Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Capsular distension in high-energy femoral shaft fractures is associated with occult femoral neck fracture: a preliminary retrospective comparative study.

OBJECTIVES: To determine the association between hip capsular distension, the computed tomography (CT) capsular sign, and lipohemarthrosis as they relate to occult femoral neck fracture (FNF) in the setting of ipsilateral femoral shaft fracture (FSF). DESIGN: Retrospective comparative study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Two hundred and forty-two patients with high-energy FSF and no evidence of FNF on preoperative radiographs and pelvis CT. All patients were stabilized with non-reconstruction style nails. INTERVENTION: Pelvis CT scans were examined for hip capsular distension irrespective of the other side, differing side-to-side measurements of capsular distension (i.e., the CT capsular sign), and lipohemarthrosis. MAIN OUTCOME MEASUREMENTS: FNF was observed for on postoperative radiographs. Relative risk (RR), number needed to treat (NNT), sensitivity (SN), and specificity (SP) were determined. RESULTS: Fifty-eight patients (24.0%) had capsular distension. Forty-two patients (17.4%) had differing capsular measurements (i.e., the CT capsular sign), and 16 (6.6%) had symmetrical distension from bilateral hip effusions. Eight patients (3.3%) had lipohemarthrosis. Four FNFs (1.7%) were identified. Three patients had capsular distension, 2 had CT capsular signs, and 1 had lipohemarthrosis. The last patient had no CT abnormalities. Only capsular distension (RR = 10, CI = 1.001-90, P = 0.049; SN = 75%, SP = 77%; NNT = 22) and lipohemarthrosis (RR = 23, CI = 1.6-335, P = 0.022; SN = 50%, SP = 96%; NNT = 8) were associated with occult FNF. CONCLUSIONS: Capsular distension is associated with FNF irrespective of the contralateral hip. Preemptive stabilization using a reconstruction nail could be considered in the setting of capsular distension or lipohemarthrosis to prevent displacement of an occult FNF. LEVEL OF EVIDENCE: Diagnostic Level III.

Does Chemo-Radiotherapy Improve Survival Outcomes vs. Radiotherapy Alone for High-Grade cT1 Urothelial Carcinoma of the Bladder?

BACKGROUND: Non-muscle invasive bladder cancer (non-MIBC) that is high-grade and confined to the lamina propria (HGT1) often has an aggressive clinical course. Currently, there is limited data on the comparative effectiveness of RT vs. CRT for HGT1 non-MIBC. We hypothesized that CRT would be associated with improved overall survival (OS) vs. RT in HGT1 bladder cancer. METHODS: Patients diagnosed with HGT1 non-MIBC, and treated with transurethral resection of bladder tumor followed by either treatment with RT alone or CRT, were identified in the National Cancer Database. Inverse probability of treatment weighting (IPTW) was employed and weight-adjusted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios. OS was the primary endpoint, and was estimated using the Kaplan-Meier method and log-rank tests. RESULTS: A total of 259 patients with HGT1 UC were treated with: (i) RT alone (n = 123) or (ii) CRT (n = 136). Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone (Hazard Ratio [HR]: 0.62, 95% Confidence Interval (95% CI): 0.44-0.88, P = .007). Four-year OS for the CRT vs. RT alone was 36% and 19%, respectively (log-rank P <.008). CONCLUSION: For patients with HGT1 bladder cancer, concurrent CRT was associated with improved OS compared with radiation alone in a retrospective cohort. These results are hypothesis-generating. The NRG is currently developing a phase II randomized clinical trial comparing CRT to other novel, bladder preservation strategies.

Unlocking the Power of ChatGPT, Artificial Intelligence, and Large Language Models: Practical Suggestions for Radiation Oncologists.

Recent advances in artificial intelligence (AI), such as generative AI and large language models (LLMs), have generated significant excitement about the potential of AI to revolutionize our lives, work, and interaction with technology. This article explores the practical applications of LLMs, particularly ChatGPT, in the field of radiation oncology. We offer a guide on how radiation oncologists can interact with LLMs like ChatGPT in their routine clinical and administrative tasks, highlighting potential use cases of the present and future. We also highlight limitations and ethical considerations, including the current state of LLMs in decision making, protection of sensitive data, and the important role of human review of AI-generated content.

p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy.

Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. SIGNIFICANCE: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design. This article is highlighted in the In This Issue feature, p. 1275.

The Association of Radiation Dose With Overall Survival for Patients Treated With Prostate Stereotactic Body Radiation Therapy.

Introduction Stereotactic body radiation therapy (SBRT) for prostate adenocarcinoma (PCa) has demonstrated excellent biochemical recurrence-free survival, with studies showing improved BRFS with higher-dose SBRT. However, current studies have been underpowered to evaluate the relationship of SBRT dose to overall survival (OS). In this retrospective study using the National Cancer Database (NCDB), we hypothesize that, given the low alpha/beta ratio of PCa, a relatively small increase in the dose-per-fraction would be associated with improved survival outcomes for intermediate-risk PCa (IR-PCa) comparing 36.25 Gy/5 fx [biologically equivalent dose (BEDα/ß = 1.5 = 211.46 Gy vs. 35 Gy (BED1.5 = 198.33 Gy)]. Materials and methods We queried records from the NCDB from 2005 to 2015 for men receiving prostate SBRT for IR-PCa (n=2673). 82% were treated using either 35 Gy/5 fx or 36.25 Gy/5 fx. We compared OS in men receiving 35 Gy versus 36.25 Gy. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances. Unweighted- and weighted-multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios, accounting for age, race, Charlson-Deyo comorbidity score, treatment facility type, prostate-specific antigen (PSA), clinical T-stage, Gleason Score, and use of androgen deprivation therapy (ADT). Kaplan-Meier analysis was performed. Results Seven hundred and eighty men (35%) were treated with 35 Gy/5 fx and 1434 men (65%) were treated with 36.25 Gy/5 fx (n=2214). Compared to 35 Gy, treatment with 36.25 Gy was associated with significantly improved OS (hazard ratio [HR]: 0.61 [95% CI: 0.43-0.89], P=0.009) on MVA. On Kaplan-Meier analysis, 36.25 Gy was associated with improved survival (p=0.034), with a five-year OS of 92% and 88%, respectively. Conclusions In a multi-institutional retrospective database of 2,214 IR patients treated with prostate SBRT, a prescription dose of 36.25 Gy/5 fx was associated with improved OS vs. 35 Gy/5 fx. Results are hypothesis-generating but do lend support to the current National Comprehensive Cancer Network (NCCN) guidelines that the minimum recommended dose for prostate SBRT is 36.25 Gy/5 fx.

Effect of histology on stereotactic body radiotherapy for non-small cell lung cancer oligometastatic pulmonary lesions.

Background: Stereotactic body radiotherapy (SBRT) is commonly used to provide targeted treatment to metastatic lung disease. Investigation is needed to understand the influence of histology on treatment outcomes. We report how tumor histology affects local control (LC) in a cohort of patients with non-small cell lung cancer (NSCLC) receiving SBRT for oligometastatic and recurrent pulmonary lesions. Methods: Patients who received SBRT to recurrent or oligometastatic NSCLC pulmonary lesions from 2015-2019 at our institution were included in this retrospective cohort study. Minimum follow-up was 2 months. Kaplan-Meier (KM) analysis was performed to assess local progression-free survival (LPFS). Local failure cumulative incidence curves using death as a competing risk factor were also generated. Results: A total of 147 treated lesions from 83 patients were included: 95 lesions from 51 patients with lung adenocarcinoma and 52 lesions from 32 patients with lung squamous cell carcinoma (SqCC). Median follow-up was 23 [interquartile range (IQR): 9.5-44.5] months for adenocarcinoma, and 11.5 (6-32.25) months for SqCC. Two-year LC was 89% for adenocarcinoma and 77% for SqCC (P=0.04). Median overall survival (OS) was 24.5 (10-46.25) months for adenocarcinoma and 14.5 (7.75-23.25) months for SqCC. Adenocarcinoma had improved LPFS over SqCC (P=0.014). SqCC was associated with increased local failure risk that approached statistical significance (P=0.061) with death as a competing risk. Overall toxicity incidence was 8.2% with no G3+ toxicities. Conclusions: For SBRT-treated oligometastatic or recurrent NSCLC pulmonary lesions, adenocarcinoma histology is associated with improved 2-year LC and LPFS compared to SqCC and reduced incidence of local recurrence (LR) with death as a competing risk.

