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BACKGROUND/AIMS: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings. METHODS: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8+ T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts. RESULTS: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8+ T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice. CONCLUSION: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation.

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Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with 18F-fluoromisonidazole (18F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret 18F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus-positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 18F-FDG PET/CT and 134 18F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no 18F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of 18F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if 18F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUVmax was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement (κ = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement (κ = 0.86). Quantitative assessment with an estimated best SUVmax ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement (κ = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement (κ = 0.86). Conclusion: Nuclear medicine physicians without 18F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

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Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches, SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and systemic anti-tumor immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies.

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THOR-AV 5F, a modified THOR-5F dummy, was designed to represent both upright and reclined occupants in vehicle crashworthiness studies. The dummy was evaluated in four test conditions: a) 25° seatback, 15 km/h, b) 25° seatback, 32 km/h, c) 45° seatback, 15 km/h, d) 45° seatback, 32 km/h. The dummy's biomechanical responses were compared against those of postmortem human subjects (PMHS) tested in the same test conditions. The latest National Highway Traffic Safety Administration (NHTSA) BioRank method was used to provide a biofidelity ranking score (BRS) for each data channel in the tests to assess the dummy's biofidelity objectively. The evaluation was categorized into two groups: restraint system and dummy. In the four test conditions, the restraint system showed good biofidelity with BRS scores of 1.49, 1.47, 1.15, and 1.79, respectively. The THOR-AV 5F demonstrated excellent biofidelity in three test conditions: 25° seatback, 15 km/h (BRS = 0.76); 25° seatback, 32 km/h (BRS = 0.89); and 45° seatback, 32 km/h (BRS = 0.93). In the fourth test condition, 45° seatback, 15 km/h, the dummy demonstrated good biofidelity with a BRS score of 1.06. The dummy demonstrated good durability. No damage was identified with a full inspection conducted after the tests.

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PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

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Lung adenocarcinoma (ADC) is the most common non-small cell lung cancer. Surgical resection is the primary treatment for early-stage lung ADC while lung-sparing surgery is an alternative for non-aggressive cases. Identifying histopathologic subtypes before surgery helps determine the optimal surgical approach. Predominantly solid or micropapillary (MIP) subtypes are aggressive and associated with a higher likelihood of recurrence and metastasis and lower survival rates. This study aims to non-invasively identify these aggressive subtypes using preoperative 18F-FDG PET/CT and diagnostic CT radiomics analysis. We retrospectively studied 119 patients with stage I lung ADC and tumors ≤ 2 cm, where 23 had aggressive subtypes (18 solid and 5 MIPs). Out of 214 radiomic features from the PET/CT and CT scans and 14 clinical parameters, 78 significant features (3 CT and 75 PET features) were identified through univariate analysis and hierarchical clustering with minimized feature collinearity. A combination of Support Vector Machine classifier and Least Absolute Shrinkage and Selection Operator built predictive models. Ten iterations of 10-fold cross-validation (10 ×10-fold CV) evaluated the model. A pair of texture feature (PET GLCM Correlation) and shape feature (CT Sphericity) emerged as the best predictor. The radiomics model significantly outperformed the conventional predictor SUVmax (accuracy: 83.5% vs. 74.7%, p = 9e-9) and identified aggressive subtypes by evaluating FDG uptake in the tumor and tumor shape. It also demonstrated a high negative predictive value of 95.6% compared to SUVmax (88.2%, p = 2e-10). The proposed radiomics approach could reduce unnecessary extensive surgeries for non-aggressive subtype patients, improving surgical decision-making for early-stage lung ADC patients.

