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It is no secret that America's population is aging rapidly. With more people in our country enjoying longer, fuller lives, our societal, governmental, and cultural structures and norms will have [...]

Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I-IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I-IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection., (© 2024. The Author(s).)

Background: Current surveillance modalities of osteosarcoma relapse exhibit limited sensitivity and specificity. Although circulating tumor DNA (ctDNA) has been established as a biomarker of minimal residual disease (MRD) in many solid tumors, a sensitive ctDNA detection technique has not been thoroughly explored for longitudinal MRD detection in osteosarcoma., Methods: From August 2019 to June 2023, 59 patients diagnosed with osteosarcoma at the First Affiliated Hospital of Sun Yat-sen University were evaluated in this study. Tumor-informed MRD panels were developed through whole exome sequencing (WES) of tumor tissues. Longitudinal blood samples were collected during treatment and subjected to multiplex PCR-based next-generation sequencing (NGS). Kaplan-Meier curves and Log-rank tests were used to compare outcomes, and Cox regression analysis was performed to identify prognostic factors., Findings: WES analysis of 83 patients revealed substantial mutational heterogeneity, with non-recurrent mutated genes accounting for 58.1%. Tumor-informed MRD panels were successfully obtained for 85.5% of patients (71/83). Among 59 patients with successful MRD panel customization and available blood samples, 13 patients exhibited positive ctDNA detection after surgery. Patients with negative post-operative ctDNA had better event-free survival (EFS) compared to those with positive ctDNA, at 1-6 months after surgery, after adjuvant chemotherapy, and more than 6 months after surgery (p < 0.05). In both univariate and multivariate Cox regression analysis, ctDNA results emerged as a significant predictor of EFS (p < 0.05). ctDNA detection preceded positive imaging in 5 patients, with an average lead time of 92.6 days. Thirty-nine patients remained disease-free, with ctDNA results consistently negative or turning negative during follow-up., Interpretation: Our study underscores the applicability of tumor-informed deep sequencing of ctDNA in osteosarcoma MRD surveillance and, to our knowledge, represents the largest cohort to date. ctDNA detection is a significant prognostic factor, enabling the early identification of tumor relapse and progression compared to standard imaging, thus offering valuable insights in guiding osteosarcoma patient management., Funding: The Grants of National Natural Science Foundation of China (No. 82072964, 82072965, 82203798, 82203026), the Natural Science Foundation of Guangdong (No. 2023A1515012659, 2023A1515010302), and the Regional Combination Project of Basic and Applied Basic Research Foundation of Guangdong (No. 2020A1515110010)., Competing Interests: Q.J., F.P., F.L. and K.W. are employees of OrigiMed. A.H.K. is a consultant for Monteris Medical and received a research grant on dural substitute from Stryker. The other authors declare no competing interests., (© 2024 The Author(s).)

Meningiomas are tumors of the central nervous system that vary in their presentation, ranging from benign and slow-growing to highly aggressive. The standard method for diagnosing and classifying meningiomas involves invasive surgery and can fail to provide accurate prognostic information. Liquid biopsy methods, which exploit circulating tumor biomarkers such as DNA, extracellular vesicles, micro-RNA, proteins, and more, offer a non-invasive and dynamic approach for tumor classification, prognostication, and evaluating treatment response. Currently, a clinically approved liquid biopsy test for meningiomas does not exist. This review provides a discussion of current research and the challenges of implementing liquid biopsy techniques for advancing meningioma patient care.

Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma samples from 1975 patients, including those with lung, breast, colorectal, ovarian, liver, gastric, head and neck, bladder, cervical, thyroid, or prostate cancer. We identified tumor-specific changes in these patients in 1280 repeat element types from the LINE, SINE, LTR, transposable element, and human satellite families. These included changes to known repeats and 820 elements that were not previously known to be altered in human cancer. Repeat elements were enriched in regions of driver genes, and their representation was altered by structural changes and epigenetic states. Machine learning analyses of genome-wide repeat landscapes and fragmentation profiles in cfDNA detected patients with early-stage lung or liver cancer in cross-validated and externally validated cohorts. In addition, these repeat landscapes could be used to noninvasively identify the tissue of origin of tumors. These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer.

