Faculty Bibliography

BACKGROUND:Adult spinal deformity (ASD) surgery can entail complex reconstructive procedures. It is unclear whether there is any effect of case start time on outcomes. We sought to evaluate the effects of case start time and day of the week on 90-day complication, readmission, and revision rates after ASD surgery. METHODS:This is a retrospective study of 1040 ASD patients from a single institution. We collected start times and day of the week for cases from 2011 to 2018. Early start was designated as any case starting either before or at 7:30 am or between 7:30 and 11 am; late start was designated as any case starting at 11 am or later. Outcome measures include 90-day complication, revision, and readmission rates. RESULTS:= 0.046). CONCLUSIONS:A late OR start time was predictive of increased risk for neurologic complication, 90-day readmission, and unplanned reoperation. The well-established protocols for first start OR times for elective ASD surgery may decrease outcome risk and reduce variability in complication rates. CLINICAL RELEVANCE/CONCLUSIONS:Understanding the impact of start time on outcomes and complications after ASD surgery is helpful for surgeons in preoperative planning and for institutions and hospitals' allocation of operating room staff and resources. LEVEL OF EVIDENCE/METHODS:3.

BACKGROUND:Interbody fusion at the caudal levels of long constructs for adult spinal deformity (ASD) surgery is used to promote fusion and secure a solid foundation for maintenance of deformity correction. We sought to evaluate long-term pseudarthrosis, rod fracture, and revision rates for TLIF performed at the base of a long construct for ASD. METHODS:We reviewed 316 patients who underwent TLIF as a component of ASD surgery for medical comorbidities, surgical characteristics, and rate of unplanned reoperation for pseudarthrosis or instrumentation failure at the TLIF level. Fusion grading was assessed after revision surgery for pseudarthrosis at the TLIF level. RESULTS:Rate of pseudarthrosis at the TLIF level was 9.8% (31/316), and rate of rod fractures was 7.9% (25/316). The rate of revision surgery at the TLIF level was 8.9% (28/316), and surgery was performed at a mean of 20.4 ± 16 months from the index procedure. Current smoking status (odds ratio 3.34, P = 0.037) was predictive of pseudarthrosis at the TLIF site. At a mean follow-up of 43 ± 12 months after revision surgery, all patients had achieved bony union at the TLIF site. CONCLUSIONS:At 3-year follow-up, the rate of pseudarthrosis after TLIF performed at the base of a long fusion for ASD was 9.8%, and the rate of revision surgery to address pseudarthrosis and/or rod fracture was 8.9%. All patients were successfully treated with revision interbody fusion or posterior augmentation of the fusion mass, without need for further revision procedures at the TLIF level.

Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.

Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci represent cycles of tumor growth and dissemination that seed new clusters and drive disease progression. By using an intratibial Vk*MYC murine myeloma model, we found that CD169+ radiation-resistant tissue-resident macrophages (MPs) were critical for early dissemination of myeloma and disease progression. Depletion of these MPs had no effect on tumor proliferation, but it did reduce egress of myeloma from bone marrow (BM) and its spread to other bones. Depletion of MPs as a single therapy and in combination with BM transplantation improved overall survival. Dissemination of myeloma was correlated with an increased inflammatory signature in BM MPs. It was also correlated with the production of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) by tumor-associated MPs. Exogenous intravenous IL-6 and TNFα can trigger myeloma intravasation in the BM by increasing vascular permeability in the BM and by enhancing the motility of myeloma cells by reducing the adhesion of CD138. Moreover, mice that lacked IL-6 had defects in disseminating myeloma similar to those in MP-depleted recipients. Mice that were deficient in TNFα or TNFα receptor (TNFR) had defects in disseminating MM, and engraftment was also impaired. These effects on dissemination of myeloma required production of cytokines in the radiation-resistant compartment that contained these radiation-resistant BM MPs. Taken together, we propose that egress of myeloma cells from BM is regulated by localized inflammation in foci, driven in part by CD169+ MPs.

Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

BACKGROUND:Data on timing of complications are important for accurate quality assessments. We sought to better define pre- and postdischarge complications occurring within 90 days of adult spinal deformity (ASD) surgery and quantify the effect of multiple complications on recovery. METHODS:We performed a review of 1040 patients who underwent ASD surgery (age: 46 ± 23; body mass index: 25 ± 7, American Society of Anesthesiologists [ASA] score: 2.5 ± 0.6, levels: 10 ± 4, revision: 9%, 3-column osteotomy: 13%). We assessed pre- and postdischarge complications and risk factors for isolated versus multiple complications, as well as the impact of multiple complications. RESULTS:= .02). Patients who developed multiple complications (9.3%) had a longer length of stay, and increased risk for readmission and unplanned reoperation. CONCLUSIONS:Knowledge regarding timing of postoperative complications in relation to discharge may better inform quality improvement measures. PE and implant-related complications play a prominent role in perioperative complications and need for readmission, with several modifiable risk factors identified. LEVEL OF EVIDENCE/METHODS:Level 3. CLINICAL RELEVANCE/CONCLUSIONS:Advances in surgical techniques and instrumentation have improved postoperative radiographic and clinical outcomes after ASD surgery. The rate of complications after complex ASD surgery remains high, both at early postoperative and long term follow-up. This study reviews complications within 90 days of surgery, with an assessment of patient and surgical risk factors. We found that modifiable risk factors for early complications after ASD surgery include COPD, and current smoking. The data presented in this study also provide surgeons with knowledge of the most common complications encountered after ASD surgery, to aid in preoperative patient discussion.

The paucity of genetically informed, immune-competent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high grade serous tubo-ovarian carcinoma (HGSC) models exhibiting mutational combinations seen in HGSC patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE ;KrasOE), HR-deficient (Tp53-/-;Brca1-/-;MycOE), and unclassified (Tp53-/-;Pten-/-;Nf1-/-) organoids revealed differences in in vitro properties (proliferation, differentiation, "secretome"), copy number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T-cell dependent responses in Tp53-/-;Ccne1OE;Akt2OE;Kras HGSC; by contrast, Tp53-/-;Pten-/-;Nf1-/- tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics.