Impact of Intra-Fractional Motion on Dose Distributions in Lung IMRT.

AIM: To investigate the impact of intra-fractional motion on dose distribution in patients treated with intensity-modulated radiation therapy (IMRT) for lung cancer. MATERIALS AND METHODS: Twenty patients who had undergone IMRT for non-small cell lung cancer were selected for this retrospective study. For each patient, a four-dimensional computed tomography (CT) image set was acquired and clinical treatment plans were developed using the average CT. Dose distributions were then re-calculated for each of the 10 phases of respiratory cycle and combined using deformable image registration to produce cumulative dose distributions that were compared with the clinical treatment plans. RESULTS: Intra-fractional motion reduced planning target volume (PTV) coverage in all patients. The median reduction of PTV volume covered by the prescription isodose was 3.4%; D98 was reduced by 3.1 Gy. Changes in the mean lung dose were within ±0.7 Gy. V20 for the lung increased in most patients; the median increase was 1.6%. The dose to the spinal cord was unaffected by intra-fractional motion. The dose to the heart was slightly reduced in most patients. The median reduction in the mean heart dose was 0.22 Gy, and V30 was reduced by 2.5%.The maximum dose to the esophagus was also reduced in most patients, by 0.74 Gy, whereas V50 did not change significantly. The median number of points in which dose differences exceeded 3%/3 mm was 6.2%. FINDINGS: Intra-fractional anatomical changes reduce PTV coverage compared to the coverage predicted by clinical treatment planning systems that use the average CT for dose calculation. Doses to organs at risk were mostly over-predicted.

Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy.

BACKGROUND: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan-Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy. RESULTS: Of 143 patients identified, the median age was 66 (range, 19-90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13-25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/µL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk. CONCLUSION: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.

Cancer Cell Invasion of Mammary Organoids with Basal-In Phenotype.

This paper describes mammary organoids with a basal-in phenotype where the basement membrane is located on the interior surface of the organoid. A key materials consideration to induce this basal-in phenotype is the use of a minimal gel scaffold that the epithelial cells self-assemble around and encapsulate. When MDA-MB-231 breast cancer cells are co-cultured with epithelial cells from day 0 under these conditions, cells self-organize into patterns with distinct cancer cell populations both inside and at the periphery of the epithelial organoid. In another type of experiment, the robust formation of the basement membrane on the epithelial organoid interior enables convenient studies of MDA-MB-231 invasion in a tumor progression-relevant direction relative to epithelial cell-basement membrane positioning. That is, the study of cancer invasion through the epithelium first, followed by the basement membrane to the basal side, is realized in an experimentally convenient manner where the cancer cells are simply seeded on the outside of preformed organoids, and their invasion into the organoid is monitored. Interestingly, invasion is more prominent when tumor cells are added to day 7 organoids with less developed basement membranes compared to day 16 organoids with more defined ones.

Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons.

BACKGROUND: We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM). METHODS: Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79-0.94) for the final G3+L prediction model. CONCLUSIONS: Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.

A Dosimetric Comparison of Oral Cavity Sparing in the Unilateral Treatment of Early Stage Tonsil Cancer: IMRT, IMPT, and Tongue-Deviating Oral Stents.

INTRODUCTION: Tongue-deviating oral stents (TDOS) are commonly used during unilateral neck radiation therapy to reduce unnecessary dose to nontarget oral structures. Their benefit in the setting of highly conformal treatment techniques, however, is not defined. The goal of this study was to investigate the potential benefit of TDOS use on dosimetric parameters in unilateral intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT). METHODS: A total of 16 patients with T1-2 tonsil cancer treated at a single institution were selected, of which 8 were simulated/treated with a TDOS and 8 without a TDOS. All received definitive unilateral IMRT to a dose of 66 Gy in 30 fx. IMPT plans were generated for each patient for study purposes and optimized according to standard institutional practice. RESULTS: For IMRT plans, the presence of a TDOS (vs without) was associated with a significantly lower oral mucosa mean dose (31.4 vs 35.3 Gy; P = .020) and V30 (42.7% vs 57.1%; P = .025). For IMPT plans, the presence of TDOS (vs without) was not associated with any improvement in oral mucosa mean dose (18.3 vs 19.9 Gy; P = .274) or V30 (25.0% vs 26.2%; P = .655). IMPT plans without TDOS compared with IMRT plans with TDOS demonstrated reduced oral mucosa mean dose (P < .001) and V30 (P < .001). CONCLUSION: The use of a TDOS for the unilateral treatment of well-lateralized tonsil cancers was associated with oral mucosa sparing for IMRT, but not for IMPT. Moreover, mucosa sparing was improved for IMPT plans without a TDOS compared to IMRT plans with a TDOS.

