Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells.

IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor ß chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.

Reduction in Chest CT Severity and Improved Hospital Outcomes in SARS-CoV-2 Omicron Compared with Delta Variant Infection.

Background The SARS-Cov-2 Omicron variant demonstrates rapid spread but reduced disease severity. Studies evaluating lung imaging findings of Omicron infection versus non-Omicron infection remain lacking. Purpose To compare the Omicron variant with the SARS-CoV-2 Delta variant according to their chest CT radiologic pattern, biochemical parameters, clinical severity, and hospital outcomes after adjusting for vaccination status. Materials and Methods This retrospective study included hospitalized adult patients with reverse transcriptase-polymerase chain reaction test results positive for SARS-CoV-2, with CT pulmonary angiography performed within 7 days of admission between December 1, 2021, and January 14, 2022. Multiple readers performed blinded radiologic analyses that included RSNA CT classification, chest CT severity score (CTSS) (range, 0 [least severe] to 25 [most severe]), and CT imaging features, including bronchial wall thickening. Results A total of 106 patients (Delta group, n = 66; Omicron group, n = 40) were evaluated (overall mean age, 58 years ± 18 [SD]; 58 men). In the Omicron group, 37% of CT pulmonary angiograms (15 of 40 patients) were categorized as normal compared with 15% (10 of 66 patients) of angiograms in the Delta group (P = .016). A generalized linear model was used to control for confounding variables, including vaccination status, and Omicron infection was associated with a CTSS that was 7.2 points lower than that associated with Delta infection (ß = -7.2; 95% CI: -9.9, -4.5; P < .001). Bronchial wall thickening was more common with Omicron infection than with Delta infection (odds ratio [OR], 2.4; 95% CI: 1.01, 5.92; P = .04). A booster shot was associated with a protective effect for chest infection (median CTSS, 5; IQR, 0-11) when compared with unvaccinated individuals (median CTSS, 11; IQR, 7.5-14.0) (P = .03). The Delta variant was associated with a higher OR of severe disease (OR, 4.6; 95% CI: 1.2, 26; P = .01) and admission to a critical care unit (OR, 7.0; 95% CI: 1.5, 66; P = .004) when compared with the Omicron variant. Conclusion The SARS-CoV-2 Omicron variant was associated with fewer and less severe changes on chest CT images compared with the Delta variant. Patients with Omicron infection had greater frequency of bronchial wall thickening but less severe disease and improved hospital outcomes when compared with patients with Delta infection. © RSNA, 2022 Online supplemental material is available for this article.

IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma.

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.

Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity.

Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.

An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.

NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.

Ten year real world experience with ultrafiltration for the management of acute decompensated heart failure.

Background: Randomized controlled trials (RCT) of ultrafiltration (UF) have demonstrated conflicting results regarding its efficacy and safety. Objective: We reviewed 10 years of data for adjustable UF during heart failure hospitalizations in a real world cohort. Methods: We performed a retrospective, single center analysis of 335 consecutive patients treated with adjustable rate UF using the CHF Solutions Aquadex Flex Flo System from 2009 to 2019. Results: Compared to previous RCTs investigating UF, our cohort was older, with worse renal impairment and more antecedent HF hospitalizations in the year preceding therapy. Mean fluid removal with UF was 14.6 l. Mean weight loss with UF was 15.6 lbs (range 0.2-57 lbs) and was sustained at 1-2 week follow-up. Mean creatinine change upon stopping UF, at discharge and follow-up (mean 30 days) was +0.11 mg/dl, +0.07 mg/dl and +0.11 mg/dl, respectively. HF rehospitalizations at 30 days, 90 days and 1 year were 12.4 %, 14.9 % and 27.3 % respectively. On average patients had 1.74 fewer hospitalizations for HF in the year following UF when compared to 12 months preceding UF. Major bleeding defined as requiring discontinuation of anticoagulation occurred in 3.6 % of patients. Conclusions: Compared with previous UF trials, our study demonstrates that UF compares favorably for HF rehospitalizations, renal function response, and weight/volume loss. Importantly, our real world experience allowed for the adjustment of UF rate during therapy and we believe this is a major contributor to our favorable outcomes. In clinical practice, UF can be a safe and effective strategy for decongestion.

Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8+ T cell clone size and cytotoxicity.

The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8+ T cells. How sensitivity to ICB varies across CD8+ T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8+ T cell clones, identify baseline markers of CD8+ T cell clonal sensitivity, and chart how CD8+ T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8+ T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8+ T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8+ effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8+ T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8+ immune landscape in determining ICB response in metastatic melanoma.

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Cardiopulmonary resuscitation discussions with patients admitted to acute oncology wards: A national audit of current practice.