Durability of sustained virological response to glecaprevir/pibrentasvir and resistance development: A long-term follow-up study.

BACKGROUND AND AIMS: This study aimed to determine durability of sustained virologic response (SVR) in hepatitis C virus-infected participants treated with glecaprevir- and/or pibrentasvir-containing regimens. METHODS: M13-576, a rollover study, evaluated the durability of SVR in a follow-up period of approximately 3 years after hepatitis C virus genotype 1-6-infected participants received a glecaprevir- and/or pibrentasvir-containing regimen in previous phase 2/3 clinical trials. The primary efficacy endpoint was the percentage of participants maintaining SVR and the percentage of participants experiencing relapse or reinfections. Resistance-associated substitutions and safety outcomes related to liver progression were also assessed. RESULTS: Of 384 participants enroled, 377 participants were included in the as-observed population and 287 participants completed the study. In prior studies, 99.7% (376/377) of participants achieved SVR12; of those, an observed 99.5% (374/376) and 100% (286/286) completing the study, maintained SVR. After non-responder imputation of missing data, 286/376 participants (76%) maintained SVR. The participant previously not achieving SVR was a treatment-experienced male with compensated cirrhosis who had NS3 and NS5A substitutions at enrolment, which remained detectable for 12 months. Of the two participants not maintaining SVR, one was re-infected and one experienced late relapse at post-treatment week 60. Five participants (all with a fibrosis stage ≥F3) had hepatocellular carcinoma. No events were deemed related to glecaprevir/pibrentasvir. CONCLUSIONS: Glecaprevir/pibrentasvir demonstrated long-term durability of efficacy after SVR12 was achieved. Hepatic-related decompensation events were not seen. Owing to low incidence of virologic failure, conclusions were not drawn on persistence of resistance-associated substitutions.

First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.

Survival Outcomes in Men with Unfavorable Intermediate-Risk and High-Risk Prostate Cancer Treated with Prostate-Only versus Whole Pelvic Radiation Therapy.

PURPOSE: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy. Treatment is frequently intensified by electively treating the pelvic lymph nodes (LNs) with whole pelvis radiotherapy (WPRT), but practice patterns and the benefits of WPRT are not well defined. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy. MATERIALS AND METHODS: National Cancer Database records of men diagnosed between 2008-2015 with UIR-PCa or HR-PCa and treated with prostate EBRT±androgen deprivation therapy (72-86.4 Gy) with (15,175) or without (13,549) WPRT were reviewed. Risk of LN involvement was calculated using the Memorial Sloan Kettering Cancer Center nomogram. Measured confounders were balanced with inverse probability of treatment weighting and OS hazard ratios (HRs) were generated using multivariable Cox regression. RESULTS: Of the men, 53% received WPRT. Every 1% increase in risk of LN involvement correlated with a 1% increase in risk of death (p <0.001). WPRT trended toward improved OS in all men with UIR-PCa and HR-PCa (HR: 0.95 [95% CI: 0.90-1.006], p=0.055). WPRT correlated with improved OS in men with Gleason 9 and 10 disease (HR: 0.87 [0.78-0.98], p=0.02) or risk of LN involvement ≥10% (HR: 0.93 [0.87-0.99], p=0.03). CONCLUSIONS: Men with higher LN risk scores and Gleason grade benefited from WPRT. These results complement the recent POP-RT randomized trial in mostly positron emission tomography/computerized tomography-staged patients, demonstrating that a more heterogeneous population of men staged without functional imaging benefits from WPRT.

