Lifetime attributable risk of radiation-induced secondary cancer from proton beam therapy compared with that of intensity-modulated X-ray therapy in randomly sampled pediatric cancer patients

To investigate the amount that radiation-induced secondary cancer would be reduced by using proton beam therapy (PBT) in place of intensity-modulated X-ray therapy (IMXT) in pediatric patients, we analyzed lifetime attributable risk (LAR) as an in silico surrogate marker of the secondary cancer after these treatments. From 242 pediatric patients with cancers who were treated with PBT, 26 patients were selected by random sampling after stratification into four categories: (i) brain, head and neck, (ii) thoracic, (iii) abdominal, and (iv) whole craniospinal (WCNS) irradiation. IMXT was replanned using the same computed tomography and region of interest. Using the dose-volume histograms (DVHs) of PBT and IMXT, the LARs of Schneider et al. were calculated for the same patient. All the published dose-response models were tested for the organs at risk. Calculation of the LARs of PBT and IMXT based on the DVHs was feasible for all patients. The means +/- standard deviations of the cumulative LAR difference between PBT and IMXT for the four categories were (i) 1.02 +/- 0.52% (n = 7, P = 0.0021), (ii) 23.3 +/- 17.2% (n = 8, P = 0.0065), (iii) 16.6 +/- 19.9% (n = 8, P = 0.0497) and (iv) 50.0 +/- 21.1% (n = 3, P = 0.0274), respectively (one tailed t-test). The numbers needed to treat (NNT) were (i) 98.0, (ii) 4.3, (iii) 6.0 and (iv) 2.0 for WCNS, respectively. In pediatric patients who had undergone PBT, the LAR of PBT was significantly lower than the LAR of IMXT estimated by in silico modeling. Although a validation study is required, it is suggested that the LAR would be useful as an in silico surrogate marker of secondary cancer induced by different radiotherapy techniques

Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors

Background: Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [18F]fluoromisonidazole positron emission tomography (FMISO-PET). High FMISO uptake before RT could indicate radioresistant sites and might be associated with future local recurrence. The predictive value of FMISO-PET for intra-tumoral recurrence regions was evaluated using high-resolution semiconductor detectors in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). Methods: Nine patients with local recurrence and 12 patients without local recurrence for more than 3 years were included in this study. These patients received homogeneous and standard doses of radiation to the primary tumor irrespective of FMISO uptake. The FMISO-PET image before RT was examined via a voxel-based analysis, which focused on the relationship between the degree of FMISO uptake and recurrence region. Results: In the pretreatment FMISO-PET images, the tumor-to-muscle ratio (TMR) of FMISO in the voxels of the tumor recurrence region was significantly higher than that of the non-recurrence region (p < 0.0001). In the recurrent patient group, a TMR value of 1.37 (95% CI: 1.36-1.39) corresponded to a recurrence rate of 30%, the odds ratio was 5.18 (4.87-5.51), and the area under the curve (AUC) of the receiver operating characteristic curve was 0.613. In all 21 patients, a TMR value of 2.42 (2.36-2.49) corresponded to an estimated recurrence rate of 30%, and the AUC was only 0.591. Conclusions: The uptake of FMISO in the recurrent region was significantly higher than that in the non-recurrent region. However, the predictive value of FMISO-PET before IMRT is not sufficient for up-front dose escalation for the intra-tumoral high-uptake region of FMISO. Because of the higher mean TMR of the recurrence region, a new hypoxic imaging method is needed to improve the sensitivity and specificity for hypoxia

Present developments in reaching an international consensus for a model-based approach to particle beam therapy

Particle beam therapy (PBT), including proton and carbon ion therapy, is an emerging innovative treatment for cancer patients. Due to the high cost of and limited access to treatment, meticulous selection of patients who would benefit most from PBT, when compared with standard X-ray therapy (XRT), is necessary. Due to the cost and labor involved in randomized controlled trials, the model-based approach (MBA) is used as an alternative means of establishing scientific evidence in medicine, and it can be improved continuously. Good databases and reasonable models are crucial for the reliability of this approach. The tumor control probability and normal tissue complication probability models are good illustrations of the advantages of PBT, but pre-existing NTCP models have been derived from historical patient treatments from the XRT era. This highlights the necessity of prospectively analyzing specific treatment-related toxicities in order to develop PBT-compatible models. An international consensus has been reached at the Global Institution for Collaborative Research and Education (GI-CoRE) joint symposium, concluding that a systematically developed model is required for model accuracy and performance. Six important steps that need to be observed in these considerations include patient selection, treatment planning, beam delivery, dose verification, response assessment, and data analysis. Advanced technologies in radiotherapy and computer science can be integrated to improve the efficacy of a treatment. Model validation and appropriately defined thresholds in a cost-effectiveness centered manner, together with quality assurance in the treatment planning, have to be achieved prior to clinical implementation

Lifetime attributable risk of radiation-induced secondary cancer from proton beam therapy compared with that of intensity-modulated X-ray therapy in randomly sampled pediatric cancer patients

To investigate the amount that radiation-induced secondary cancer would be reduced by using proton beam therapy (PBT) in place of intensity-modulated X-ray therapy (IMXT) in pediatric patients, we analyzed lifetime attributable risk (LAR) as an in silico surrogate marker of the secondary cancer after these treatments. From 242 pediatric patients with cancers who were treated with PBT, 26 patients were selected by random sampling after stratification into four categories: (i) brain, head and neck, (ii) thoracic, (iii) abdominal, and (iv) whole craniospinal (WCNS) irradiation. IMXT was replanned using the same computed tomography and region of interest. Using the dose–volume histograms (DVHs) of PBT and IMXT, the LARs of Schneider et al. were calculated for the same patient. All the published dose–response models were tested for the organs at risk. Calculation of the LARs of PBT and IMXT based on the DVHs was feasible for all patients. The means ± standard deviations of the cumulative LAR difference between PBT and IMXT for the four categories were (i) 1.02 ± 0.52% (n = 7, P = 0.0021), (ii) 23.3 ± 17.2% (n = 8, P = 0.0065), (iii) 16.6 ± 19.9% (n = 8, P = 0.0497) and (iv) 50.0 ± 21.1% (n = 3, P = 0.0274), respectively (one tailed t-test). The numbers needed to treat (NNT) were (i) 98.0, (ii) 4.3, (iii) 6.0 and (iv) 2.0 for WCNS, respectively. In pediatric patients who had undergone PBT, the LAR of PBT was significantly lower than the LAR of IMXT estimated by in silico modeling. Although a validation study is required, it is suggested that the LAR would be useful as an in silico surrogate marker of secondary cancer induced by different radiotherapy techniques

Dose-volume analysis for respiratory toxicity in intrathoracic esophageal cancer patients treated with definitive chemoradiotherapy using extended fields

Purpose: We evaluated the relationship between dosimetric parameters (DPs) and the incidence of radiation pneumonitis (RP) and investigated the feasibility of a proposed treatment planning technique with the potential of reducing RP in esophageal cancer patients treated with definitive chemoradiotherapy using extended fields. Patients and Methods: A total of 149 patients with locally advanced esophageal cancer were prospectively enrolled for extended-field radiotherapy (EFRT) to three-field regional lymphatics between September 2004 and June 2009. We retrospectively reviewed 86 consecutive patients who were treated with a total dose of 50.4 Gy (plus an optional 9 Gy boost) and were available for dose-volume analysis. Lung DPs of patients in the Grade 0-1 RP (RPG = 2) group were compared. We compared the proposed plan with the conventional plan to 50.4 Gy on DPs for each case. Results: Of these 86 patients, 10 (12%) developed RPG >= 2 (Grade 2, n = 2 patients; Grade 3, n = 3; Grade 4, n = 3; Grade 5, n = 2). The patients in the RPG = 2 group. There were two advantages gained from the proposed plan for V5 (< 55%) and V10 (< 37%) values and the conformity of the PTV. Conclusion: The increase in the volume of the lung exposed to low doses of EFRT was found to be associated with the incidence of RP. Our proposed plan is likely to reduce the incidence of RP

Assessing the uncertainty in a normal tissue complication probability difference (ΔNTCP) : radiation-induced liver disease (RILD) in liver tumour patients treated with proton vs X-ray therapy

Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (ΔNTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance-covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ΔNTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ΔNTCP threshold

Evaluation of the motion of lung tumors during stereotactic body radiation therapy (SBRT) with four-dimensional computed tomography (4DCT) using real-time tumor-tracking radiotherapy system (RTRT)

Purpose: We investigated the usefulness of four-dimensional computed tomography (4DCT) performed before stereotactic body radiation therapy (SBRT) in determining the internal margins for peripheral lung tumors. Methods and Materials: The amplitude of the movement of a fiducial marker near a lung tumor measured using the maximum intensity projection (MIP) method in 4DCT imaging was acquired before the SBRT (Amp(CT)) and compared with the mean amplitude of the marker movement during SBRT (Amp(mean)) and with the maximum amplitude of the marker movement during SBRT (Amp(max)) using a real-time tumortracking radiotherapy (RTRT) system with 22 patients. Results: There were no significant differences between the means of the Amp(mean) and the means of the Amp(CT) in all directions (LR, P = 0.45; CC, P = 0.80; AP, P = 0.65). The means of the Amp(max) were significantly larger than the means of the Amp(CT) in all directions (LR, P < 0.01; CC, P = 0.03; AP, P < 0.01). In the lower lobe, the mean difference of the Amp(CT) from the mean of the Amp(max) was 5.7 +/- 8.0 mm, 12.5 +/- 16.7 mm, and 6.8 +/- 8.5 mm in the LR, CC, and AP directions, respectively. Conclusions: Acquiring 4DCT MIP images before the SBRT treatment is useful to establish the mean amplitude for a patient during SBRT but it underestimates the maximum amplitude during actual SBRT. Caution must be paid to determine the margin with the 4DCT especially for tumors at the lower lobe where it is of the potentially greatest benefit