Background: The diagnostic workup of individuals suspected of having lung cancer can be complex and protracted because conventional symptoms of lung cancer have low specificity and sensitivity., Research Question: Among individuals with symptoms of lung cancer, can a blood-based approach to analyze cell-free DNA (cfDNA) fragmentation (the DNA evaluation of fragments for early interception [DELFI] score) enhance evaluation for the possible presence of lung cancer?, Study Design and Methods: Adults were referred to Bispebjerg Hospital (Copenhagen, Denmark) for diagnostic evaluation of initial imaging anomalies and symptoms consistent with lung cancer. Numbers and types of symptoms were extracted from medical records. cfDNA from plasma samples obtained at the prediagnostic visit was isolated, sequenced, and analyzed for genome-wide cfDNA fragmentation patterns. The relationships among clinical presentation, cancer status, and DELFI score were examined., Results: A total of 296 individuals were analyzed. Median DELFI scores were higher for those with lung cancer (n = 98) than those without cancer (n = 198; 0.94 vs 0.19; P < .001). In a multivariate model adjusted for age, smoking history, and presenting symptoms, the addition of the DELFI score improved the prediction of lung cancer for those who demonstrated symptoms (area under the receiver operating characteristic curve, 0.74-0.94)., Interpretation: The DELFI score distinguishes individuals with lung cancer from those without cancer better than suspicious symptoms do. These results represent proof-of-concept support that fragmentation-based biomarker approaches may facilitate diagnostic resolution for patients with concerning symptoms of lung cancer., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The lateral transorbital approach (LTOA) is a relatively new minimal access skull base approach suited for addressing paramedian pathology of the anterior and middle fossa. The authors define target zones for this approach and describe a series of cases with detailed measurements of visual outcomes, including those obtained with exophthalmometry., Methods: The authors performed a retrospective analysis of a consecutive series of LTOA patients. Seven target zones were identified: 1) the orbit, 2) the lesser sphenoid wing and anterior clinoid, 3) the middle fossa, 4) the lateral wall of the cavernous sinus and Meckel's cave, 5) the infratemporal fossa, 6) the petrous apex, and 7) the anterior fossa. The authors used volumetric analyses of preoperative and postoperative MR and CT imaging data to calculate the volume of bone and tumor removed and to provide detailed ophthalmological, neurological, and cosmetic outcomes., Results: Of the 20 patients in this cohort, pathology was in zone 2 (n = 10), zone 4 (n = 6), zone 3 (n = 2), zone 1 (n = 1), and zone 5 (n = 1). Pathology was meningioma (n = 10), schwannoma (n = 2), metastasis (n = 2), epidermoid (n = 1), dermoid (n = 1), encephalocele (n = 1), adenoma (n = 1), glioblastoma (n = 1), and inflammatory lesion (n = 1). The goal was gross-total resection (GTR) in 9 patients, all of whom achieved GTR. Subtotal resection (STR) was the goal in 8 patients (5 spheno-orbital meningiomas, 1 giant cavernous sinus/Meckel's cave schwannoma, 1 cavernous sinus prolactinoma, and 1 cavernous sinus dermoid), 7 of whom achieved STR and 1 of whom achieved GTR. The goal was biopsy in 2 patient and repair of encephalocele in 1. Visual acuity was stable or improved in 18 patients and worse in 2. Transient early postoperative diplopia, ptosis, eyelid swelling, and peri-orbital numbness were common. All 9 patients with preoperative diplopia improved at their last follow-up. Seven of 8 patients with preoperative exophthalmos improved after surgery (average correction of 64%). There were no cases of clinically significant (> 2 mm) postoperative enophthalmos. The most frequent postoperative complaint was peri-orbital numbness (40%). There was 1 CSF leak. Most patients were satisfied with their ocular (84%-100% of patients provided positive satisfaction-related responses) and cosmetic (75%-100%) outcomes., Conclusions: The LTOA is a safe minimal access approach to a variety of paramedian anterior skull base pathologies in several locations. Early follow-up revealed excellent resolution of exophthalmos with little risk of clinically significant enophthalmos. Transient diplopia, ptosis, and peri-orbital numbness were common but improved. Careful case selection is critical to ensure good outcome.