Recursive Partitioning Analysis for Local Control Achieved With Stereotactic Body Radiation Therapy for the Liver, Spine, or Lymph Nodes.

PURPOSE: This study aims to develop a local control risk stratification using recursive partitioning analysis (RPA) for patients receiving stereotactic body radiation therapy (SBRT) for metastatic cancer. METHODS AND MATERIALS: A single institutional database of 397 SBRT treatments to the liver, spine, and lymph nodes was constructed. All treatments required imaging follow-up to assess for local control. Cox proportional hazards analysis was implemented before the decision tree analysis. The data were split into training (70%), validation (10%), and testing (20%) sets for RPA to optimize the training set. RESULTS: In the study, 361 treatments were included in the local control analysis. Two-year local control was 71%. A decision tree analysis was used and the resulting model demonstrated 93.10% fidelity for the validation set and 87.67% for the test set. RPA class 3 was composed of patients with non-small cell lung cancer (NSCLC) primary tumors and treatment targets other than the cervical, thoracic, and lumbar spines. RPA class 2 included patients with primary cancers other than NSCLC or breast and treatments targets of the sacral spine or liver. RPA class 1 consisted of all other patients (including lymph node targets and patients with primary breast cancer). Classes 3, 2, and 1 demonstrated 3-year local controls rates of 29%, 50%, and 83%, respectively. On subgroup analysis using the Kaplan-Meier method, treatments for lymph nodes and primary ovarian disease demonstrated improved local control relative to other treatment targets (P < .005) and primary disease sites (P < .005), respectively. CONCLUSIONS: A local control risk stratification model for SBRT to sites of metastatic disease was developed. Treatment target and primary tumor were identified as critical factors determining local control. NSCLC primary lesions have increased local failure for targets other than the cervical, thoracic, or lumbar spines, and improved local control was identified for lymph node sites and breast or ovarian primary tumors.

Integrating imaging and RNA-seq improves outcome prediction in cervical cancer.

Approaches using a single type of data have been applied to classify human tumors. Here we integrate imaging features and transcriptomic data using a prospectively collected tumor bank. We demonstrate that increased maximum standardized uptake value on pretreatment 18F-fluorodeoxyglucose-positron emission tomography correlates with epithelial-to-mesenchymal transition (EMT) gene expression. We derived and validated 3 major molecular groups, namely squamous epithelial, squamous mesenchymal, and adenocarcinoma, using prospectively collected institutional (n = 67) and publicly available (n = 304) data sets. Patients with tumors of the squamous mesenchymal subtype showed inferior survival outcomes compared with the other 2 molecular groups. High mesenchymal gene expression in cervical cancer cells positively correlated with the capacity to form spheroids and with resistance to radiation. CaSki organoids were radiation-resistant but sensitive to the glycolysis inhibitor, 2-DG. These experiments provide a strategy for response prediction by integrating large data sets, and highlight the potential for metabolic therapy to influence EMT phenotypes in cervical cancer.

A single institutional experience with central lung stereotactic body radiation therapy demonstrating encouraging results with increased inter-fraction time.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an effective treatment modality for non-small cell lung cancer (NSCLC); however, there are concerns regarding potential toxicity for centrally located tumors. METHODS: This retrospective study considered patients with SBRT for central lung NSCLC (defined as a tumor within 2 cm of any mediastinal critical structure). The institutional protocol was that patients with central tumors received SBRT less frequently than daily-generally once or twice weekly. RESULTS: A total of 115 patients with 148 lesions were treated with SBRT to a median 45 [5-60] Gy in 4 [1-5] fractions over a median 5.3 [0-18] days. Many patients treated with this method presented with advanced disease: 58 treatments involved nodal targets, and 42 had stage 3 disease. 52% of patients had chronic obstructive pulmonary disease (COPD), and only 49% had a biopsy, often due to concerns regarding other medical comorbidities. Rates of prior chemotherapy, thoracic surgery, and thoracic radiotherapy were 32%, 21%, and 49%, respectively. Via the Kaplan-Meier method, 2-year overall survival was 65%, and 2-year local control was 77%. Two-year local-progression free survival was 53%, and 2-year progression-survival was 48%. Treatments for stage 3 disease had an impressive 82% 2-year local control that was comparable to early stage treatments. Patients with stage 3 disease had a 2-year overall survival of 59%, which trended towards decreased overall survival compared to early stage patients. There were 13 grade 1 (9%) and 14 grade 2 (9%) toxicities. There were no reported grade ≥3 acute or late toxicities and only 3 cases of pneumonitis. CONCLUSIONS: Our series demonstrates encouraging local control with low rates of toxicity for central lung SBRT, including many stage 3 patients. This may be the result of the relatively large inter-fraction interval. This interval may allow for greater tumor effects (such as reoxygenation) and improved tolerance from normal tissues.