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A single-institution prospective pilot clinical trial was performed to demonstrate the feasibility of combining [177Lu]Lu-PSMA-617 radiopharmaceutical therapy (RPT) with stereotactic body radiotherapy (SBRT) for the treatment of oligometastatic castration-sensitive prostate cancer. Methods: Six patients with 9 prostate-specific membrane antigen (PSMA)-positive oligometastases received 2 cycles of [177Lu]Lu-PSMA-617 RPT followed by SBRT. After the first intravenous infusion of [177Lu]Lu-PSMA-617 (7.46 ± 0.15 GBq), patients underwent SPECT/CT at 3.2 ± 0.5, 23.9 ± 0.4, and 87.4 ± 12.0 h. Voxel-based dosimetry was performed with calibration factors (11.7 counts per second/MBq) and recovery coefficients derived from in-house phantom experiments. Lesions were segmented on baseline PSMA PET/CT (50% SUVmax). After a second cycle of [177Lu]Lu-PSMA-617 (44 ± 3 d; 7.50 ± 0.10 GBq) and an interim PSMA PET/CT scan, SBRT (27 Gy in 3 fractions) was delivered to all PSMA-avid oligometastatic sites, followed by post-PSMA PET/CT. RPT and SBRT voxelwise dose maps were scaled (α/ß = 3 Gy; repair half-time, 1.5 h) to calculate the biologically effective dose (BED). Results: All patients completed the combination therapy without complications. No grade 3+ toxicities were noted. The median of the lesion SUVmax as measured on PSMA PET was 16.8 (interquartile range [IQR], 11.6) (baseline), 6.2 (IQR, 2.7) (interim), and 2.9 (IQR, 1.4) (post). PET-derived lesion volumes were 0.4-1.7 cm3 The median lesion-absorbed dose (AD) from the first cycle of [177Lu]Lu-PSMA-617 RPT (ADRPT) was 27.7 Gy (range, 8.3-58.2 Gy; corresponding to 3.7 Gy/GBq, range, 1.1-7.7 Gy/GBq), whereas the median lesion AD from SBRT was 28.1 Gy (range, 26.7-28.8 Gy). Spearman rank correlation, ρ, was 0.90 between the baseline lesion PET SUVmax and SPECT SUVmax (P = 0.005), 0.74 (P = 0.046) between the baseline PET SUVmax and the lesion ADRPT, and -0.81 (P = 0.022) between the lesion ADRPT and the percent change in PET SUVmax (baseline to interim). The median for the lesion BED from RPT and SBRT was 159 Gy (range, 124-219 Gy). ρ between the BED from RPT and SBRT and the percent change in PET SUVmax (baseline to post) was -0.88 (P = 0.007). Two cycles of [177Lu]Lu-PSMA-617 RPT contributed approximately 40% to the maximum BED from RPT and SBRT. Conclusion: Lesional dosimetry in patients with oligometastatic castration-sensitive prostate cancer undergoing [177Lu]Lu-PSMA-617 RPT followed by SBRT is feasible. Combined RPT and SBRT may provide an efficient method to maximize the delivery of meaningful doses to oligometastatic disease while addressing potential microscopic disease reservoirs and limiting the dose exposure to normal tissues.

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PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.

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PURPOSE: To evaluate the yttrium-90 (90Y) activity distribution in biopsy tissue samples of the treated liver to quantify the dose with higher spatial resolution than positron emission tomography (PET) for accurate investigation of correlations with microscopic biological effects and to evaluate the radiation safety of this procedure. MATERIALS AND METHODS: Eighty-six core biopsy specimens were obtained from 18 colorectal liver metastases (CLMs) immediately after 90Y transarterial radioembolization (TARE) with either resin or glass microspheres using real-time 90Y PET/CT guidance in 17 patients. A high-resolution micro-computed tomography (micro-CT) scanner was used to image the microspheres in part of the specimens and allow quantification of 90Y activity directly or by calibrating autoradiography (ARG) images. The mean doses to the specimens were derived from the measured specimens' activity concentrations and from the PET/CT scan at the location of the biopsy needle tip for all cases. Staff exposures were monitored. RESULTS: The mean measured 90Y activity concentration in the CLM specimens at time of infusion was 2.4 ± 4.0 MBq/mL. The biopsies revealed higher activity heterogeneity than PET. Radiation exposure to the interventional radiologists during post-TARE biopsy procedures was minimal. CONCLUSIONS: Counting the microspheres and measuring the activity in biopsy specimens obtained after TARE are safe and feasible and can be used to determine the administered activity and its distribution in the treated and biopsied liver tissue with high spatial resolution. Complementing 90Y PET/CT imaging with this approach promises to yield more accurate direct correlation of histopathological changes and absorbed dose in the examined specimens.

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PURPOSE: To determine the mechanisms involved in partial volume radiation therapy (RT)-induced tumor response. METHODS AND MATERIALS: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and Lewis lung carcinoma (LLC cells; WT, Crispr/Cas9 Sting KO, and Atm KO) injected in the flank of C57Bl/6, cGAS, or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2 × 2 cm collimator on a microirradiator allowing precise irradiation. Tumors and blood were collected at 6, 24, and 48 hours post-RT and assessed for cytokine measurements. RESULTS: There is a significant activation of the cGAS/STING pathway in the hemi-irradiated tumors compared with control and to 100% exposed 67NR tumors. In the LLC model, we determined that an ATM-mediated noncanonical activation of STING is involved. We demonstrated that the partial exposure RT-mediated immune response is dependent on ATM activation in the tumor cells and on the STING activation in the host, and cGAS is dispensable. Our results also indicate that partial volume RT stimulates a proinflammatory cytokine response compared with the anti-inflammatory profile induced by 100% tumor volume exposure. CONCLUSIONS: Partial volume RT induces an antitumor response by activating STING, which stimulates a specific cytokine signature as part of the immune response. However, the mechanism of this STING activation, via the canonical cGAS/STING pathway or a noncanonical ATM-driven pathway, depends on the tumor type. Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade and other antitumor therapies.

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Pelvis and lumbar spine fractures occur in falls, motor vehicle crashes, and military combat events. They are attributed to vertical impact from the pelvis to the spine. Although whole-body cadavers were exposed to this vector and injuries were reported, spinal loads were not determined. While previous studies determined injury metrics such as peak forces using isolated pelvis or spine models, they were not conducted using the combined pelvis-spine columns, thereby not accounting for the interaction between the two body regions. Earlier studies did not develop response corridors. The study objectives were to develop temporal corridors of loads at the pelvis and spine and assess clinical fracture patterns using a human cadaver model. Vertical impact loads were delivered at the pelvic end to twelve unembalmed intact pelvis-spine complexes, and pelvis forces and spinal loads (axial, shear and resultant and bending moments) were obtained. Injuries were classified using clinical assessments from post-test computed tomography scans. Spinal injuries were stable in eight and unstable in four specimens. Pelvis injuries included ring fractures in six and unilateral pelvis in three, sacrum fractures in ten, and two specimens did not sustain any injuries to the pelvis or sacrum complex. Data were grouped based on time to peak velocity, and ± one standard deviation corridors about the mean of the biomechanical metrics were developed. Time-history corridors of loads at the pelvis and spine, hitherto not reported in any study, are valuable to assess the biofidelity of anthropomorphic test devices and assist validating finite element models.

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PURPOSE: Intraventricular compartmental radioimmunotherapy (cRIT) with 131-I-omburtamab is a potential therapy for recurrent primary brain tumors that can seed the thecal space. These patients often previously received external beam radiotherapy (EBRT) to a portion or full craniospinal axis (CSI) as part of upfront therapy. Little is known regarding outcomes after re-irradiation as part of multimodality therapy including cRIT. This study evaluates predictors of response, patterns of failure, and radiologic events after cRIT. METHODS: Patients with recurrent medulloblastoma or ependymoma who received 131-I-omburtamab on a prospective clinical trial were included. Extent of disease at cRIT initiation (no evidence of disease [NED] vs measurable disease [MD]) was assessed as associated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. RESULTS: All 27 patients (20 medulloblastoma, 7 ependymoma) had EBRT preceding cRIT: most (22, 81%) included CSI (median dose 2340 cGy, boost to 5400 cGy). Twelve (44%) also received EBRT at relapse as bridging to cRIT. There were no cases of radionecrosis. At cRIT initiation, 11 (55%) medulloblastoma and 3 (43%) ependymoma patients were NED, associated with improved PFS (p = 0.002) and OS (p = 0.048) in medulloblastoma. Most relapses were multifocal. With medium follow-up of 3.0 years (95% confidence interval, 1.8-7.4), 6 patients remain alive with NED. CONCLUSION: For patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis.