OBJECTIVES: To map current practice regarding discussions around resuscitation across England and Scotland in patients with cancer admitted acutely to hospital and to demonstrate the value of medical students in rapidly collecting national audit data. METHODS: Collaborators from the Macmillan medical student network collected data from 251 patient encounters across eight hospitals in England and Scotland. Data were collected to identify whether discussion regarding resuscitation was documented as having taken place during inpatient admission to acute oncology. As an audit standard, it was expected that all patients should be invited to discuss resuscitation within 24 hr of admission. RESULTS: Resuscitation discussions were had in 43.1% of admissions and of these 64.0% were within 24 hr; 27.6% of all admissions. 6.5% of patients had a "do not attempt resuscitation" order prior to admission with a difference noted between patients receiving palliative and curative treatment (8.5% and 0.39%, respectively, p < .05). Discussions regarding escalation of care took place in only 29.3% of admissions. CONCLUSIONS: These data highlight deficiencies in the number of discussions regarding resuscitation that are being conducted with cancer patients that become acutely unwell. It also demonstrates the value of medical student collaboration in rapidly collecting national audit data.

Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma.

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.

Tumor heterogeneity: does it matter?

Introduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter? Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments. Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field.

Is microwave ablation an alternative to stereotactic ablative body radiotherapy in patients with inoperable early-stage primary lung cancer?

A best evidence topic was written according to a structured protocol. The question addressed was: in patients with inoperable early-stage primary lung cancer does microwave ablation (MWA) or stereotactic ablative body radiotherapy (SBRT) achieve improved outcomes in terms of local control, recurrence, survival and complications? Altogether, more than 550 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. No single study directly compared the effects of MWA with SBRT. However, the best available evidence for MWA (7 studies) was compared to that for SBRT (5 studies). The range of 3-year survival reported for MWA was 29.2-84.7%, compared with 42.7-63.5% for SBRT. The range of median survival was 35-60 months for MWA and 32.6-48 months for SBRT. This suggests similar outcomes between these two 2 techniques. Different side-effect profiles were observed between techniques with MWA associated with pneumothorax and fever and SBRT most commonly causing radiation pneumonitis and rib fractures. The evidence base for MWA is less than that for SBRT and is heterogenous in terms of participants and technical design. However, within these limitations, we conclude that MWA appears comparable with SBRT in terms of local control and survival rates.

Development of a best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours in the UK.

Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK.

Effects of economic downturns on child mortality: a global economic analysis, 1981-2010.

OBJECTIVES: To analyse how economic downturns affect child mortality both globally and among subgroups of countries of variable income levels. DESIGN: Retrospective observational study using economic data from the World Bank's Development Indicators and Global Development Finance (2013 edition). Child mortality data were sourced from the Institute for Health Metrics and Evaluation. SETTING: Global. PARTICIPANTS: 204 countries between 1981 and 2010. MAIN OUTCOME MEASURES: Child mortality, controlling for country-specific differences in political, healthcare, cultural, structural, educational and economic factors. RESULTS: 197 countries experienced at least 1 economic downturn between 1981 and 2010, with a mean of 7.97 downturns per country (range 0-21; SD 0.45). At the global level, downturns were associated with significant (p<0.0001) deteriorations in each child mortality measure, in comparison with non-downturn years: neonatal (coefficient: 1.11, 95% CI 0.855 to 1.37), postneonatal (2.00, 95% CI 1.61 to 2.38), child (2.93, 95% CI 2.26 to 3.60) and under 5 years of age (5.44, 95% CI 4.31 to 6.58) mortality rates. Stronger (larger falls in the growth rate of gross domestic product/capita) and longer (lasting 2 years rather than 1) downturns were associated with larger significant deteriorations (p<0.001). During economic downturns, countries in the poorest quartile experienced ∼1½ times greater deterioration in neonatal mortality, compared with their own baseline; a 3-fold deterioration in postneonatal mortality; a 9-fold deterioration in child mortality and a 3-fold deterioration in under-5 mortality, than countries in the wealthiest quartile (p<0.0005). For 1-5 years after downturns ended, each mortality measure continued to display significant deteriorations (p<0.0001). CONCLUSIONS: Economic downturns occur frequently and are associated with significant deteriorations in child mortality, with worse declines in lower income countries.

Value of Supraregional Multidisciplinary Review for the Contemporary Management of Testicular Tumors.