Comparison of aspiration-first versus stentriever-first techniques in performing mechanical thrombectomy for large vessel occlusions.

BACKGROUND: Both stentriever and direct-aspiration thrombectomy effectively treat large-vessel occlusions. However, data are limited comparing clinical outcomes after aspiration-first versus stentriever-assisted aspiration for thrombectomy. METHODS: A retrospective cohort study compared procedure times and radiographic outcomes after two mechanical thrombectomy techniques (aspiration first or stentriever). To minimize bias and variability inherent to multi-operator series, we assessed consecutive patients with cerebrovascular occlusions treated by a single surgeon during a 1 year period at two stroke centers. Expanded Thrombolysis in Cerebral Infarction (eTICI) grades were assessed by an investigator blinded to treatment. RESULTS: Data from 93 patients (median age 70 years) were analyzed: 73 patients (78.5%) were treated with a strentriever-first strategy and 20 (21.5%) were treated with aspiration first, with stentriever rescue therapy required in only three of these cases following unsuccessful aspiration. There were no significant differences in patient demographics, sites of occlusion, or rates of tandem occlusions between aspiration-first and stentriever-assisted groups (p≥0.36). The rate of first-pass eTICI ≥2b was 75.0% (15/20) for aspiration-first and 52.1% (38/73) for strentriever-first groups (p=0.07), while the rate of final eTICI ≥2b was 100% (20/20) and 82.2% (60/72), respectively (p=0.04). The aspiration-first technique was associated with procedural times ≤25 min in a multivariable analysis (adjusted OR 4.77, 95% CI 1.15 to 18.39; p=0.03). CONCLUSIONS: In this single-surgeon series, an aspiration-first technique was associated with a statistically significant improvement in eTICI outcomes and faster procedure times compared with stentriever-assisted aspiration. Further prospective studies are necessary to minimize selection bias inherent in this study design.

Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G.

BACKGROUND AND AIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS: PHx was performed on C57BL/6 mice lacking GHR (Ghr-/- ), disabled for all GH-dependent Janus kinase 2 signaling (Box1-/- ), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391-/- ), and wild-type littermates. C57BL/6 Ghr-/- mice showed striking mortality within 48 hours after PHx, whereas Box1-/- or Ghr391-/- mice survived with normal liver regeneration. Ghr-/- mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr-/- backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CONCLUSIONS: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.

A comparison of stereotactic body radiation therapy for metastases to the sacral spine and treatment of the thoracolumbar spine.

Background: This study compares the outcomes of stereotactic body radiation therapy (SBRT) for sacral and thoracolumbar spine metastases. Methods: This analysis considered each sacral spine SBRT treatment at a single institution and a cohort of consecutive thoracolumbar treatments. Results: 28 patients with 35 sacral treatments and 41 patients with 49 thoracolumbar treatments were included. Local control was 63% and 90%, respectively. The sacral cohort contained more lesions with ≥2 vertebrae and epidural and paraspinal involvement. Sacral patients had larger treatment volumes, increased rates of subsequent SBRT, decreased propensity for pain improvement, and decreased local control (p=0.02 on Kaplan-Meier analysis). Multivariate analysis demonstrated that PTV > 50 cc and epidural involvement were correlated with decreased local control. No cases had grade ≥3 toxicity. Conclusion: SBRT for sacral spine metastases is a distinct disease process than metastases to the thoracolumbar spine, resulting in lower rates of local control and pain improvement.

