Decisional regret following corrective adult spinal deformity surgery: a single institution study of incidence and risk factors.

PURPOSE: To assess the characteristics and risk factors for decisional regret following corrective adult spinal deformity (ASD) surgery at our hospital. METHODS: This is a retrospective cohort study of a single-surgeon ASD database. Adult patients (> 40 years) who underwent ASD surgery from May 2016 to December 2020 with minimum 2-year follow-up were included (posterior-only, ≥ 4 levels fused to the pelvis) (n = 120). Ottawa decision regret questionnaires, a validated and reliable 5-item Likert scale, were sent to patients postoperatively. Regret scores were defined as (1) low regret: 0-39 (2) medium to high regret: 40-100. Risk factors for medium or high decisional regret were identified using multivariate models. RESULTS: Ninety patients were successfully contacted and 77 patients consented to participate. Nonparticipants were older, had a higher incidence of anxiety, and higher ASA class. There were 7 patients that reported medium or high decisional regret (9%). Ninety percentage of patients believed that surgery was the right decision, 86% believed that surgery was a wise choice, and 87% would do it again. 8% of patients regretted the surgery and 14% believed that surgery did them harm. 88% of patients felt better after surgery. On multivariate analysis, revision fusion surgery was independently associated with an increased risk of medium or high decisional regret (adjusted odds ratio: 6.000, 95% confidence interval: 1.074-33.534, p = 0.041). CONCLUSIONS: At our institution, we found a 9% incidence of decisional regret. Revision fusion was associated with increased decisional regret. Estimates for decisional regret should be based on single-institution experiences given differences in patient populations.

Pre-operative bone quality deficits and risk of complications following spine fusion surgery among postmenopausal women.

Poor bone quality is a risk factor for complications after spinal fusion surgery. This study investigated pre-operative bone quality in postmenopausal women undergoing spine fusion and found that those with small bones, thinner cortices and surgeries involving more vertebral levels were at highest risk for complications. PURPOSE: Spinal fusion is one of the most common surgeries performed worldwide. While skeletal complications are common, underlying skeletal deficits are often missed by pre-operative DXA due to artifact from spinal pathology. This prospective cohort study investigated pre-operative bone quality using high resolution peripheral CT (HRpQCT) and its relation to post-operative outcomes in postmenopausal women, a population that may be at particular risk for skeletal complications. We hypothesized that women with low volumetric BMD (vBMD) and abnormal microarchitecture would have higher rates of post-operative complications. METHODS: Pre-operative imaging included areal BMD (aBMD) by DXA, cortical and trabecular vBMD and microarchitecture of the radius and tibia by high resolution peripheral CT. Intra-operative bone quality was subjectively graded based on resistance to pedicle screw insertion. Post-operative complications were assessed by radiographs and CTs. RESULTS: Among 50 women enrolled (age 65 years), mean spine aBMD was normal and 35% had osteoporosis by DXA at any site. Low aBMD and vBMD were associated with "poor" subjective intra-operative quality. Skeletal complications occurred in 46% over a median follow-up of 15 months. In Cox proportional models, complications were associated with greater number of surgical levels (HR 1.19 95% CI 1.06-1.34), smaller tibia total area (HR 1.67 95% CI1.16-2.44) and lower tibial cortical thickness (HR 1.35 95% CI 1.05-1.75; model p < 0.01). CONCLUSION: Women with smaller bones, thinner cortices and procedures involving a greater number of vertebrae were at highest risk for post-operative complications, providing insights into surgical and skeletal risk factors for complications in this population.

Vitamin D and SARS-CoV-2 Infection: SERVE Study (SARS-CoV-2 Exposure and the Role of Vitamin D among Hospital Employees).