PURPOSE: Testicular cancers are an uncommon and highly curable group of tumors that are typically managed by specialist multidisciplinary teams (MDTs). Although recent guidelines have emphasized the importance of tumor prognostic factors in predicting recurrence and personalizing therapy in early-stage disease, the role of central pathology review in determining these factors is unclear. PATIENTS AND METHODS: We compared the referral histopathology reports with those obtained after expert central review for all cases reviewed by the UK Thames Valley Cancer Network testicular tumor MDT from August 2004 to September 2012. For cases in which the findings differed, we recorded the effect of the alteration on the estimates of patient prognosis and predicted clinical management using international (European Society of Medical Oncology [ESMO]) and local guidelines. RESULTS: The histopathology reports were altered after central review in 129 of 465 cases (27.7%) referred to the testicular tumor MDT during the study period. These resulted in changes in the estimation of prognosis for 42 patients (9.0% total), with a predicted affect on management according to the ESMO guidelines in 30 cases (6.5%). These proportions were broadly similar for both seminoma and nonseminoma, although the reasons for the discrepancies differed between the 2 (principally errors in categorization of rete testis invasion in seminoma and of lymphovascular invasion in nonseminoma). Changes to the tumor type were uncommon (2 cases). CONCLUSION: Central MDT review results in frequent, clinically relevant alterations to testicular tumor histopathology reports for testicular tumors. The results of our study demonstrate the importance of specialist MDTs to inform patient-centered care and ensure best practice in the management of these uncommon cancers.

Unemployment, public-sector healthcare expenditure and colorectal cancer mortality in the European Union: 1990-2009.

OBJECTIVES: We examined the association between unemployment and government spending on healthcare with colorectal cancer mortality. METHODS: Retrospective observational study using data from the World Bank and WHO. Multivariate regression analysis was used, controlling for country-specific differences in infrastructure and demographics. RESULTS: A 1 % increase in unemployment was associated with a significant increase in colorectal cancer mortality in both men and women [men: coefficient (R) = 0.0995, 95 % confidence interval (CI) 0.0132-0.1858, P = 0.024; women: R = 0.0742, 95 % CI 0.0160-0.1324, P = 0.013]. A 1 % increase in government spending on healthcare was associated with a statistically significant decrease in colorectal cancer mortality across both sexes (men: R = -0.4307, 95 % CI -0.6057 to -0.2557, P < 0.001; women: R = -0.2162, 95 % CI -0.3407 to -0.0917, P = 0.001). The largest changes in mortality occurred 3-4 years following changes in either economic variable. CONCLUSIONS: Unemployment rises are associated with a significant increase in colorectal cancer mortality, whilst government healthcare spending rises are associated with falling mortality. This is likely due, in part, to reduced access to healthcare services and has major implications for clinicians and policy makers alike.

Use of a machine learning algorithm to classify expertise: analysis of hand motion patterns during a simulated surgical task.

PURPOSE: To test the hypothesis that machine learning algorithms increase the predictive power to classify surgical expertise using surgeons' hand motion patterns. METHOD: In 2012 at the University of North Carolina at Chapel Hill, 14 surgical attendings and 10 first- and second-year surgical residents each performed two bench model venous anastomoses. During the simulated tasks, the participants wore an inertial measurement unit on the dorsum of their dominant (right) hand to capture their hand motion patterns. The pattern from each bench model task performed was preprocessed into a symbolic time series and labeled as expert (attending) or novice (resident). The labeled hand motion patterns were processed and used to train a Support Vector Machine (SVM) classification algorithm. The trained algorithm was then tested for discriminative/predictive power against unlabeled (blinded) hand motion patterns from tasks not used in the training. The Lempel-Ziv (LZ) complexity metric was also measured from each hand motion pattern, with an optimal threshold calculated to separately classify the patterns. RESULTS: The LZ metric classified unlabeled (blinded) hand motion patterns into expert and novice groups with an accuracy of 70% (sensitivity 64%, specificity 80%). The SVM algorithm had an accuracy of 83% (sensitivity 86%, specificity 80%). CONCLUSIONS: The results confirmed the hypothesis. The SVM algorithm increased the predictive power to classify blinded surgical hand motion patterns into expert versus novice groups. With further development, the system used in this study could become a viable tool for low-cost, objective assessment of procedural proficiency in a competency-based curriculum.

A low-cost surgical application of additive fabrication.

OBJECTIVE: This study was used to test the feasibility of using additive fabrication techniques 3-dimensional (3D) printing to create personalized/patient-specific hepatic 3D physical models from clinical radiology studies for surgical resident education. DESIGN: Patient-specific imaging data from either computed tomography or magnetic resonance imaging scans, in Digital Imaging and Communications in Medicine format, were rendered and manipulated with computer software, translating the medical imaging data sets into useful 3D geometry files in stereo lithography format for 3D printing. A commercial third party was used to print the 3D models in laser sintered nylon, which provided access to expensive, industrial-grade, high-resolution 3-D printers at a low cost. RESULTS: Multiple patient-specific preoperative 3D physical models were printed of portal and hepatic venous anatomy at a cost of less than $100 per model. CONCLUSION: Current 3D printing techniques can be used to create low-cost personalized/patient-specific hepatic 3D models from clinical radiology studies for surgical resident education.