Stereotactic body radiation therapy for empirically treated hypermetabolic lung lesions: a single-institutional experience identifying the Charlson score as a key prognostic factor.

BACKGROUND: Though pathologic evidence for non-small cell lung cancer (NSCLC) is preferred, many patients do not receive a biopsy prior to treatment with stereotactic body radiation therapy (SBRT). This study seeks to analyze the overall survival (OS), local control, and toxicity rates for such patients. METHODS: This retrospective review included patients empirically treated with SBRT for presumed non-metastatic NSCLC at a single institution. Inclusion criteria included a hypermetabolic pulmonary lesion noted on positron emission tomography (PET) imaging but no pathological evidence of NSCLC. Patients with another known metastatic tumor were excluded. Statistical analysis was conducted with Cox proportional hazards analysis, univariate analysis, and the Kaplan-Meier method. RESULTS: Ninety-one treatments in 90 unique patients met inclusion criteria. Patients were a median 77.9 years at the start of treatment and had a median Charlson score of 7. Pre-treatment standardized uptake value (SUV) was a median 4.5 and 1.5 after treatment. At a median follow-up of 12.9 months, 36-month local control of 91.3% was achieved. Twenty-four-month OS and progression-free survival were 65.4% and 44.8%, respectively. On univariate analysis, biologically effective dose (BED) ≥120 Gy was predictive of improved OS (P=0.001), with 36-month OS of 50.5% for patients with BED ≥120 Gy and only 31.6% for patients with BED <120 Gy. On Kaplan-Meier analysis, Charlson score ≥9 was predictive of decreased OS (P=0.04), and BED ≥120 Gy trended towards improved OS (P=0.08). Thirty-two cases of grade <3 toxicity were reported, and only two cases of grade 3 morbidity (fatigue) were noted. CONCLUSIONS: Local control rates for empiric SBRT treatment for hypermetabolic, non-metastatic NSCLC are similar to those for biopsied NSCLC. OS is primarily dependent on a patient's overall health status, which can be accurately assessed with the Charlson score. BED ≥120 Gy may also contribute to improved OS.

A single-institutional experience with low dose stereotactic body radiation therapy for liver metastases.

AIM: This study reports a single-institutional experience treating liver metastases with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: 107 patients with 169 lesions were assessed to determine factors predictive for local control, radiographic response, and overall survival (OS). Machine learning techniques, univariate analysis, and the Kaplan-Meier method were utilized. RESULTS: Patients were treated with a relatively low median dose of 30 Gy in 3 fractions. Fractions were generally delivered once weekly. Median biologically effective dose (BED) was 60 Gy, and the median gross tumor volume (GTV) was 12.16 cc. Median follow-up was 7.36 months. 1-year local control was 75% via the Kaplan-Meier method. On follow-up imaging, 43%, 40%, and 17% of lesions were decreased, stable, and increased in size, respectively. 1-year OS was 46% and varied by primary tumor, with median OS of 34.3, 25.1, 12.5, and 4.6 months for ovarian, breast, colorectal, and lung primary tumors, respectively. Breast and ovarian primary patients had better OS (p < 0.0001), and lung primary patients had worse OS (p = 0.032). Higher BED values, the number of hepatic lesions, and larger GTV were not predictive of local control, radiographic response, or OS. 21% of patients suffered from treatment toxicity, but no grade ≥3 toxicity was reported. CONCLUSION: Relatively low-dose SBRT for liver metastases demonstrated efficacy and minimal toxicity, even for patients with large tumors or multiple lesions. This approach may be useful for patients in whom higher-dose therapy is contraindicated or associated with high risk for toxicity. OS depends largely on the primary tumor.

Stereotactic body radiation therapy for spinal metastases: a novel local control stratification by spinal region.

OBJECTIVE: This study evaluated a large cohort of patients treated with stereotactic body radiation therapy for spinal metastases and investigated predictive factors for local control, local progression-free survival (LPFS), overall survival, and pain response between the different spinal regions. METHODS: The study was undertaken via retrospective review at a single institution. Patients with a tumor metastatic to the spine were included, while patients with benign tumors or primary spinal cord cancers were excluded. Statistical analysis involved univariate analysis, Cox proportional hazards analysis, the Kaplan-Meier method, and machine learning techniques (decision-tree analysis). RESULTS: A total of 165 patients with 190 distinct lesions met all inclusion criteria for the study. Lesions were distributed throughout the cervical (19%), thoracic (43%), lumbar (19%), and sacral (18%) spines. The most common treatment regimen was 24 Gy in 3 fractions (44%). Via the Kaplan-Meier method, the 24-month local control was 80%. Sacral spine lesions demonstrated decreased local control (p = 0.01) and LPFS (p < 0.005) compared with those of the thoracolumbar spine. The cervical spine cases had improved local control (p < 0.005) and LPFS (p < 0.005) compared with the sacral spine and trended toward improvement relative to the thoracolumbar spine. The 36-month local control rates for cervical, thoracolumbar, and sacral tumors were 86%, 73%, and 44%, respectively. Comparably, the 36-month LPFS rates for cervical, thoracolumbar, and sacral tumors were 85%, 67%, and 35%, respectively. A planning target volume (PTV) > 50 cm3 was also predictive of local failure (p = 0.04). Fewer cervical spine cases had disease with PTV > 50 cm3 than the thoracolumbar (p = 5.87 × 10-8) and sacral (p = 3.9 × 10-3) cases. Using decision-tree analysis, the highest-fidelity models for predicting pain-free status and local failure demonstrated the first splits as being cervical and sacral location, respectively. CONCLUSIONS: This study presents a novel risk stratification for local failure and LPFS by spinal region. Patients with metastases to the sacral spine may have decreased local control due to increased PTV, especially with a PTV of > 50 cm3. Multidisciplinary care should be emphasized in these patients, and both surgical intervention and radiotherapy should be strongly considered.

Low-dose hilar and mediastinal stereotactic body radiation therapy for non-small cell lung cancer: Analysis of outcomes in patients receiving one or multiple courses of treatment.

BACKGROUND: This study reports the outcomes of a single institutional experience treating non-small cell lung cancer (NSCLC) involving the pulmonary hilum with low-dose stereotactic body radiation therapy (SBRT). The authors also present a series of repeat hilar SBRT. METHODS: Inclusion criteria required treatment with SBRT for NSCLC involving regional lymph nodes of the: (i) hilum, (ii) mediastinum, (iii) aortopulmonary window (station 5), or (iv) mainstem bronchus. At least one clinical follow-up with imaging was required, unless the patient had a prior documented death from cancer. RESULTS: A total of 32 patients with 44 treatments were included, and 37 treatments targeted the hilum directly, with seven concerning the mediastinum, AP window, or mainstem bronchus. Median dose was 28 Gy in four fractions with once-weekly fractionation. At a median clinical follow-up of 23 months, local control was 64%. Median overall survival was 24 months, and median progression-free survival was 15 months. A total of 48% of treatments resulted in complete radiographic response on last imaging follow-up, and no cases of grade ≥ 3 toxicity were reported. For repeat SBRT (after prior hilar SBRT), local control was 92%. Median overall survival was 20 months, and median progression-free survival was 19 months. Complete radiographic response was noted after 58% of treatments, with 0 instances of progressive response and no reported side effects. CONCLUSIONS: Low-dose hilar SBRT was efficacious and well-tolerated, with impressive overall survival and no grade ≥ 3 toxicity. Repeat treatments with SBRT were feasible and effective, demonstrating overall survival, local control, and toxicity comparable to primary treatments. KEY POINTS: Significant findings of the study Low-dose hilar SBRT was efficacious and well-tolerated Repeated treatments with SBRT demonstrated encouraging results, comparable to primary treatments What this study adds This study contributes to the small body of literature concerning hilar SBRT Repeat hilar SBRT was safe and feasible Toxicity was minimal with low-dose SBRT Once-weekly fractionation may have contributed to low rate of side effects.