BACKGROUND: Recognition of the role of vitamin D in immune function has led to interest in its relationship with SARS-CoV-2 infection. Although clinical studies to date have had conflicting results, many individuals currently take high doses of vitamin D to prevent infection. OBJECTIVE: The goal of this study was to investigate the relationship between serum 25-hydroxyvitamin D (25OHD) and vitamin D supplement use with incident SARS-CoV-2 infection. METHODS: In this prospective cohort study, 250 health care workers were enrolled at a single institution and observed for 15 mo. Participants completed questionnaires every 3 mo regarding new SARS-CoV-2 infection, vaccination, and supplement use. Serum was drawn at baseline, 6, and 12 mo for 25OHD and SARS-CoV-2 nucleocapsid antibodies. RESULTS: The mean age of the participants was 40 y, BMI 26 kg/m2, 71% were Caucasian, and 78% female. Over 15 mo, 56 participants (22%) developed incident SARS-CoV-2 infections. At baseline, ∼50% reported using vitamin D supplements (mean daily dose 2250 units). Mean serum 25OHD was 38 ng/mL. Baseline 25OHD did not predict incident SARS-CoV-2 infection (OR: 0.98; 95% CI: 0.80, 1.20). Neither the use of vitamin D supplements (OR: 1.18; 95% CI: 0.65, 2.14) or supplement dose was associated with incident infection (OR: 1.01 per 100-units increase; 95% CI: 0.99, 1.02). CONCLUSION: In this prospective study of health care workers, neither serum 25OHD nor the use of vitamin D supplements was associated with the incident SARS-CoV-2 infection. Our findings argue against the common practice of consuming high-dose vitamin D supplements for the presumed prevention of COVID-19.

Opportunistic Evaluation of Trabecular Bone Texture by MRI Reflects Bone Mineral Density and Microarchitecture.

CONTEXT: Many individuals at high risk for fracture are never evaluated for osteoporosis and subsequently do not receive necessary treatment. Utilization of magnetic resonance imaging (MRI) is burgeoning, providing an ideal opportunity to use MRI to identify individuals with skeletal deficits. We previously reported that MRI-based bone texture was more heterogeneous in postmenopausal women with a history of fracture compared to controls. OBJECTIVE: The present study aimed to identify the microstructural characteristics that underlie trabecular texture features. METHODS: In a prospective cohort, we measured spine volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT), peripheral vBMD and microarchitecture by high-resolution peripheral QCT (HRpQCT), and areal BMD (aBMD) by dual-energy x-ray absorptiometry. Vertebral trabecular bone texture was analyzed using T1-weighted MRIs. A gray level co-occurrence matrix was used to characterize the distribution and spatial organization of voxelar intensities and derive the following texture features: contrast (variability), entropy (disorder), angular second moment (ASM; uniformity), and inverse difference moment (IDM; local homogeneity). RESULTS: Among 46 patients (mean age 64, 54% women), lower peripheral vBMD and worse trabecular microarchitecture by HRpQCT were associated with greater texture heterogeneity by MRI-higher contrast and entropy (r ∼ -0.3 to 0.4, P < .05), lower ASM and IDM (r ∼ +0.3 to 0.4, P < .05). Lower spine vBMD by QCT was associated with higher contrast and entropy (r ∼ -0.5, P < .001), lower ASM and IDM (r ∼ +0.5, P < .001). Relationships with aBMD were less pronounced. CONCLUSION: MRI-based measurements of trabecular bone texture relate to vBMD and microarchitecture, suggesting that this method reflects underlying microstructural properties of trabecular bone. Further investigation is required to validate this methodology, which could greatly improve identification of patients with skeletal fragility.

Peripheral cortical bone density predicts vertebral bone mineral properties in spine fusion surgery patients.

Spine fusion surgery is one of the most common orthopedic procedures, with over 400,000 performed annually to correct deformities and pain. However, complications occur in approximately one third of cases. While many of these complications may be related to poor bone quality, it is difficult to detect bone abnormalities prior to surgery. Areal BMD (aBMD) assessed by DXA may be artifactually high in patients with spine pathology, leading to missed diagnosis of deficits. In this study, we related preoperative imaging characteristics of both central and peripheral sites to direct measurements of bone quality in vertebral biopsies. We hypothesized that pre-operative imaging outcomes would relate to vertebral bone mineralization and collagen properties. Pre-operative assessments included DXA measurements of aBMD of the spine, hip, and forearm, central quantitative computed tomography (QCT) of volumetric BMD (vBMD) at the lumbar spine, and high resolution peripheral quantitative computed tomography (HRpQCT; Xtreme CT2) measurements of vBMD and microarchitecture at the distal radius and tibia. Bone samples were collected intraoperatively from the lumbar vertebrae and analyzed using Fourier-transform Infrared (FTIR) spectroscopy. Bone samples were obtained from 23 postmenopausal women (mean age 67 ± 7 years, BMI 28 ± 8 kg/m2). We found that patients with more mature bone by FTIR, measured as lower acid phosphate content and carbonate to phosphate ratio, and greater collagen maturity and mineral maturity/crystallinity (MMC), had greater cortical vBMD at the tibia and greater aBMD at the lumbar spine and one-third radius. Our data suggests that bone quality at peripheral sites may predict bone quality at the spine. As bone quality at the spine is challenging to assess prior to surgery, there is a great need for additional screening tools. Pre-operative peripheral bone imaging may provide important insight into vertebral bone quality and may foster identification of patients with bone quality deficits.

Epidural Steroid Injections Acutely Suppress Bone Formation Markers in Postmenopausal Women.

CONTEXT: Over 9 million epidural steroid injections (ESIs) are performed annually in the United States. Although these injections effectively treat lumbar radicular pain, they may have adverse consequences, including bone loss. OBJECTIVE: To investigate acute changes in bone turnover following ESI. We focused on postmenopausal women, who may be at greatest risk for adverse skeletal consequences due to the combined effects of ESIs with aging and estrogen deficiency. METHODS: Single-center prospective observational study. Postmenopausal women undergoing lumbar ESIs and controls with no steroid exposure were included. Outcomes were serum cortisol, markers of bone formation, osteocalcin, and procollagen type-1 N-terminal propeptide (P1NP), and bone resorption by C-telopeptide (CTX) measured at baseline, 1, 4, 12, 26, and 52 weeks after ESIs. RESULTS: Among ESI-treated women, serum cortisol declined by ~50% 1 week after injection. Bone formation markers significantly decreased 1 week following ESIs: osteocalcin by 21% and P1NP by 22%. Both markers remained suppressed at 4 and 12 weeks, but returned to baseline levels by 26 weeks. There was no significant change in bone resorption measured by CTX. Among controls, there were no significant changes in cortisol or bone turnover markers. CONCLUSION: These results provide evidence of an early and substantial reduction in bone formation markers following ESIs. This effect persisted for over 12 weeks, suggesting that ESIs may have lasting skeletal consequences. Given the large population of older adults who receive ESIs, further investigation into the long-term skeletal sequelae of these injections is warranted.

Patients with abnormal microarchitecture have an increased risk of early complications after spinal fusion surgery.

Spine fusion is one of the most common orthopedic surgeries, with more than 400,000 cases performed annually. While these procedures correct debilitating pain and deformities, complications occur in up to 45%. As successful fusion rests upon early stability of hardware in bone, patients with structural skeletal deficits may be at particular risk for complications. Few studies have investigated this relationship, and none have used higher order imaging to evaluate microstructural mechanisms for complications. Standard DXA measurements are subject to artifact in patients with spinal disease and therefore provide limited information. The goal of this prospective study was to investigate pre-operative bone quality as a risk factor for early post-operative complications using high resolution peripheral QCT (HR-pQCT) measurements of volumetric BMD (vBMD) and microarchitecture. We hypothesized that patients with low vBMD and abnormal microarchitecture at baseline would have more skeletal complications post-operatively. Conversely, we hypothesized that pre-operative DXA measurements would not be predictive of complications. Fifty-four subjects (mean age 63 years, BMI 27 kg/m2) were enrolled pre-operatively and followed for 6 months after multi-level lumbar spine fusion. Skeletal complications occurred in 14 patients. Patients who developed complications were of similar age and BMI to those who did not. Baseline areal BMD and Trabecular Bone Score by DXA did not differ. In contrast, HR-pQCT revealed that patients who developed complications had lower trabecular vBMD, fewer and thinner trabeculae at both the radius and tibia, and thinner tibial cortices. In summary, abnormalities of both trabecular and cortical microarchitecture were associated the development of complications within the first six months following spine fusion surgery. Our results suggest a mechanism for early skeletal complications after fusion. Given the burgeoning number of fusion surgeries, further studies are necessary to investigate strategies that may improve bone quality and lower the risk of post-operative complications.

Abnormal microarchitecture and stiffness in postmenopausal women with isolated osteoporosis at the 1/3 radius.

BACKGROUND: Postmenopausal women with isolated osteoporosis at the 1/3 radius (1/3RO) present a therapeutic dilemma. Little is known about whether these patients have generalized skeletal fragility, and whether this finding warrants treatment. The aim of this study was to investigate the biochemical and microarchitectural phenotype of women with 1/3RO compared to women with classic postmenopausal osteoporosis by DXA at the spine and hip (PMO), and controls without osteoporosis at any site. METHODS: This cross-sectional study enrolled 266 postmenopausal women, who were grouped according to densitometric pattern. Subjects had serum biochemistries, areal BMD (aBMD) measured by DXA, trabecular and cortical vBMD, microarchitecture, and stiffness by high resolution peripheral QCT (HR-pQCT, voxel size ~82 µm) of the distal radius and tibia. RESULTS: Mean age was 68 ± 7 years. DXA T-Scores reflected study design. By HR-pQCT, 1/3RO had abnormalities at both radius and tibia compared to controls: lower total, cortical and trabecular vBMD, cortical thickness and trabecular number, higher trabecular separation and heterogeneity, and lower whole bone stiffness. In contrast, the magnitude and pattern of abnormalities in vBMD, microarchitecture and stiffness in 1/3RO were similar to those in PMO; the difference compared to controls was similar among the two groups. Serum calcium, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 24-hour urine calcium did not differ. CONCLUSIONS: Although aBMD appeared relatively preserved at the spine and hip by DXA, women with 1/3RO had significant microarchitectural and biomechanical deficits comparable to those in women with typical PMO. Further study is required to guide treatment decisions in this population.

JAK/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models.

The concept of using viruses to treat cancer has now shown proof of concept in several recent clinical trials, leading to the first FDA approval of virotherapy for melanoma last year. Vesicular stomatitis virus (VSV) is a promising oncolytic virus that has inhibitory effects on a number of cancer types including non-small cell lung cancer. One of the major mechanisms of resistance to VSV infection is the type I interferon (IFN) response, leading to the development of VSV expressing IFNß which will lead to resistance of viral replication in normal cells which have intact IFN signaling but allow replication in cancer cells with defective IFNß signaling. However, some cancer cells have intact or partially intact IFN signaling pathways leading to resistance to virotherapy. Here we utilized JAK/STAT inhibitor, ruxolitinib, in combination with VSV-IFNß to see if inhibition of JAK/STAT signaling will enhance VSV-IFNß therapy for lung cancer. We used five human and two murine NSCLC cell lines in vitro, and the combination treatment was assayed for cytotoxicity. We performed western blots on treated cells to see the effects of ruxolitinib on JAK/STAT signaling and PDL-1 expression in treated cells. Finally, the combination of VSV-IFNß and ruxolitinib was tested in an immune competent murine model of NSCLC. Ruxolitinib enhanced virotherapy in resistant and sensitive NSCLC cells. The addition of ruxolitinib inhibited STAT1 phosphorylation and to a lesser extent STAT3 phosphorylation. Ruxolitinib treatment prevented NSCLC cells from enhancing PDL-1 expression in response to virotherapy. Combination ruxolitinib and VSV-IFNß therapy resulted in a trend toward improved survival of mice without substantially effecting PDL-1 levels or levels of immune infiltration into the tumor. These results support further clinical evaluation of the combination of JAK/STAT inhibition with virotherapy.

Lower Spine Volumetric Bone Density in Patients With a History of Epidural Steroid Injections.