Hyperintense putaminal rim at 1.5 T: prevalence in normal subjects and distinguishing features from multiple system atrophy

Background Hyperintense putaminal rim (HPR) is an important magnetic resonance imaging (MRI) sign for multiple system atrophy (MSA). Recent studies have suggested that it can also be observed in normal subjects at 3 T. Whether it can be observed in normal subjects at 1.5 T is not known. This study aimed to determine whether HPR could be observed in normal subjects at 1.5 T; and if so, to establish its prevalence, the MRI characteristics, and the features which distinguish from HPR in MSA patients. Methods Axial T2-weighted images of 130 normal subjects were evaluated for the prevalence of HPR, its age and gender distribution, laterality, maximum dimension, association with hypointensity of nearby putamen, and presence of discontinuity. To distinguish from that observed in MSA, axial T2-weighted images of 6 MSA patients with predominant parkinsonism (MSA-P) and 15 MSA patients with predominant cerebellar symptoms (MSA-C) were also evaluated. The characteristics of HPR were compared between these patients and age-matched normal subjects. The mean diffusivity (MD) values of putamen were also compared. Fisher’s exact test, t-test, and one way analysis of variance were used to determine significance at corrected p < 0.05. Results HPR was observed in 38.5% of normal subjects. Age and gender predilection and laterality were not observed. In most cases, it occupied the full length or anterior half of the lateral margin of putamen, and was continuous throughout its length. Maximum transverse dimension was 2 mm. There was no association with hypointensity of nearby putamen. However, in MSA-P, HPR was located predominantly at the posterolateral aspect of putamen, and associated with putaminal atrophy. Discontinuity of HPR was more frequently observed in MSA-P. On visual analysis, the characteristics of HPR were similar between MSA-C patients and normal subjects. Patients with MSA of either type had significantly higher MD values of putamen than normal subjects. Conclusions HPR can be observed in 38.5% of normal subjects at 1.5 T. Thin linear hyperintensity without discontinuity, occupying the full length or anterior half of the lateral margin of the putamen, is suggestive of “normal.” In doubtful cases, measurement of the MD values of nearby putamen may be valuable

A Case of Sarcoid-Lymphoma Syndrome with Various Etiological Factors

A 75-year-old female with a history of stomach cancer and depression was referred to our hospital for left cervical lymphadenopathy. The biopsy of her left cervical lymph node revealed noncaseating granulomas with multinucleated giant cells. The positron emission tomography/computed tomography (PET/CT) indicated general lymphadenopathy (left supraclavicular left axillary, hepatic lymph nodes), except for the hilar lymph node. Both histology by transbronchial lung biopsy (TBLB) and analysis of broncho alveolar lavage fluid (BALF) were indicative of sarcoidosis. C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were increased in the sera. An alternative cause of granulomatous disease was ruled out, and on follow-up, she was diagnosed with sarcoidosis. Two years later, she was hospitalized for fever, anorexia, lymph node tenderness, and erythema nodosum with significant increases in CRP and sIL-2R. After admission, the repetitive axillary lymph biopsy showed the same histological findings as before, but the G-band staining showed clonal abnormalities. Bone marrow biopsy revealed abnormal lymphocytes with petal-like nuclei. Finally, she was diagnosed with malignant lymphoma infiltrating the bone marrow. After CHOP-based chemotherapy, her laboratory data, lymphadenopathy, and clinical findings improved, and she was discharged from the hospital on the 90th day. Careful medical treatment, including genetic analysis of the lymph node, is necessary in patients with sarcoidosis if lymphadenopathy is predominant

Successful Treatment of a COVID-19 Case with Pneumonia and Renal Injury Using Tocilizumab

A 49-year-old male Japanese patient was admitted to our hospital under the diagnosis of COVID-19 pneumonia. For 5 days before admission, he had experienced various symptoms, including high fever, watery diarrhea, dyspnea, and cough, and he tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid. The patient is a smoker who was on medication for hypertension. A chest computed tomography scan showed bilateral multiple patchy ground-glass opacities. Despite being treated with several therapeutic agents, he still exhibited dyspnea (oxygen saturation [SpO2] in ambient air: 88%), a high fever (axillary temperature: 39 &deg;C), and high blood pressure (148/98 mmHg). Because laboratory data revealed high levels of C-reactive protein (CRP; 2.10 mg/dL) and urinary &beta;2-microglobulin (B2M; 33,683 &micro;g/mL), the anti-interleukin-6 receptor antibody tocilizumab (TCZ; 400 mg) was administered intravenously. One day after injection, he was afebrile. Four days after the TCZ injection, his CRP level dropped to 0.27 mg/dL, B2M level decreased to 3817 &micro;g/mL, and viral load became low. No adverse drug reaction due to TCZ was observed. The patient was discharged 15 days after admission. The early administration of TCZ in this patient prevented the pneumonia and kidney injury caused by COVID-19 from progressing to hyperinflammation syndrome