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Radiolabeled antibody treatment with 131I-omburtamab, administered intraventricularly into the cerebrospinal fluid (CSF) space, can deliver therapeutic absorbed doses to sites of leptomeningeal disease. Assessment of distribution and radiation dosimetry is a key element in optimizing such treatments. Using a theranostic approach, we performed pretreatment 131I-omburtamab imaging and dosimetric analysis in patients before therapy. Methods: Whole-body planar images were acquired 3 ± 1, 23 ± 2, and 47 ± 2 h after intracranioventricular administration of 75 ± 5 MBq of 131I-omburtamab via an Ommaya reservoir. Multiple blood samples were also obtained for kinetic analysis. Separate regions of interest (ROIs) were manually drawn to include the lateral ventricles, entire spinal canal CSF space, and over the whole body. Count data in the ROIs were corrected for background and physical decay, converted to activity, and subsequently fitted to an exponential clearance function. The radiation absorbed dose was estimated to the CSF, separately to the spinal column and ventricles, and to the whole body and blood. Biodistribution of the injected radiolabeled antibody was assessed for all patients. Results: Ninety-five patients were included in the analysis. Biodistribution showed prompt localization in the ventricles and spinal CSF space with low systemic distribution, noted primarily as hepatic, renal, and bladder activity after the first day. Using ROI analysis, the effective half-lives were 13 ± 11 h (range, 5-75 h) for CSF in the spinal column, 8 ± 3 h (range, 3-17 h) for ventricles, and 41 ± 11 (range, 23-81 h) for the whole body. Mean absorbed doses were 0.63 ± 0.38 cGy/MBq (range, 0.24-2.25 cGy/MBq) for CSF in the spinal column, 1.03 ± 0.69 cGy/MBq (range, 0.27-5.15 cGy/MBq) for the ventricular CSF, and 0.45 ± 0.32 mGy/MBq (range, 0.05-1.43 mGy/MBq) for the whole body. Conclusion: Pretherapeutic imaging with 131I-omburtamab allows assessment of biodistribution and dosimetry before the administration of therapeutic activity. Absorbed doses to the CSF compartments and whole body derived from the widely applicable serial 131I-omburtamab planar images had acceptable agreement with previously reported data determined from serial 124I-omburtamab PET scans.

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Increased interest in the airline industry to enhance occupant comfort and maximize seating density has prompted the design and installation of obliquely mounted seats in aircraft. Previous oblique whole-body sled tests demonstrated multiple failures, chiefly distraction-associated spinal injuries under oblique impacts. The present computational study was performed with the rationale to examine how oblique loading induces component level responses and associated injury occurrence. The age-specific human body model (HBM) was simulated for two oblique seating conditions (with and without an armrest). The boundary conditions consisted of a 16 g standard aviation crash pulse, 45 deg seat orientation, and with restrained pelvis and lower extremities. The overall biofidelity rating for both conditions ranged from 0.5 to 0.7. The validated models were then used to investigate the influence of pulse intensity and seat orientation by varying the pulse from 16 g to 8 g and seat orientation from 0 deg to 90 deg. A total of 12 parametric simulations were performed. The pulse intensity simulations suggest that the HBM could tolerate 11.2 g without lumbar spine failure, while the possibility of cervical spine failure reduced with the pulse magnitude <9.6 g pulse. The seat orientation study demonstrated that for all seat angles the HBM predicted failure in the cervical and lumbar regions at 16 g; however, the contribution of the tensile load and lateral and flexion moments varied with respect to the change in seat angle. These preliminary outcomes are anticipated to assist in formulating safety standards and in designing countermeasures for oblique seating configurations.