Evaluation of the high definition field of view option of a large-bore computed tomography scanner for radiation therapy simulation.

BACKGROUND AND PURPOSE: Computed tomography (CT) scanning is the basis for radiation treatment planning, but the 50-cm standard scanning field of view (sFOV) may be too small for imaging larger patients. We evaluated the 65-cm high-definition (HD) FOV of a large-bore CT scanner for CT number accuracy, geometric distortion, image quality degradation, and dosimetric accuracy of photon treatment plans. MATERIALS AND METHODS: CT number accuracy was tested by placing two 16-cm acrylic phantoms on either side of a 40-cm phantom to simulate a large patient extending beyond the 50-cm-diameter standard scanning FOV. Dosimetric accuracy was tested using anthropomorphic pelvis and thorax phantoms, with additional acrylic body parts on either side of the phantoms. Two volumetric modulated arc therapy beams (a 15-MV and a 6-MV) were used to cover the planning target volumes. Two-dimensional dose distributions were evaluated with GAFChromic film and point dose accuracy was checked with multiple thermoluminescent dosimeter (TLD) capsules placed in the phantoms. Image quality was tested by placing an American College of Radiology accreditation phantom inside the 40-cm phantom. RESULTS: The HD FOV showed substantial changes in CT numbers, with differences of 314 HU-725 HU at different density levels. The volume of the body parts extending into the HD FOV was distorted. However, TLD-reported doses for all PTVs agreed within ± 3%. Dose agreement in organs at risk were within the passing criteria, and the gamma index pass rate was >97%. Image quality was degraded. CONCLUSIONS: The HD FOV option is adequate for RT simulation and met accreditation standards, although care should be taken during contouring because of reduced image quality.

Xerostomia-related quality of life for patients with oropharyngeal carcinoma treated with proton therapy.

PURPOSE: We report longitudinal patient-reported quality-of-life (QoL) outcomes related to xerostomia in patients with oropharyngeal cancer treated with intensity-modulated proton therapy (IMPT). MATERIALS AND METHODS: Patients treated from May 2012 through December 2016 at a single institution for AJCC7 stage III-IV, M0 oropharyngeal cancer were given the 15-item Xerostomia-Related QoL Scale (XeQoLS) before, during, and for up to 2 years after treatment. We evaluated the evolution of xerostomia-related QoL over that time, and examined potential associations between those measures with clinical characteristics. RESULTS: Sixty-nine patients had XeQoLS scores at baseline and at least once either during or after treatment. The mean (±SD) XeQoLS score (0-4) was 0.24 ±â€¯0.57 at baseline. Subsequent scores were 2.00 ±â€¯1.01 at 6 weeks on treatment, and 1.03 ±â€¯0.76, 0.97 ±â€¯0.78, 0.82 ±â€¯0.69, and 0.70 ±â€¯0.75 at 10 weeks, 6 months, 1 year, and 2 years after treatment, respectively. All were statistically different from baseline (p < 0.001). Univariate analyses demonstrated associations between XeQoLS score and time (p < 0.0001 for each interval), baseline XeQoLS score (p < 0.0001), stage (p = 0.008), N status (p = 0.006), and mean oral cavity dose (p = 0.038), but not for age, sex, T status, receipt of chemotherapy, smoking history, disease site, laterality of neck irradiation, mean parotid dose, or mean submandibular dose. Multivariate analysis suggested that baseline XeQoLS scores, phase of treatment, and N status were associated with XeQoLS scores measured during treatment and recovery. CONCLUSIONS: Patients receiving IMPT reported the greatest xerostomia-related QoL impairment at 6 weeks on treatment, with a 49% improvement by 10 weeks after treatment; however, XeQoLS scores remained above baseline after 2 years. As we aim to establish the value of IMPT in oropharyngeal tumors to de-intensify treatment over conventional therapy, these data help inform discussions about xerostomia-related quality of life for patients with oropharyngeal cancer treated with IMPT.