Introduction  Pedicled nasoseptal flap (NSF) placement is a critical component of skull base reconstruction after endoscopic endonasal approaches (EEAs). The effectiveness of NSF reuse has not been thoroughly studied. Prior reports using flaps harvested at one center and reused at another may have technical variability bias. Methods  We identified patients who underwent both their initial and NSF-reused surgeries at Weill Cornell Medical College from 2004 to 2022 using a prospective database of all EEAs. Surgical pathology, intraoperative leak grade, use of cerebrospinal fluid (CSF) diversion and skull base coverage were examined. The primary outcome measure was occurrence of CSF leak. Results  Fourteen patients (six women, eight men) underwent 14 first time and 14 revision operations with median age of 36.6 years (interquartile range [IQR]: 23.9-61.3) at the time of the NSF reuse. The median interval between the first NSF use and reuse was 70.6 months (IQR: 16.6-87). Eight patients were operated on for pituitary adenoma. Nonadenomas included three craniopharyngiomas and one case each of epidermoid, ependymoma, and chordoma. There were 16 high-flow, 8 low-flow intraoperative leaks, and 4 with no leak. CSF diversion was used in 24 operations. There were three postoperative leaks, one after a first operation and two after NSF reuse. All postoperative CSF leaks, whether first or second operations, occurred in cases with both high-flow intraoperative CSF leak and incomplete NSF coverage ( p  = 0.006). Conclusion  NSF reuse is effective at preventing postoperative CSF leak. The primary predictors of leak are high-flow intraoperative leak and inadequate defect coverage with NSF, regardless of the operation number., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background: The repair of lateral sphenoid sinus cerebrospinal fluid leaks is routinely accomplished through the use of the endonasal endoscopic approach (EEA) with a transpterygoidal extension. This approach can incur sinus morbidity, damage to the vidian, palatine and trigeminal nerves, and the contents of the pterygopalatine fossa, particularly if the encephalocele is lateral to the foramen rotundum (FR) and V2., Objective: To investigate the use of the lateral transorbital approach (LTOA) as an alternative approach for repair of lateral sphenoid sinus encephaloceles that avoids the potential morbidity of EEA., Methods: We performed cadaveric dissections of 2 specimens (4 sides) and present one of the first cases of a lateral sphenoid sinus encephalocele repair lateral to the FR in a patient through an ipsilateral LTOA., Results: We find that the LTOA provides a shorter distance to target compared with the EEA (56 vs 89.5 mm, P = .002). The LTOA field of view also affords excellent visualization of both the medial and lateral aspects of V2, whereas the EEA is less effective at exposing lateral to V2, even after sacrifice of the vidian nerve and maximal pterygopalatine fossa content retraction. We report a case of LTOA to repair a meningoencephalocele lateral to V2 in the sphenoid sinus., Conclusion: The LTOA to the foramen rotundum is a more direct approach that minimizes the morbidity associated with EEA to repair meningoencephaloceles both medial and lateral to foramen rotundum., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring., (© 2023. The Author(s).)

