To study the effect of image enhancement on tumor auto-detection, a tumor tracking algorithm was adopted in which the tumor position was determined as the minimum point of the mean of the sum of squared pixel differences (MSSD) between two images. The detectability and accuracy were compared. RESULTS: Deblurring of a quality phantom image yielded sharper edges, while the contrast-enhanced image was more readable with improved structural differentiation. Meanwhile, the denoising operation resulted in noise reduction, however, at the cost of sharpness. Based on comparison of pixel value profiles, contrast enhancement outperformed others in image perception. During the tracking experiment, only contrast enhancement resulted in tumor detection in all images using our tracking algorithm. Deblurring failed to determine the target position in two frames out of a total of 75 images. For original and denoised set, target location was not determined for the same five images. Meanwhile, deblurred image showed increased detection accuracy compared with the original set. The denoised image resulted in decreased accuracy. In the case of contrast-improved set, the tracking accuracy was nearly maintained as that of the original image. CONCLUSIONS: Considering the effect of each processing on tumor tracking and the visual perception in a limited time, contrast enhancement would be the first consideration to visually verify the tracking accuracy of tumors on MV EPID without sacrificing tumor detectability and detection accuracy.

Inhibition of STAT3 enhances the radiosensitizing effect of temozolomide in glioblastoma cells in vitro and in vivo.

Even with aggressive treatment involving radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential for targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome in glioblastoma. We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188, combined with temozolomide and radiation using in vitro assays with two established glioblastoma cell lines (U251 and U87) and two patient-derived glioblastoma cell lines (GBL12 and GBL28) as well as in vivo studies with nude mice bearing intracranial U251 xenografts. Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cells, which have high p-STAT3 expression levels. The enhanced radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and reversion of the epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 in GBL28 cells, which were originated from a patient with a high level of STAT3 expression and unmethylated MGMT. Targeting STAT3 using Cpd188 could be a viable therapeutic approach for improving the outcome of current standard therapy in glioblastoma patients with high p-STAT3 expression.

Evaluation of variability in target volume delineation for newly diagnosed glioblastoma: a multi-institutional study from the Korean Radiation Oncology Group.

BACKGROUND: This study aimed for a collaborative evaluation of variability in the target volumes for glioblastoma, determined and contoured by different radiotherapy (RT) facilities in Korea. METHODS: Fifteen panels of radiation oncologists from independent institutions contoured the gross target volumes (GTVs) and clinical target volumes (CTVs) for 3-dimensional conformal RT or intensity-modulated RT on each simulation CT images, after scrutinizing the enhanced T1-weighted and T2-weighted-fluid-attenuated inversion recovery MR images of 9 different cases of glioblastoma. Degrees of contouring agreement were analyzed by the kappa statistics. Using the algorithm of simultaneous truth and performance level estimation (STAPLE), GTVSTAPLE and CTVSTAPLE contours were derived. RESULTS: Contour agreement was moderate (mean kappa 0.58) among the GTVs and was substantial (mean kappa 0.65) among the CTVs. However, each panels' GTVs and modification of CTVs regarding anatomical structures varied. Three-fourth of contoured panels' CTVs encompassed the peritumoral areas of T2-high signal intensity (T2-HSI). Nine of nine GTVSTAPLE encompased the surgical cavity and the T1-enhanced lesions. Eight of nine CTVSTAPLE encompassed the peritumoral T2-HSI area. The median MARGIN90 and the median MARGIN95 were 1.4 cm and 1.5 cm, respectively. CONCLUSIONS: Moderate to substantial agreement existed in target volumes for 3-dimensional or intensity-modulated RT determined by radiation oncologists in Korea. According to the estimated consensus contours, the initial CTV encompassed the GTV with margin less than 2.0 cm and the whole peritumoral areas of T2-HSI. The findings of our study propose the need for further studies and modified guidelines.

Electron dose distributions caused by the contact-type metallic eye shield: Studies using Monte Carlo and pencil beam algorithms.

A metallic contact eye shield has sometimes been used for eyelid treatment, but dose distribution has never been reported for a patient case. This study aimed to show the shield-incorporated CT-based dose distribution using the Pinnacle system and Monte Carlo (MC) calculation for 3 patient cases. For the artifact-free CT scan, an acrylic shield machined as the same size as that of the tungsten shield was used. For the MC calculation, BEAMnrc and DOSXYZnrc were used for the 6-MeV electron beam of the Varian 21EX, in which information for the tungsten, stainless steel, and aluminum material for the eye shield was used. The same plan was generated on the Pinnacle system and both were compared. The use of the acrylic shield produced clear CT images, enabling delineation of the regions of interest, and yielded CT-based dose calculation for the metallic shield. Both the MC and the Pinnacle systems showed a similar dose distribution downstream of the eye shield, reflecting the blocking effect of the metallic eye shield. The major difference between the MC and the Pinnacle results was the target eyelid dose upstream of the shield such that the Pinnacle system underestimated the dose by 19 to 28% and 11 to 18% for the maximum and the mean doses, respectively. The pattern of dose difference between the MC and the Pinnacle systems was similar to that in the previous phantom study. In conclusion, the metallic eye shield was successfully incorporated into the CT-based planning, and the accurate dose calculation requires MC simulation.

Hypofractionated chemoradiotherapy with temozolomide as a treatment option for glioblastoma patients with poor prognostic features.

BACKGROUND: Although the optimal treatment of frail glioblastoma patients is still controversial, previous randomized trials have excluded such patients. This study aimed to evaluate the feasibility and safety of hypofractionated radiotherapy (RT) with concomitant temozolomide for glioblastoma patients with poor prognostic features. METHODS: We retrospectively reviewed 33 glioblastoma patients who underwent postoperative hypofractionated chemoradiotherapy. The patient criteria were either ≥70 years or <70 years with one or more risk factors: pre-RT performance status (ECOG score) ≥3, biopsy only, or rapid disease progression immediately after surgery. The median RT dose was 45 Gy (range 30-45) with a fraction size of 3 Gy. RESULTS: The median age was 66.0 years. Eighteen patients (55 %) had poor pre-RT performance status (ECOG ≥3), and 16 patients (48 %) underwent stereotactic biopsy only. The median overall survival (OS) and progression-free survival were 10.6 and 7.5 months, respectively. Poor pre- and post-RT performance status [hazard ratio (HR) 3.12, 95 % confidence interval (CI) 1.21-8.07 and HR 4.51, 95 % CI 1.44-14.12, respectively] and no pseudoprogression (HR 5.43, 95 % CI 1.58-18.61) were associated with poorer OS. While acute neurologic symptoms were reported in 5 patients (15 %), toxicity profiles were acceptable without treatment-related aggravation of performance status. CONCLUSIONS: Concurrent chemoradiotherapy with temozolomide, the current standard treatment after surgery for glioblastoma, could be shortened without increasing side effects for patients with poor prognostic features.

Comparison of treatment outcomes between involved-field and elective nodal irradiation in limited-stage small cell lung cancer.

OBJECTIVE: The present study was performed to assess the usefulness of involved-field irradiation and the impact of (18)F-fluorodeoxyglucose-positron emission tomography-based staging on treatment outcomes in limited-stage small cell lung cancer. METHODS: Eighty patients who received definitive chemoradiotherapy for limited-stage small cell lung cancer were retrospectively analyzed. Fifty patients were treated with involved-field irradiation, which means that the radiotherapy portal includes only clinically identifiable tumors. The other 30 patients were irradiated with a comprehensive portal, including uninvolved mediastinal and/or supraclavicular lymph nodes, so-called elective nodal irradiation. No significant difference was seen in clinical factors between the two groups. RESULTS: At a median follow-up of 27 months (range, 5-75 months), no significant differences were observed in 3 year overall survival (44.6 vs. 54.1%, P= 0.220) and 3 year progression-free survival (24.4 vs. 42.8%, P= 0.133) between the involved-field irradiation group and the elective nodal irradiation group, respectively. For patients who did not undergo positron emission tomography scans, 3 year overall survival (29.3 vs. 56.3%, P= 0.022) and 3 year progression-free survival (11.0 vs. 50.0%, P= 0.040) were significantly longer in the elective nodal irradiation group. Crude incidences of isolated nodal failure were 6.0% in the involved-field irradiation group and 0% in the elective nodal irradiation group, respectively. All isolated nodal failures were developed in patients who had not undergone positron emission tomography scans in their initial work-ups. CONCLUSION: If patients did not undergo positron emission tomography-based staging, the omission of elective nodal irradiation resulted in impaired survival outcomes and raised the risk of isolated nodal failure. Therefore, involved-field irradiation for limited-stage small cell lung cancer might be reasonable only with positron emission tomography scan implementation.

The prognostic value of the nodal ratio in N1 breast cancer.

BACKGROUND: Although the nodal ratio (NR) has been recognized as a prognostic factor in breast cancer, its clinical implication in patients with 1-3 positive nodes (N1) remains unclear. Here, we evaluated the prognostic value of the NR and identified other clinico-pathologic variables associated with poor prognosis in these patients. METHODS: We analyzed 130 patients with N1 invasive breast cancer who were treated at Seoul National University Bundang Hospital from March 2003 to December 2007. Disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were compared according to the NR with a cut-off value of 0.15. RESULTS: We followed patients' recovery for a median duration of 59 months. An NR > 0.15 was found in 23.1% of patients, and a median of 18 nodes were dissected per patient (range 1-59). The NR was statistically independent from other prognostic variables, such as patient age, T stage, extent of surgery, pathologic factors in the chi square test. On univariate analysis, patients with a NR > 0.15 had significantly lower 5-year LRRFS (88.7% vs. 97.9%, p = 0.033) and 5-year DMFS (81.3% vs. 96.4%, p = 0.029) and marginally lower 5-year DFS (81.3% vs. 94.0%, p = 0.069) than those with a NR ≤0.15, respectively. Since the predictive power of the NR was found to differ with diverse clinical and pathologic variables, we performed adjusted analysis stratified by age, pathologic characteristics, and adjuvant treatments. Only young patients with a NR > 0.15 showed significantly lower DFS (p = 0.027) as well as those presenting an unfavorable pathologic profile such as advanced T stage (p = 0.034), histologic grade 3 (p = 0.034), positive lymphovascular invasion (p = 0.037), involved resection margin (p = 0.007), and no chemotherapy (p = 0.014) or regional radiotherapy treatment (p = 0.039). On multivariate analysis, a NR > 0.15 was significantly associated with lower DFS (p = 0.043) and DMFS (p = 0.012), but not LRRFS (p = 0.064). CONCLUSIONS: A NR > 0.15 was associated with an increased risk of recurrence, especially in young patients with unfavorable pathologic profiles.

The short-term effect of neoadjuvant chemoradiation on anorectal function in low and midrectal cancer: analysis using preoperative manometric data.

PURPOSE: The purpose of this study was to evaluate the short-term preoperative effects of neoadjuvant chemoradiation on anorectal function, excluding the bias of postoperative impairment. METHODS: We analyzed 80 patients on whom preoperative anorectal manometry data were available for both prechemoradiation and postchemoradiation. Patients were divided into 2 groups according to the tumor location; lower rectum (n = 52) and mid rectum (n = 28). The paired t test was used to compare prechemoradiation and postchemoradiation parameters including the mean resting pressure, maximum squeeze pressure, percentage asymmetry of the resting and squeeze sphincter, length of the high-pressure zone, rectal sensory threshold, and rectal compliance. RESULTS: In patients with a lower rectal cancer, there were significant differences in the percentage asymmetry of the squeeze sphincter (27.81 +/- 6.46 vs 25.38 +/- 5.93%, P < .01), length of the high-pressure zone (2.14 +/- 0.74 vs 2.33 +/- 0.72 cm, P = .05), and rectal compliance (1.14 +/- 0.41 vs 1.02 +/- 0.40 mL/mmHg, P = .04). In patients with midrectal cancer, only the mean resting pressure increased significantly (45.08 +/- 18.57 vs 52.83 +/- 17.87 mmHg, P < .01). Clinical symptom evaluation demonstrated a significant decrease in the number of defecations and the frequency of tenesmus. CONCLUSION: Neoadjuvant chemoradiation did not impair overall short-term sphincter function significantly, regardless of the location of the primary tumor. Although there was a decrease in rectal compliance, it seemed that the tumor-downsizing effect compensated the expected worsening of anorectal function in the early postchemoradiation period.

Low initial human papilloma viral load implicates worse prognosis in patients with uterine cervical cancer treated with radiotherapy.