Prediction of Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Development and Validation of a Pretreatment Nomogram.

INTRODUCTION: In patients with esophageal cancer, occurrence of severe radiation-induced lymphopenia during chemoradiation therapy has been associated with worse progression-free and overall survival. The aim of this study was to develop and validate a pretreatment clinical nomogram for the prediction of grade 4 lymphopenia. METHODS AND MATERIALS: A development set of consecutive patients who underwent chemoradiation therapy for esophageal cancer and an independent validation set of patients from another institution were identified. Grade 4 lymphopenia was defined as an absolute lymphocyte count nadir during chemoradiation therapy of <0.2 × 103/µL. Multivariable logistic regression analysis was used to create a prediction model for grade 4 lymphopenia in the development set, which was internally validated using bootstrapping and externally validated by applying the model to the validation set. The model was presented as a nomogram yielding 4 risk groups. RESULTS: Among 860 included patients, 322 (37%) experienced grade 4 lymphopenia. Higher age, larger planning target volume in interaction with lower body mass index, photon- rather than proton-based therapy, and lower baseline absolute lymphocyte count were predictive in the final model (corrected c-statistic, 0.76). External validation in 144 patients, among whom 58 (40%) had grade 4 lymphopenia, yielded a c-statistic of 0.71. Four nomogram-based risk groups yielded predicted risk rates of 10%, 24%, 43%, and 70%, respectively. CONCLUSIONS: A pretreatment clinical nomogram was developed and validated for the prediction of grade 4 radiation-induced lymphopenia during chemoradiation therapy for esophageal cancer. The nomogram can risk stratify individual patients suitable for lymphopenia-mitigating strategies or potential future therapeutic approaches to ultimately improve survival.

Evaluation of the accuracy of deformable image registration on MRI with a physical phantom.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) has gained popularity in radiation therapy simulation because it provides superior soft tissue contrast, which facilitates more accurate target delineation compared with computed tomography (CT) and does not expose the patient to ionizing radiation. However, image registration errors in commercial software have not been widely reported. Here we evaluated the accuracy of deformable image registration (DIR) by using a physical phantom for MRI. METHODS AND MATERIALS: We used the "Wuphantom" for end-to-end testing of DIR accuracy for MRI. This acrylic phantom is filled with water and includes several fillable inserts to simulate various tissue shapes and properties. Deformations and changes in anatomic locations are simulated by changing the rotations of the phantom and inserts. We used Varian Velocity DIR software (v4.0) and CT (head and neck protocol) and MR (T1- and T2-weighted head protocol) images to test DIR accuracy between image modalities (MRI vs CT) and within the same image modality (MRI vs MRI) in 11 rotation deformation scenarios. Large inserts filled with Mobil DTE oil were used to simulate fatty tissue, and small inserts filled with agarose gel were used to simulate tissues slightly denser than water (e.g., prostate). Contours of all inserts were generated before DIR to provide a baseline for contour size and shape. DIR was done with the MR Correctable Deformable DIR method, and all deformed contours were compared with the original contours. The Dice similarity coefficient (DSC) and mean distance to agreement (MDA) were used to quantitatively validate DIR accuracy. We also used large and small regions of interest (ROIs) during between-modality DIR tests to simulate validation of DIR accuracy for organs at risk (OARs) and propagation of individual clinical target volume (CTV) contours. RESULTS: No significant differences in DIR accuracy were found for T1:T1 and T2:T2 comparisons (P > 0.05). DIR was less accurate for between-modality comparisons than for same-modality comparisons, and was less accurate for T1 vs CT than for T2 vs CT (P < 0.001). For between-modality comparisons, use of a small ROI improved DIR accuracy for both T1 and T2 images. CONCLUSION: The simple design of the Wuphantom allows seamless testing of DIR; here we validated the accuracy of MRI DIR in end-to-end testing. T2 images had superior DIR accuracy compared with T1 images. Use of small ROIs improves DIR accuracy for target contour propagation.

Quantifying the accuracy of deformable image registration for cone-beam computed tomography with a physical phantom.