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Issue: Phenomenology has proven to be a very useful tool for medicine. Descriptive, first-person accounts of patient experiences can reveal new and unique insights. These insights can inform renewed approaches to medical education and practice. However, comparatively little research has been done on the other side of the clinical encounter. This leaves the lived experiences of doctors diagnosing and treating illness unaddressed and the ontological transformation of medical students through medical education unexplored. Evidence: This paper provides a phenomenological description of the clinical encounter and ontological transformation of the medical student into the doctor. I argue doctors have a unique ontology, rooted in the objectification of the patient, for which I use the term being-opposite-illness This is achieved, through phenomenological examination of my experiences as a medical student and through descriptions of three distinct types of face-to-face encounters: the basic encounter with the Other, the encounter with illness, and the clinical encounter, which I argue are all metaphysically distinct. Finally, textual analysis of popular first-person accounts from two doctors, Henry Marsh and Paul Kalanithi, provide an illustration of being-opposite-illness in clinical practice and how this ontological transformation occurs through medical education. Implications: Together, the phenomenology of the clinical encounter and textual analysis of Marsh and Kalanithi reveal clinical practice and medical education be an ontological transformative process. This paper attempts a new understanding of this experience of doctors by accounting for their unique ontology. In sum, I suggest being-opposite-illness can represent a new lens for analyzing the experience of doctors. Through this, I hope to promote new medical education and practice approaches.

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OBJECTIVE: The objective of the study was to investigate the difference between elderly and young occupant injury risks using human body finite element modeling in frontal impacts. METHODS: Two elderly male occupant models (representative age 70-80 years) were developed using the Global Human Body Consortium (GHBMC) 50th percentile as the baseline model. In the first elderly model (EM-1), material property changes were incorporated, and in the second elderly model (EM-2), material and anthropometric changes were incorporated. Material properties were based on literature. The baseline model was morphed to elderly anthropometry for EM-2. The three models were simulated in a frontal crash vehicle environment at 56 km/h. Responses from the two elderly and baseline models were compared with cadaver experimental data in thoracic, abdominal, and frontal impacts. Correlation and analysis scores were used for correlation with experimental data. The probabilities of head, neck, and thoracic injuries were assessed. RESULTS: The elderly models showed a good correlation with experimental responses. The elderly EM-1 had higher risk of head and brain injuries compared to the elderly EM-2 and baseline GHBMC models. The elderly EM-2 demonstrated higher risk of neck, chest, and abdominal injuries than the elderly EM-1 and baseline models. CONCLUSIONS: The study investigated injury risks of two elderly occupants and compared to a young occupant in frontal crashes. The change in the material properties alone (EM-1) suggested that elderly occupants may be vulnerable to a greater risk of head and thoracic injuries, whereas change in both anthropometric and material properties (EM-2) suggested that elderly occupants may be vulnerable to a greater risk of thoracic and neck injuries. The second elderly model results were in better agreement with field injury data from the literature; thus, both anthropometric and material properties should be considered when assessing the injury risks of elderly occupants. The elderly models developed in this study can be used to simulate different impact conditions and determine injury risks for this group of our population.

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Previous full body cadaver testing has shown that both obliquely oriented seats in survivable aircraft crashes and far-side oblique crashes in vehicles present distinctive occupant kinematics that are not yet well understood. Knowledge surrounding how these loading scenarios affect the lumbar spine is particularly lacking as there exists minimal research concerning oblique loading. The current study was created to evaluate a novel experimental method through comparison with existing literature, and to examine the impact of a static bending pre-load (posture) on the load-displacement response for the whole lumbar spine loaded in non-destructive axial distraction. T12-S1 lumbar spines were tested in tension to 4 mm of displacement while positioned in one of three pre-load postures. These postures were: the spine's natural, unloaded curvature (neutral), flexed forward (flexed), and combined flexion and lateral bending (oblique). Deviations from a neutral spine position were shown to significantly increase peak loads and tensile stiffness. The presence of a flexion pre-load caused statistically significant increases in tensile stiffness, tensile force, and bending moments. The addition of a lateral bending pre-load to an already flexed spine did not significantly alter the tensile response. However, the flexion moment response was significantly affected by the additional postural pre-load. This work indicates that the initial conditions of distraction loading significantly affect lumbar spine load response. Therefore, future testing that seeks to emulate crash dynamics of obliquely seated occupants must account for multi-axis loading.

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BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

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