Background: The most common presenting symptom in patients with both small and large Rathke cleft cysts (RCC) is headache (H/A). It is well established that patients with large RCC can have significant symptomatic improvement after cyst drainage. However, patients with small RCC (≤ 1 cm) are rarely operated on, even if they present with debilitating H/A. It is not well understood whether resection of these smaller RCCs can lead to durable H/A resolution., Methods: A retrospective search of our institutional database for sub-centimeter RCCs presenting with intractable H/A and treated with an endoscopic endonasal approach was carried out. A detailed H/A questionnaire as well as patient chart review was conducted to assess the long-term outcome of these patients after surgical intervention., Results: Ten consecutive patients with 11 endonasal surgeries met inclusion criteria. Eight responded to the questionnaire. The median cyst diameter was 6 mm (IQR 3-9). Median preoperative H/A duration was 12 months (range 2 months-15 years). H/As occurred on average for 20 days per month and all required analgesics for symptomatic control for more than 15 of these 20 days. Half of the patients also had to miss work because of H/A. Average preoperative H/A intensity was 8.7 (scale 0-10) compared with postoperative scores of 2.9 at one month, 1.6 at 3 months, and 0.9 at 1 year. There were no permanent endocrinological or other surgical complications. After a median follow-up of 2 years, one patient had radiographic and symptomatic recurrence which resolved after re-operation., Conclusions: Endoscopic fenestration of sub-centimeter RCCs provides a safe and durable treatment for patients with intractable H/A., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Craniopharyngioma is a benign but surgically challenging brain tumor. Controversies exist regarding its ideal treatment strategy, goals of surgery, efficacy of radiation, and the long-term outcomes of these decisions. The authors of this study performed a detailed analysis of factors predictive of the extent of resection and recurrence in large series of craniopharyngiomas removed via an endoscopic endonasal approach (EEA) with long-term follow-up., Methods: From a prospective database of all EEAs done at Weill Cornell Medical College by the senior author from 2004 to 2022, a consecutive series of histologically proven craniopharyngiomas were identified. Gross-total resection (GTR) was generally the goal of surgery. Radiation was often given if GTR had not been achieved. The stalk was preserved if not infiltrated with tumor but was sacrificed to achieve GTR. Intentional subtotal resection (STR) was performed in select cases to avoid hypothalamic injury., Results: Among the 111 identified cases were 88 adults and 23 children. Newly diagnosed cases comprised 58.6% of the series. GTR was attempted in 77.5% of the patients and among those cases was achieved in 89.5% of treatment-naive tumors and 72.4% of recurrent tumors. An inability to achieve GTR was predicted by prior surgical treatment (OR 0.13, 95% CI 0.03-0.6, p = 0.009), tumor diameter ≥ 3.5 cm (OR 0.11, 95% CI 0.02-0.53, p = 0.006), and encasement of the optic nerve or a major artery (OR 0.11, 95% CI 0.01-0.8, p = 0.03). GTR with stalk preservation maintained some anterior pituitary function in 64.5% of cases and prevented diabetes insipidus in 25.8%. After a median follow-up of 51 months (IQR 17-80 months), the recurrence rate after GTR was 12.5% compared with 38.5% after non-GTR. The median recurrence-free survival was 5.5 years after STR, 8.3 years after near-total resection (≥ 98%), and not reached after GTR (p = 0.004, log-rank test). GTR was the strongest predictor of recurrence-free survival (OR 0.09, 95% CI 0.02-0.42, p = 0.002), whereas radiation did not show a statistically significant impact (OR 1.17, 95% CI 0.45-3.08). In GTR cases, the recurrence rate was higher if the stalk had been preserved (22.6%) as opposed to a sacrificed stalk (4.9%; OR 5.69, 95% CI 1.09-29.67)., Conclusions: The study data show that GTR should be the goal of surgery in craniopharyngiomas if it can be achieved safely. Although stalk preservation can maintain some endocrine function, the risk of recurrence is higher in such cases. Radiation may not be as effective as previously reported.