PURPOSE: Kilo-voltage cone-beam computed tomography (CBCT) is widely used for patient alignment, contour propagation, and adaptive treatment planning in radiation therapy. In this study, we evaluated the accuracy of deformable image registration (DIR) for CBCT under various imaging protocols with different noise and patient dose levels. METHODS: A physical phantom previously developed to facilitate end-to-end testing of the DIR accuracy was used with Varian Velocity v4.0 software to evaluate the performance of image registration from CT to CT, CBCT to CT, and CBCT to CBCT. The phantom is acrylic and includes several inserts that simulate different tissue shapes and properties. Deformations and anatomic changes were simulated by changing the rotations of both the phantom and the inserts. CT images (from a head and neck protocol) and CBCT images (from pelvis, head and "Image Gently" protocols) were obtained with different image noise and dose levels. Large inserts were filled with Mobil DTE oil to simulate soft tissue, and small inserts were filled with bone materials. All inserts were contoured before the DIR process to provide a ground truth contour size and shape for comparison. After the DIR process, all deformed contours were compared with the originals using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). Both large and small volume of interests (VOIs) for DIR volume selection were tested by simulating a DIR process that included whole patient image volume and clinical target volumes (CTV) only (for CTVs propagation). RESULTS: For cross-modality DIR registration (CT to CBCT), the DSC were >0.8 and the MDA were <3 mm for CBCT pelvis, and CBCT head protocols. For CBCT to CBCT and CT to CT, the DIR accuracy was improved relative to the cross-modality tests. For smaller VOIs, the DSC were >0.8 and MDA <2 mm for all modalities. CONCLUSIONS: The accuracy of DIR depends on the quality of the CBCT image at different dose and noise levels.

Characterization of a new physical phantom for testing rigid and deformable image registration.

The purpose of this study was to describe a new user-friendly, low-cost phantom that was developed to test the accuracy of rigid and deformable image registration (DIR) systems and to demonstrate the functional efficacy of the new phantom. The phantom was constructed out of acrylic and includes a variety of inserts that simulate different tissue shapes and properties. It can simulate deformations and location changes in patient anatomy by changing the rotations of both the phantom and the inserts. CT scans of this phantom were obtained and used to test the rigid and deformable registration accuracy of the Velocity software. Eight rotation and translation scenarios were used to test the rigid registration accuracy, and 11 deformation scenarios were used to test the DIR accuracy. The mean rotation accuracies in the X-Y (axial) and X-Z (coronal) planes were 0.50° and 0.13°, respectively. The mean translation accuracy was 1 mm in both the X and Y direction and was tested in soft tissue and bone. The DIR accuracies for soft tissue and bone were 0.93 (mean Dice similarity coefficient), 8.3 and 4.5 mm (mean Hausdouff distance), 0.95 and 0.79 mm (mean distance), and 1.13 and 1.12 (mean volume ratio) for soft tissue content (DTE oil) and bone, respectively. The new phantom has a simple design and can be constructed at a low cost. This phantom will allow DIR systems to be effectively and efficiently verified to ensure system performance.

High background in ELISpot assays is associated with elevated levels of immune activation in HIV-1-seronegative individuals in Nairobi.

INTRODUCTION: Spontaneous interferon-γ (IFNγ) released detected by enzyme-linked immunospot (ELISpot) assays may be a biological phenomenon. Markers of immune activation levels were assessed as correlates of high background among individuals in Kenya. METHODS: Couples concordantly seronegative for HIV-1 were enrolled. IFN-γ ELISpot assays were conducted and negative control wells were categorized as having either high or low background (≥50 and <50 SFU/106 peripheral blood mononuclear cells [PBMC], respectively). PBMC were stained for CD4, CD8, and immune activation markers (CD38 and HLA-DR) and analyzed using flow cytometry. Proportions of activated T-cells were compared between those with low and high background by Mann-Whitney U test. Correlates of background SFU and immune activation were assessed using regression models. RESULTS: Among 58 individuals, 14 (24%) had high background. Frequencies of CD4+ CD38+ HLA-DR+ and CD8+ CD38+ HLA-DR+ cells were higher in individuals with high background compared to those with low background (P = 0.02). Higher background SFU was associated with history of sexually transmitted infections (P = 0.03), and illness in the past 3 months (P = 0.005), in addition to increased levels of activated CD4+ and CD8+ cells (P range = 0.008-0.03). Female gender and male circumcision decreased levels of CD4+ and CD8+ immune activation (P range = 0.002-0.03). Additionally, higher background SFU and activated CD4+ and CD8+ cells were individually associated with positive ELISpot responses to HIV-1 peptide pools (P range = 0.01-0.03). CONCLUSIONS: These findings suggest that increased basal immune responses may be a biological mechanism contributing to higher background ELISpot SFU. Systematic exclusion of data from individuals with increased background in IFN-γ release assays may bias results in population-based studies.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Intensity-Modulated Proton Therapy Adaptive Planning for Patients with Oropharyngeal Cancer.

PURPOSE: The authors aimed to illustrate the potential dose differences to clinical target volumes (CTVs) and organs-at-risk (OARs) volumes after proton adaptive treatment planning was used. PATIENTS AND METHODS: The records of 10 patients with oropharyngeal cancer were retrospectively reviewed. Each patient's treatment plan was generated by using the Eclipse treatment planning system. Verification computed tomography (CT) scan was performed during the fourth week of treatment. Deformable image registrations were performed between the 2 CT image sets, and the CTVs and major OARs were transferred to the verification CT images to generate the adaptive plan. We compared the accumulated doses to CTVs and OARs between the original and adaptive plans, as well as between the adaptive and verification plans to simulate doses that would have been delivered if the adaptive plans were not used. RESULTS: Body contours were different on planning and week-4 verification CTs. Mean volumes of all CTVs were reduced by 4% to 8% (P ≤ .04), and the volumes of left and right parotid glands also decreased (by 11% to 12%, P ≤ .004). Brainstem and oral cavity volumes did not significantly differ (all P ≥ .14). All mean doses to the CTV were decreased for up to 7% (P ≤ .04), whereas mean doses to the right parotid and oral cavity increased from a range of 5% to 8% (P ≤ .03), respectively. CONCLUSION: Verification and adaptive planning should be recommended during the course of proton therapy for patients with head and neck cancer to ensure adequate dose deliveries to the planned CTVs, while safe doses to OARs can be respected.

Quantitative analysis of treatment process time and throughput capacity for spot scanning proton therapy.

PURPOSE: To determine the patient throughput and the overall efficiency of the spot scanning system by analyzing treatment time, equipment availability, and maximum daily capacity for the current spot scanning port at Proton Therapy Center Houston and to assess the daily throughput capacity for a hypothetical spot scanning proton therapy center. METHODS: At their proton therapy center, the authors have been recording in an electronic medical record system all treatment data, including disease site, number of fields, number of fractions, delivered dose, energy, range, number of spots, and number of layers for every treatment field. The authors analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the patient census, patient distribution as a function of the number of fields and total target volume, and equipment clinical availability. The duration of each treatment session from patient walk-in to patient walk-out of the spot scanning treatment room was measured for 64 patients with head and neck, central nervous system, thoracic, and genitourinary cancers. The authors retrieved data for total target volume and the numbers of layers and spots for all fields from treatment plans for a total of 271 patients (including the above 64 patients). A sensitivity analysis of daily throughput capacity was performed by varying seven parameters in a throughput capacity model. RESULTS: The mean monthly equipment clinical availability for the spot scanning port in April 2012-March 2015 was 98.5%. Approximately 1500 patients had received spot scanning proton therapy as of March 2015. The major disease sites treated in September 2012-August 2014 were the genitourinary system (34%), head and neck (30%), central nervous system (21%), and thorax (14%), with other sites accounting for the remaining 1%. Spot scanning beam delivery time increased with total target volume and accounted for approximately 30%-40% of total treatment time for the total target volumes exceeding 200 cm(3), which was the case for more than 80% of the patients in this study. When total treatment time was modeled as a function of the number of fields and total target volume, the model overestimated total treatment time by 12% on average, with a standard deviation of 32%. A sensitivity analysis of throughput capacity for a hypothetical four-room spot scanning proton therapy center identified several priority items for improvements in throughput capacity, including operation time, beam delivery time, and patient immobilization and setup time. CONCLUSIONS: The spot scanning port at our proton therapy center has operated at a high performance level and has been used to treat a large number of complex cases. Further improvements in efficiency may be feasible in the areas of facility operation, beam delivery, patient immobilization and setup, and optimization of treatment scheduling.

Idiopathic multicentric Castleman's disease: a systematic literature review.

BACKGROUND: Multicentric Castleman's disease describes a group of poorly understood lymphoproliferative disorders driven by proinflammatory hypercytokinaemia. Patients have heterogeneous clinical features, characteristic lymph node histopathology, and often deadly multiple organ dysfunction. Human herpesvirus 8 (HHV8) causes multicentric Castleman's disease in immunosuppressed patients. The cause of HHV8-negative multicentric Castleman's disease is idiopathic; such cases are called idiopathic multicentric Castleman's disease. An absence of centralised information about idiopathic multicentric Castleman's disease represents a major challenge for clinicians and researchers. We aimed to characterise clinical features of, treatments for, and outcomes of idiopathic multicentric Castleman's disease. METHODS: We did a systematic literature review and searched PubMed, the Cochrane database, and ClinicalTrials.gov from January, 1995, with keywords including "Castleman's disease" and "giant lymph node hyperplasia". Inclusion criteria were pathology-confirmed Castleman's disease in multiple nodes and minimum clinical and treatment information on individual patients. Patients with HHV8 or HIV infection or diseases known to cause Castleman-like histopathology were excluded. FINDINGS: Our search identified 626 (33%) patients with HHV8-negative multicentric Castleman's disease from 1923 cases of multicentric Castleman's disease. 128 patients with idiopathic multicentric Castleman's disease met all inclusion criteria for the systematic review. Furthermore, aggregated data for 127 patients with idiopathic multicentric Castleman's disease were presented from clinical trials, which were excluded from primary analyses because patient-level data were not available. Clinical features of idiopathic multicentric Castleman's disease included multicentric lymphadenopathy (128/128), anaemia (79/91), elevated C-reactive protein (65/79), hypergammaglobulinaemia (63/82), hypoalbuminaemia (57/63), elevated interleukin 6 (57/63), hepatomegaly or splenomegaly (52/67), fever (33/64), oedema, ascites, anasarca, or a combination (29/37), elevated soluble interleukin 2 receptor (20/21), and elevated VEGF (16/20). First-line treatments for idiopathic multicentric Castleman's disease included corticosteroids (47/128 [37%]), cytotoxic chemotherapy (47/128 [37%]), and anti-interleukin 6 therapy (11/128 [9%]). 49 (42%) of 116 patients failed first-line therapy, 2-year survival was 88% (95% CI 81-95; 114 total patients, 12 events, 36 censored), and 27 (22%) of 121 patients died by the end of their observed follow-up (median 29 months [IQR 12-50]). 24 (19%) of 128 patients with idiopathic multicentric Castleman's disease had a diagnosis of a separate malignant disease, significantly higher than the frequency expected in age-matched controls (6%). INTERPRETATION: Our systematic review provides comprehensive information about clinical features, treatment, and outcomes of idiopathic multicentric Castleman's disease, which accounts for at least 33% of all cases of multicentric Castleman's disease. Our findings will assist with prompt recognition, diagnostic criteria development, and effective management of the disease. FUNDING: None.

Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Disease Research.

Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in "omics" technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN's collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care.

Prevention of type 2 diabetes through lifestyle modification: is there a role for higher-protein diets?

Type 2 diabetes (T2D) incidence is increasing worldwide, driven by a rapidly changing environment and lifestyle and increasing rates of overweight and obesity. Prevention of diabetes is key and is most likely achieved through prevention of weight gain and/or successful long-term weight loss maintenance. Weight loss is readily achievable but there is considerable challenge in maintaining that weight loss over the long term. Lower-fat carbohydrate-based diets are widely used for T2D prevention. This is supported primarily by 3 successful long-term interventions, the US Diabetes Prevention Program, the Finnish Diabetes Prevention Study, and the Chinese Da Qing Study, but evidence is building in support of novel higher-protein (>20% of energy) diets for successful weight loss maintenance and prevention of T2D. Higher-protein diets have the advantage of having relatively low energy density, aiding longer-term appetite suppression, and preserving lean body mass, all central to successful weight loss and prevention of weight regain. Here, we review the carbohydrate-based intervention trials and present mechanistic evidence in support of increased dietary protein for weight loss maintenance and a possible novel role in prevention of dysglycemia and T2D.

Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.