PURPOSE: To evaluate whether human papillomavirus (HPV) viral load measured in cervical smear and HPV type 18 are associated with radiotherapy outcomes in uterine cervical cancer. PATIENTS AND METHODS HPV DNA: was semiquantitatively measured in the cervical smears of 169 radiotherapy patients. HPV viral load was classified as low or high according to median HPV DNA titer and examined for its prognostic value. The multivariable Cox proportional hazards model was used to adjust for covariates. A relapse-predicting model was constructed to classify three risk groups for disease-free survival (DFS), which were used for internal validation. RESULTS: Patients with lower HPV viral load showed worse DFS in univariate analysis. HPV type 18, younger patient age, stage group, nodal status, histologic grade, and histologic type were other prognostic factors for poor DFS. Among these factors, all except stage group were associated with HPV viral load. Multivariate analysis showed the strong influence of HPV viral load for poor DFS. The prognostic model developed using our outcome data performed well in predicting the risk of relapse. CONCLUSION: Our data suggest that HPV viral load is a strong independent prognostic factor for DFS. HPV type 18 showed a significant relationship with poor radiotherapy outcome in univariate analysis, but not in multivariate analysis.

Synchronous multifocal HPV-related neoplasm involving both the genital tract and the head-and-neck area: a case report of Fanconi anemia.

We report the case of a 32-year-old woman who presented with multiple squamous cell neoplasms synchronously arising in the cervix, vulva, oral cavity and oropharynx. During the period when the patient was treated by radiotherapy, she developed severe radiation mucositis and pancytopenia. Immunofluorescence staining for foci of the monoubiquitinated form of FANCD2 revealed a complete absence of such foci in all cancer tissues that were examined.

[Development of Secondary Order System for Laboratory Tests without Additional Blood Sampling.].

BACKGROUND: Additional tests ordered by doctors after checking abnormal routine test results for inpatients are usually delayed for one day or more, which in turn delays diagnostic and therapeutic procedures and prolongs length of stay (LOS) for the patients. We at Department of Laboratory Medicine, Asan Medical Center (AMC), established a "secondary order system for laboratory tests without additional blood sampling" to improve the conventional reflexive tests. METHODS: Oracle 8.0 (Oracle Co., Belmont, CA, USA) was used for data base software and Powerbuilder (Powersoft, Burlington, UK) for client development tool. Specimens subjected to "reflexive tests by doctors without additional blood sampling" were SST tubes for routine chemistry and EDTA for routine hematology requested in the morning of additional requests of the laboratory tests. RESULTS: Programs of registration and request for "reflexive tests by doctors without additional blood sampling" and bar code printing were developed for clinicians to check the routine test results and to order additional tests, if necessary, and for laboratory to perform the requested tests using the same samples used for routine chemistry and hematology tests in the morning. Additionally requested tests were done by finding the SST and EDTA samples, putting newly printed bar code, and processing them as usual. In February 2004, right after introducing reflexive tests by doctors without additional blood sampling, 75 additional requests were made for 50 patients, but they increased gradually up to 1,020 tests for 698 patients in December 2004. In 2005, the monthly average number of tests was 1,035 for 742 patients. CONCLUSIONS: The reflexive tests by doctors without additional blood sampling developed at AMC helped establish a rapid reporting of test results, which in turn reduced LOS related to laboratory. It also increased patient satisfactory indices by reducing repeated blood sampling and would also contribute to the financial health of the hospital.

ABA and polyamines act independently in primary leaves of cold-stressed tomato (Lycopersicon esculentum).

The effects of ABA and putrescine, a polyamine, on cold-induced membrane leakage were investigated using primary leaves of wild-type and an ABA-deficient mutant, flacca, of tomato (Lycopersicon esculentum Mill.). The amount of chilling-induced electrolyte leakage from flacca leaves was much higher than that from the wild-type leaves. When applied exogenously ABA reduced cold-induced electrolyte leakage from leaves of both wild-type and the flacca mutant. However, the cold-induced electrolyte leakage from flacca leaves was not as pronounced as in the wild-type indicating that ABA is an important mediator in response to cold stress in the leaves. Putrescine reduced cold-induced electrolyte leakage from both wild-type and flacca leaves. Synthesis of putrescine in the leaves was increased by cold treatment. DFMO, a biosynthetic inhibitor of the polyamine, increased electrolyte leakage from cold-treated leaves, and exogenously applied putrescine decreased the enhanced leakage to the control level. Therefore, this polyamine is thought also to be involved in the response to cold stress of tomato leaves. Both ABA and putrescine were protective against cold stress, but exogenously applied ABA decreased the endogenous level of putrescine in the leaves. Furthermore, the DMFO-increased electrolyte leakage in cold-stressed leaves was completely abolished by the application of ABA. These results suggest that ABA is a major regulator in the response to cold stress in tomato leaves and that it does not exert its role via putrescine in the response to cold stress.