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Retrospective radiologic analysis.The aim was to investigate if lateral flexion-extension radiographs identify additional cases of degenerative cervical spondylolisthesis (DCS) that would be missed by obtaining solely neutral upright radiographs, and determine the reliability of magnetic resonance imaging (MRI) in diagnosis.DCS and instability can be a cause of neck pain, radiculopathy, and even myelopathy. Standard anteroposterior and lateral radiographs and MRI of the cervical spine will identify most cervical spine pathology, but spondylolisthesis and instability are dynamic issues. Standard imaging may also miss DCS in some cases.We compared the number of patients who demonstrated cervical spondylolisthesis on lateral neutral and flexion-extension radiographs in addition to MRI. We used established criteria to define instability as ≥2 mm of listhesis on neutral imaging, and ≥1 mm of motion between flexion-extension radiographs.A total of 111 patients (555 cervical levels) were analyzed. In all, 41 patients (36.9%) demonstrated cervical spondylolisthesis on neutral and/or flexion-extension radiographs. Of the 77 levels of spondylolisthesis, 17 (22.1%) were missed on neutral radiographs ( P ,0.05). Twenty levels (26.0%) were missed when flexion-extension radiographs were used alone ( P =0.02). Twenty-nine levels (37.7%) of DCS identified on radiograph were missed by MRI ( P =0.004).Lateral flexion-extension views can be useful in the diagnosis of DCS. These views provide value by identifying a significant cohort of patients that would be undiagnosed based on neutral radiographs alone. Moreover, MRI missed 38% of DCS cases identified by radiographs. Therefore, lateral radiographs can be a useful adjunct to neutral radiographs and MRI when instability is suspected or if these imaging modalities are unable to identify the source of a patient's neck or arm pain.

Funding Information: The study was funded by the U.S. President’s Malaria Initiative and the Advanced Molecular Detection program at CDC. Funding Information: We thank all study staff and participants, Venceslau Mambi Pelenda, José Bumba da Cunha, Oliveira Kiatoko, Felismina Caquece, Luzala Elisabeth Armando Garcia, Djos Kialanda, Garcia Pembele, Domingos Jandondo, and Belmira José Bondo. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention or the U.S. Agency for International Development. The study was funded by the U.S. President’s Malaria Initiative and the Advanced Molecular Detection program at CDC. P.R.D., C.M.F., B.N.A., S.L., R.H., J.F.M.M., F.F., J.F.M., and M.M.P. designed and participated in the specimen collection. P.R.D., A.L.M.C., S.R.R., and J.K. performed the laboratory analysis. P.R.D., A.L.M.C., J.K., S.R.R., J.-H.M.O., and E.T. analyzed the sequencing data. S.R.R. and M.M.P. wrote the manuscript. All authors read and approved the final version of the manuscript. Publisher Copyright: Copyright © 2023 Rosillo et al. Sulfadoxine-pyrimethamine (SP) is used for prevention of malaria in pregnant women in Angola. We sequenced the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes, implicated in SP resistance, in samples collected during a 2019 study of artemisinin-based combination therapy efficacy in Benguela, Lunda Sul, and Zaire provinces. A total of 90 day 0 and day of failure samples were individually sequenced, while 508 day 0 samples from participants without recurrent parasitemia were pooled after DNA extraction into 61 pools. The N51I, C59R, and S108N pfdhfr mutations and A437G pfdhps mutations were present at high proportions in all provinces (weighted allele frequencies, 62% to 100%). The K540E pfdhps mutation was present at lower proportions (10% to 14%). The A581G pfdhps mutation was only observed in Zaire, at a 4.6% estimated prevalence. The I431V and A613S mutations were also only observed in Zaire, at a prevalence of 2.8% to 2.9%. The most common (27% to 66%) reconstructed haplotype in all three provinces was the canonical quadruple pfdhfr pfdhps mutant. The canonical quintuple mutant was absent in Lunda Sul and Benguela and present in 7.9% of samples in Zaire. A single canonical sextuple (2.6%) mutant was observed in Zaire Province. Proportions of the pfdhps K540E and A581G mutations were well below the World Health Organization thresholds for meaningful SP resistance (prevalence of 95% for K540E and 10% for A581G). Samples from therapeutic efficacy studies represent a convenient source of samples for monitoring SP resistance markers. publishersversion published

Purpose:RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response.Experimental Design:Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68–73 clinically relevant cancer genes.Results:A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non–small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors.Conclusions:In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.

Supplementary Data

PDF file - 251K, Fig. 1S: Depiction of drug model for nanoparticle release and delayed transmembrane transport of self-assembling cis-platinum nanoparticles (SACNs) and free cisplatin in an acidic environment. Fig. 2S: Flowchart showing the computational algorithm used to fit parameters in the mathematical model. Fig. 3S: (Data points) The release profile of cisplatin nanoparticles was evaluated at 37 degrees C in neutral and acidic (tumor like) pH in triplicates.

BACKGROUND Primary spinal infections (PSIs) are a group of uncommon but serious infectious diseases that are characterized by inflammation of the endplate-disc unit. Pediatric spinal infection is rare and challenging to diagnose due to vague presenting symptoms. Most cases are conservatively managed with surgery rarely indicated. The authors performed a systematic review to study the baseline characteristics, clinical presentation, and outcomes of pediatric patients with PSIs who underwent surgical treatment. OBSERVATIONS PSI in pediatric patients might behave differently in terms of epidemiology, clinical presentation, and outcomes when compared with nonpediatric patients. Overall, PSI ultimately managed surgically in pediatric patients is associated with a high rate of localized pain, neurological compromise, and treatment failure when compared with nonsurgically managed pediatric spinal infections. LESSONS PSIs managed surgically in the pediatric population were found to be caused by Mycobacterium tuberculosis in 74.4% of cases and were associated with higher rates of localized pain, neurological compromise, and treatment failure than nonsurgically managed pediatric spinal infections. Thoracic involvement (71.8%) in the spinal infection was reported most commonly in our review. When omitting the cases involving M. tuberculosis infection, it was revealed that 50% of the pediatric cases involved infection in the cervical region, suggesting increased severity and disease course of cervical spinal infections in the pediatric population. Surgical treatment is indicated only in cases of severe neurological compromise and treatment failure.

Background: Preoperative optimization in patients undergoing posterior spinal fusion is essential to limit the number and severity of postoperative complications. Here, we, additionally, evaluated the impact of hypoalbuminemia on morbidity and mortality after posterior spinal fusion surgery. Methods: This retrospective analysis was performed using data from a prospective multicentric database (ACSNSQIP:2015–2020) regarding patients undergoing posterior spinal fusions. Factors studied included; baseline demographics and 30-day postoperative complications (i.e., reoperations, readmissions, and mortality rates). Results: There were 6805 patients who met the inclusion criteria. They averaged 62 years of age and had an average BMI of 30.2. Within the 30-day postoperative period, 634 (9.3%) sustained complications; 467 (6.9%) were readmitted, 263 (3.9%) required reoperations, and 37 (0.5%) expired. Although multiple preoperative risk factors were analyzed, hypoalbuminemia, severe hypoalbuminemia, and dialysis were the strongest independent risk factors associated with complications (i.e., reoperations, readmissions, and mortality). Conclusion: Hypoalbuminemia, severe hypoalbuminemia, and dialysis were significant predictors for morbidity and mortality after posterior spinal fusion surgery.

BACKGROUND Pyogenic spinal infections (PSIs) are a group of uncommon but serious infectious diseases that are characterized by inflammation of the endplate–disc unit. PSIs are considered more prevalent and aggressive among patients with chronic immunocompromised states. Association between PSIs and liver disease has not been systematically analyzed. The authors performed a systematic review to study baseline characteristics, clinical presentation, and mortality of patients with PSI in the setting of chronic liver disease. OBSERVATIONS The authors presented the case of a 72-year-old female patient with chronic liver disease who presented with severe low back pain and bilateral lower weakness. Imaging studies showed T10–11 spondylodiscitis. The patient received decompression and fusion surgery with partial neurological improvement. The authors performed a systematic literature search of spondylodiscitis and liver disease, and eight published articles met the studies inclusion and exclusion criteria. These studies featured a total of 144 patients, of whom 129 met inclusion criteria (mean age, 60.5 years, range 40 to 83 years; 62% males). Lumbar infection was the most common report (67%), with Staphylococcus aureus (48%) as the main causative microorganism. Neurological compromise was present in 69% of patients. Surgical intervention occurred in 70.5% of patients, and the average duration of antibiotic treatment was 69.4 days. Postoperative complication rate was 28.5%, with a 30- and 90-day mortality of 17.2% and 24.8%, respectively. LESSONS Pyogenic spondylodiscitis in patients with liver disease was associated with a high rate of neurological compromise, postoperative complications, and mortality.

BACKGROUND Primary spinal infections (PSIs) are a group of uncommon but serious infectious diseases considered more prevalent and aggressive among patients with chronic immunocompromised states. Association of PSI and solid organ transplant has not been systematically analyzed. The authors performed a systematic review analyzing clinical presentation and mortality of patients with PSI in the setting of solid organ transplant. OBSERVATIONS PSIs in patients with immunosuppressive therapy, such as those with solid organ transplant, may behave differently in terms of epidemiology, clinical presentation, and outcomes compared with nonimmunosuppressed patients. Overall PSI in solid organ transplant patients is associated with a high rate of neurological compromise, postoperative complications, and mortality. LESSONS Accurate diagnosis and appropriate treatment of PSI require a multidisciplinary effort. Localized pain is the most frequently reported symptom associated with PSI. As opposed to PSI in patients without transplant, inflammatory and infectious markers such as white blood cells and C-reactive protein are often not elevated. Furthermore, the causative microorganism profile varies significantly when compared to pyogenic spinal infection in patients without transplant. Aspergillus species was responsible for spondylodiscitis in transplant patients in more than 50% of cases, and the incidence of Aspergillus infection is projected to rise in the coming years.

Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million individuals worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of non-small cell lung cancer (NSCLC) patients harbor somatic co-mutations in Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes, whose tumors are characterized by a predominance of neutrophils and an immune suppressive tumor microenvironment (TME) that are resistant to ICI. Our studies revealed that all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized a murine model of NSCLC (Kras G12D P53−/−Lkb1−/−; KPL) to PD-1 blockade. The ATRA and anti-PD-1 combination therapy improved local and systemic T cell activation and generated systemic tumor-specific immunity. We further observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models with or without LKB1 loss. To understand ATRA-mediated anti-tumor effects, we performed single cell RNA sequencing (scRNA-seq) of KPL murine tumors with or without 6 daily ATRA treatments. scRNA-seq analysis indicated a reduction of neutrophils as well as an enrichment in T cell and natural killer (NK) cell populations in the TME. Furthermore, scRNA-seq analysis revealed elevated expression of interferon (IFN) downstream genes in multiple immune subpopulations in the TME. Preliminary ex vivo studies indicated that ATRA increases NOX2 levels, intracellular reactive oxygen species (ROS), and IFN signaling in the myeloid-derived suppressor cells (MDSC) of KPL tumors. Our findings suggest that ATRA may reshape the TME by activating IFN signaling in multiple cell subtypes to sensitize resistant tumors to ICI immunotherapy. Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Michael Oh, Camelia Dumitras, Nico Edgar, Ryan Chew, Rashel Jacobo, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Steven Dubinett, Bin Liu. ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5157.

Background Chronic low back pain secondary to degenerative changes in the spine is a common cause of disability, and disc degeneration is one of the most frequent imaging findings. Intervertebral vacuum phenomenon (IVP) is usually observed in advanced degeneration. Recently, this phenomenon has gained interest due to a relatively new surgical technique called percutaneous discoplasty, aimed at treating low back pain secondary to degenerative disc disease in elderly patients. Purpose To analyze the prevalence and related factors of the vacuum phenomenon in adult patients. Material and Methods A retrospective cohort study was performed of patients who underwent abdominal computed tomography (CT) for non-spine-related reasons. Age, body mass index, smoking, and CT-based characteristics as presence of IVP, subchondral sclerosis, and facet joint degeneration at the lumbar spine from L1 to the sacrum were included in order to determine the prevalence of the vacuum phenomenon in this population and establish a relationship between this condition and patient demographics and other signs of spine degeneration, such as sclerosis and facet joint disease. Results A total of 238 patients were included in the study (114 men, 124 women; mean age = 75.6 ± 12.3 years. In total, 91 (38%) patients had at least one level of IVP; 59 (25%) patients exhibited subchondral sclerosis, and 235 (98%) facet joint degeneration. Among risk factors, age, smoking, and subchondral sclerosis were significantly associated with the presence of vacuum. Conclusion IVP was present in 38% of participants. Risk factors associated with vacuum were age, smoking, and subchondral sclerosis.

Current transcriptomic classification of Glioblastoma Multiforme (GBM) has been ineffective to predict survival and therapeutic vulnerabilities. Recently, we proposed a four-group functional classification of GBM that included proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic subtypes with prognostic and therapeutic implications as the mitochondrial subtype carries the best survival and exhibits distinct sensitivity to mitochondrial OXPHOS inhibitors. To uncover novel therapeutic targets for each functional GBM subtype, we focused on protein kinases for their attractive features as both drivers and drug targets, with current availability of 62 FDA-approved inhibitors available for cancer precision therapeutics. We designed an unbiased integrative, machine learning-based proteomics/phosphoproteomics network for the identification of Master Kinases (MKs) responsible for effecting key phenotypic hallmarks of each of the four GBM subtypes. Here we report the identification and validation of protein kinase C delta (PRKCd) and DNA-PKcs as MKs that sustain the glycolytic/plurimetabolic and proliferative/progenitor GBM subtypes, respectively. Genetic and pharmacologic inactivation of PKCd in GBM patient-derived organoids of the glycolytic/plurimetabolic subtype blocked glucose uptake and lipid accumulation, resulting in marked anti-tumor effects. We also validated the role of PKCd in oncometabolic processes at the intersection between insulin, IGF, and lipid metabolism. DNA-PKcs was qualified as MK for the proliferative/progenitor GBM subtype, which is characterized by high basal level of replication stress. Biochemical experiments showed activation of DNA-PK in GBM patient-derived organoids of the proliferative/progenitor subgroup. Targeting DNA-PK in proliferative/progenitor GBM organoids with the clinically tested DNA-PKcs inhibitor nedisertib in association with gamma irradiation, the essential component of the standard of care for patients with GBM, led to an unsustainable level of DNA damage and massive GBM cell death selectively in this GBM subtype. As DNA-PKcs inhibitors have been introduced into clinical trials, our findings suggest that pre-selection of patient with PPR tumors is likely to enhance therapeutic success.

Introduction Presently, programmed death ligand 1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in NSCLC. Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindels) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs. Positive correlation of fsindels with ICI response has been studied in melanoma and renal cell carcinoma. We investigated the implication of fsindels in the clinical outcomes and immune landscape of patients with NSCLC treated with ICIs. Methods We utilized The Cancer Genome Atlas data set to analyze tumor mutational burden, neoantigen burden, and immune landscape in relation to fsindel status. In addition, utilizing the clinical data from 122 patients treated with ICIs, we evaluated the influence of fsindels on disease response rates and survival outcomes. Results A positive correlation between fsindel burden and tumor mutational burden and activated CD4/CD8 T-cell infiltration was shown. Presence of fsindels was also associated with significant prolongation of progression-free survival in patients treated with ICIs (median 6.2 versus 2.7 months [p = 0.01]). In addition, significant differences in the overall response rates (26% versus 12% [p = 0.04]) and disease control rates (68% versus 48% [p = 0.02]) were observed in patients with fsindels. Conclusion Our findings suggest that fsindels may have a predictive role for ICI response in NSCLC.

Study design Retrospective review of multicentric data. Objectives The modified 5-item frailty index is a relatively new tool to assess the post-operative complication risks. It has been recently shown a good predictive value after posterior lumbar fusion. We aimed to compare the predictive value of the modified 5-item frailty index in cervical, thoracic and lumbar surgery. Methods The American College of Surgeons - National Surgical Quality Improvement Program (ACS-NSQIP) Database 2015-2020 was used to identify patients who underwent elective posterior cervical, thoracic, or lumbar fusion surgeries for degenerative conditions. The mFI-5 score was calculated based on the presence of 5 co-morbidities: congestive heart failure within 30 days prior to surgery, insulin-dependent or noninsulin-dependent diabetes mellitus, chronic obstructive pulmonary disease or pneumonia, partially dependent or totally dependent functional health status at time of surgery, and hypertension requiring medication. Multivariate analysis was used to assess the independent impact of increasing mFI-5 score on the postoperative morbidity while controlling for baseline clinical characteristics. Results 53 252 patients were included with the mean age of 64.2 ± 7.2. 7946 suffered medical complications (14.9%), 1565 had surgical complications (2.9%), and 3385 were readmitted (6.3%), 363 died (.68%) within 30 days postoperative (6.3%). The mFI-5 items score was significantly associated with higher rates of complications, readmission, and mortality in cervical, thoracic, and lumbar posterior fusion surgery. Conclusion The modified 5-item frailty score is a reliable tool to predict complications, readmission, and mortality in patients planned for elective posterior spinal fusion surgery.

BACKGROUND Intraoperative neurophysiologic monitoring (IOM) has been used clinically since the 1970s and is a reliable tool for detecting impending neurologic compromise. However, there are mixed data as to whether long-term neurologic outcomes are improved with its use. We investigated whether IOM used in conjunction with image guidance produces different patient outcomes than with image guidance alone. METHODS We reviewed 163 consecutive cases between January 2015 and December 2018 and compared patients undergoing posterior lumbar instrumentation with image guidance using and not using multimodal IOM. Monitored and unmonitored surgeries were performed by the same surgeons, ruling out variability in intersurgeon technique. Surgical and neurologic complication rates were compared between these 2 cohorts. RESULTS A total of 163 patients were selected (110 in the nonmonitored cohort vs. 53 in the IOM cohort). Nineteen signal changes were noted. Only 3 of the 19 patients with signal changes had associated neurologic deficits postoperatively (positive predictive value 15.7%). There were 5 neurologic deficits that were observed in the nonmonitored cohort and 8 deficits observed in the monitored cohort. Transient neurologic deficit was significantly higher in the monitored cohort per case (P < 0.0198) and per screw (P < 0.0238); however, there was no difference observed between the 2 cohorts when considering permanent neurologic morbidity per case (P < 0.441) and per screw (P < 0.459). CONCLUSIONS The addition of IOM to cases using image guidance does not appear to decrease long-term postoperative neurologic morbidity and may have a reduced diagnostic role given availability of intraoperative image-guidance systems.

Background: Although immune checkpoint blockade (ICB) targeting Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) alone or in combination with chemotherapy is now a first-line option for patients with advanced NSCLC, the majority of patients do not benefit from anti-PD-1/PD-L1 monotherapy, and the combination with chemotherapy is often associated with toxicity. For patients who initially respond to PD-1/PD-L1 inhibition, many relapse after an initial response and are in need for innovative strategies to overcome the resistance to ICB. One possible approach is to utilize in situ vaccination with functional chemokine gene-modified antigen presenting cells (APCs) that take advantage of the full repertoire of tumor antigens in the tumor microenvironment (TME) in order to restore tumor antigen presentation, promote tumor infiltration of immune cells driven by chemokine gradient, and facilitate tumor-specific T cell activation, both locally and systemically. The chemokine CCL21 is a therapeutic candidate due to its ability to promote infiltration and co-localization of naïve T cells and antigen-experienced dendritic cells (DCs) and facilitate T cell activation. In preclinical studies as well as a phase I clinical trial, we observed that intratumoral (IT) injection of CCL21-DC induces the infiltration of autologous DC and T cells into the TME, and generates systemic tumor-specific immune responses against multiple tumor antigens. We also observed tumoral PD-L1 upregulation following CCL21-DC injection, which may hinder T cell function. Similarly, the lack of efficacy of PD-1/PD-L1 inhibitors could potentially be combated by enhanced T cell infiltration and augmented APC function in the TME following in situ vaccination with CCL21-DC. Therefore, we are currently evaluating the safety and efficacy of combining IT CCL21-DC and intravenous (IV) pembrolizumab in advanced NSCLC patients following progression on ICB or tyrosine kinase inhibitor (TKI) therapy in a phase I trial (NCT03546361). Methods: Phase I, dose-escalating, multi-cohort trial followed by dose expansion. Maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or EGFR/ALK mutant after progression on TKI. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC when combined with pembrolizumab. Primary objective of dose expansion is objective response rate at MTD. Secondary objectives include adverse event profiling and immune monitoring studies. [B.L. and A.L. contributed equally to this work as first authors.] Citation Format: Bin Liu, Aaron Lisberg, Ramin Salehi-Rad, Jay Lee, Linh M. Tran, Kostyantyn Krysan, Raymond Lim, Camelia Dumitras, Zhe Jing, Michael Oh, Fereidoun Abtin, Robert Suh, Scott Genshaft, Scott Oh, Gregory Fishbein, Ciara M. O'Higgins, Anita Kaul, Kanwarpal Kahlon, Shahryar Ashouri, Jonathan Goldman, David Elashoff, Edward Garon, Steven Dubinett. Phase I trial of in situ vaccination with autologous CCL21 gene-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT219.

Background VeriStrat test is a serum assay which uses a mass spectrometry (MS)-based proteomic signature derived from machine learning. It is currently used as a prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy. However, little is known about its role for NSCLC patients receiving immune checkpoint inhibitors (ICIs). Methods This is a retrospective study that includes 47 patients with advanced stage NSCLC without an activating EGFR mutation, who underwent the VeriStrat test from 2016 to 2018. Spectra from blood samples were evaluated to assign patients into the VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) risk group. The clinical outcomes of 32 patients who received programmed cell death 1 (PD-1) inhibitors nivolumab or pembrolizumab were analyzed by VeriStrat status. Results The VS-G group demonstrated significantly higher progression-free survival (PFS) and overall survival (OS) compared to the VS-P group among overall NSCLC patients regardless of treatment (median PFS of 7.1 vs. 4.2 months, P=0.013, and median OS, not reached vs. 17.2 months, P=0.012). Among NSCLC patients treated with ICIs, VS-G classification was associated with significantly increased PFS in comparison to VS-P classification (median PFS of 6.2 vs. 3.0 months, P=0.012), while the differences in OS trended towards significance (median OS, not reached vs. 16.5 months P=0.076). Multivariate analysis showed that the VeriStrat status was significantly correlated with PFS and OS in NSCLC patients treated with ICIs (P=0.017, P=0.034, respectively). Conclusions MS-based serum proteomic signature has potential as a biomarker for survival outcome in NSCLC patients receiving immunotherapy.

Polyether ether ketone (PEEK, 1) is an important material for the fabrication of implants employed in spinal fusion surgery. Although its radiolucency and favorable elastic modulus have made PEEK an attractive choice for interbody fusion devices, its poor osseointegrative properties prevent the formation of a strong union between implant and surrounding bone structures and remain a major liability. Recent advancements in PEEK surface technology have resulted in improved osseointegration; however, the identification of an ideal implant material has proven challenging. In this manuscript, we describe our preliminary investigation into the realm of PEEK-based fusion devices that has culminated in the discovery of a mild, solution-based process for the preparation of covalently surface modified PEEK biomaterials that display enhanced osteoconductive properties. Surface modification occurred under mild reaction conditions via the acid-mediated addition of various commercially available hydrophilic oxyamine and...

Background Despite requiring successful trials prior to implantation, spinal cord stimulation (SCS) systems for pain are often later removed. Removing surgically implanted hardware subjects patients to the risks and discomfort of a second surgery, threatens the cost-effectiveness of SCS, and limits the perceived durability of SCS technology for pain problems. Objective To investigate patterns of reasons given among patients who underwent SCS explant surgery (SCSES). Methods Retrospective review of SCSES cases over 17 years at Allegheny General Hospital, Pittsburgh, PA. Results 165 patients underwent SCSES between 1997 and 2014. The top three reasons for explantation were inadequate pain control (IPC, 73%), hardware discomfort (22%), and need for an MRI (10%). Other less frequent reasons were infection (9%), painful dysesthesias (9%), electrical arcing (4%), resolution of inciting symptoms (4%), weakness (2%), pseudomeningocele (1%) and muscle spasms (1%). Conclusion IPC is the most common reason for SCSES. Advances in technology are needed to improve the quality and duration of pain control, in addition to design improvements to make the hardware more comfortable. There is a significant number of implants removed due to need for MRI, a fact obviating the need for MRI-compatible systems. Patients considering SCS paddle lead placement should be counseled on the most common reasons for later explantation. This article is protected by copyright. All rights reserved.

A 14 GS/s direct digital synthesizer (DDS) heterogeneously integrated with InP and GaN on CMOS is presented. The DDS includes over 6 million 45 nm CMOS FETs, 2151 InP HBTs, 2 GaN HEMTs, and 9930 heterogeneous interconnects, making it the most complex heterogeneously integrated mixed-signal circuit reported to date. By heterogeneously integrating multiple technologies, a high output power of 6.9 dBm is achieved while maintaining better than 37 dBc Nyquist SFDR and 8.7 W power consumption – performance currently unachievable with state-of-the-art single-technology approaches.

Background Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR). Methods An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events. Results Median follow-up was 18.2 months (95% CI: 15.9–19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22–0.43, p p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort. Conclusion The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.

PURPOSE: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. EXPERIMENTAL DESIGN: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68–73 clinically relevant cancer genes. RESULTS: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. CONCLUSIONS: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.

Sacroiliac joint (SIJ) dysfunction and its surgical treatment remain a controversial topic in spine surgery. Determining success after SIJ fusion may be difficult due to preexisting back pain, lumbar fusion (LF), and functional disability. We examine the utility of Oswestry Disability Index (ODI) as a measure of clinical outcomes after minimally invasive SIJ fusion. A retrospective review of 24 patients with at least 12- months follow-up. Patients were divided into two groups based on presence of previous LF. Their post-operative ODI was compared with overall satisfaction, pain reduction, and return to work status. No difference in demographics was found in patients with and without prior LF with 92% of patients reporting lower post-operative pain and 96% being satisfied. Presence of LF did not show any statistically significant differences in pain or satisfaction. However, patient with prior LF reported lower ODI than those without LF at 1-year post-operatively (P=0.015). Postoperative ODI may give a falsely pessimistic impression of outcomes in SIJ fusion patients with prior LF, and its use and limitations should be carefully considered in future studies.