Context: Epidural steroid injections (ESIs) are a common, effective treatment of lumbar radiculopathy and sciatica. Although the negative skeletal effects of oral glucocorticoids are well established, little is known about the impact of ESI on bone quality. Objective: To investigate the relationship between ESI exposure and volumetric bone mineral density (vBMD) at the lumbar spine (LS) using central quantitative CT. Design: Retrospective study. Setting: University hospital outpatient facility. Patients: All patients had CT scans of the LS between 2011 and 2016. Cases received at least three ESIs prior to the date of CT (n = 121). Controls were matched for age and sex (n = 121). Main Outcome Measures: Cumulative ESI dose was calculated. vBMD was measured at T12 through L5 using QCT Pro phantomless software (MindWays). Results: Mean age of subjects was 65 ± 14 years, and 49% were women. Median number of ESIs was 4 (range: 3 to 16). Median cumulative ESI dosage was 340 mg of triamcinolone or equivalent (range: 150 to 1400 mg). Compared with controls, ESI subjects had lower vBMD at each vertebral level. Higher cumulative dose was associated with lower mean vBMD at T12 to L5 (r = -0.22, P = 0.02). Conclusions: Greater cumulative ESI dose was related to lower vBMD at the LS. To our knowledge, this is the first study to measure vBMD in patients treated with ESIs. Prospective studies are needed to confirm these findings and to help identify the best strategies for preventing bone loss in this population.

Viroimmunotherapy of Thoracic Cancers.

Thoracic cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and malignant pleural mesothelioma (MM), cause the highest rate of cancer mortality worldwide. Most of these deaths are as a result of NSCLC; however, prognoses for the other two diseases remain as some of the poorest of any cancers. Recent advances in immunotherapy, specifically immune checkpoint inhibitors, have begun to help a small population of patients with advanced lung cancer. People who respond to these immune therapies generally have a durable response and many see dramatic decreases in their disease. However, response to immune therapies remains relatively low. Therefore, intense research is now underway to rationally develop combination therapies to expand the range of patients who will respond to and benefit from immune therapy. One promising approach is with oncolytic viruses. These oncolytic viruses (OVs) have been found to be selective for or have been engineered to preferentially infect and kill cancer cells. In pre-clinical models of different thoracic cancers, it has been found that these viruses can induce immunogenic cell death, increase the number of immune mediators brought into the tumor microenvironment and broaden the neoantigen-specific T cell response. We will review here the literature regarding the application of virotherapy toward augmenting immune responses in thoracic cancers.

Vesicular stomatitis virus expressing interferon-ß is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer.

Vesicular stomatitis virus (VSV) is a potent oncolytic virus for many tumors. VSV that produces interferon-ß (VSV-IFNß) is now in early clinical testing for solid tumors. Here, the preclinical activity of VSV and VSV-IFNß against non-small cell lung cancer (NSCLC) is reported. NSCLC cell lines were treated in vitro with VSV expressing green fluorescence protein (VSV-GFP) and VSV-IFNß. VSV-GFP and VSV-IFNß were active against NSCLC cells. JAK/STAT inhibition with ruxolitinib re-sensitized resistant H838 cells to VSV-IFNß mediated oncolysis. Intratumoral injections of VSV-GFP and VSV-IFNß reduced tumor growth and weight in H2009 nude mouse xenografts (p < 0.01). A similar trend was observed in A549 xenografts. Syngeneic LM2 lung tumors grown in flanks of A/J mice were injected with VSV-IFNß intratumorally. Treatment of LM2 tumors with VSV-IFNß resulted in tumor regression, prolonged survival (p < 0.0001), and cure of 30% of mice. Intratumoral injection of VSV-IFNß resulted in decreased tumor-infiltrating regulatory T cells (Treg) and increased CD8+ T cells. Tumor cell expression of PDL-1 was increased after VSV-IFNß treatment. VSV-IFNß has potent antitumor effects and promotes systemic antitumor immunity. These data support further clinical investigation of VSV-IFNß for NSCLC.