Objective: Endonasal endoscopic odontoidectomy (EEO) is an alternative to transoral surgery for symptomatic ventral compression of the anterior cervicomedullary junction (CMJ), allowing for earlier extubation and feeding. Because the procedure destabilizes the C1-2 ligamentous complex, posterior cervical fusion is often performed concomitantly. The authors' institutional experience was reviewed to describe the indications, outcomes, and complications in a large series of EEO surgical procedures in which EEO was combined with posterior decompression and fusion., Methods: A consecutive, prospective series of patients who underwent EEO between 2011 and 2021 was studied. Demographic and outcome metrics, radiographic parameters, extent of ventral compression, extent of dens removal, and increase in CSF space ventral to the brainstem were measured on the preoperative and postoperative scans (first and most recent scans)., Results: Forty-two patients (26.2% pediatric) underwent EEO: 78.6% had basilar invagination, and 76.2% had Chiari type I malformation. The mean ± SD age was 33.6 ± 3.0 years, with a mean follow-up of 32.3 ± 4.0 months. The majority of patients (95.2%) underwent posterior decompression and fusion immediately before EEO. Two patients underwent prior fusion. There were 7 intraoperative CSF leaks but no postoperative CSF leaks. The inferior limit of decompression fell between the nasoaxial and rhinopalatine lines. The mean ± SD vertical height of dens resection was 11.98 ± 0.45 mm, equivalent to a mean ± SD resection of 74.18% ± 2.56%. The mean increase in ventral CSF space immediately postoperatively was 1.68 ± 0.17 mm (p < 0.0001), which increased to 2.75 ± 0.23 mm (p < 0.0001) at the most recent follow-up (p < 0.0001). The median (range) length of stay was 5 (2-33) days. The median time to extubation was 0 (0-3) days. The median time to oral feeding (defined as, at minimum, toleration of a clear liquid diet) was 1 (0-3) day. Symptoms improved in 97.6% of patients. Complications were rare and mostly associated with the cervical fusion portion of the combined surgical procedures., Conclusions: EEO is safe and effective for achieving anterior CMJ decompression and is often accompanied by posterior cervical stabilization. Ventral decompression improves over time. EEO should be considered for patients with appropriate indications.

Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection., Significance: There is a great need for accessible and sensitive screening approaches for HCC worldwide. We have developed an approach for examining genome-wide cfDNA fragmentation features to provide a high-performing and cost-effective approach for liver cancer detection. See related commentary Rolfo and Russo, p. 532. This article is highlighted in the In This Issue feature, p. 517., (©2022 The Authors; Published by the American Association for Cancer Research.)

There have been significant strides toward understanding the molecular landscape of brain cancer. These advances have been focused on analyses of the tumor microenvironment and have recently expanded to include liquid biopsies to identify molecular biomarkers noninvasively. Moving from tissue to liquid-based analyses of molecular biomarkers has been challenging and currently, there are no approved noninvasive tests that are clinically useful. However, the emerging field of molecular liquid biopsy assay development in the neuro-oncology space has great potential to revolutionize the detection and monitoring of patients with brain cancer., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Introduction: Post-traumatic syringomyelia is an uncommon complication after traumatic spinal cord injury. This case study details our decision-making and surgical approach for a patient with symptomatic post-traumatic syringomyelia after sustaining a gunshot wound., Case Presentation: A 24-year-old man with past medical history of distant American Spinal Injury Association Impairment Grade B spinal cord injury due to ballistic injury developed delayed post-traumatic syringomyelia, resulting in unilateral sensory loss and left upper extremity weakness. CT and MR imaging revealed a syrinx spanning his cervical and thoracic spine causing significant spinal cord compression. To relieve achieve decompression and restore CSF flow dynamics, we performed a bony extradural decompression, bullet fragment extraction, spinal cord untethering, and midline myelotomy. Postoperatively, the patient demonstrated clinical and radiographical improvement., Discussion: Post-traumatic syringomyelia is potentially morbid sequalae of spinal cord injuries. Suspicion for post-traumatic syringomyelia should be maintained in patients with delayed, progressive neurologic deficits. In this setting, surgical intervention may require extradural and intradural procedures to mitigate neural compression along the dilated central canal by the syrinx., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Glioblastoma is the most common primary malignant brain tumor and one of the most aggressive tumors across all cancer types with remarkable resistance to any treatment. While immunotherapy has shown a robust clinical benefit in systemic cancers, its benefit is still under investigation in brain cancers. The broader use of immunotherapy in clinical trials for glioblastoma has highlighted the challenges of traditional methods of monitoring progression via imaging. Development of new guidelines, advanced imaging techniques, and immune profiling have emerged to counter premature diagnoses of progressive disease. However, these approaches do not provide a timely diagnosis and are costly and time consuming. Surgery is currently the standard of care for diagnosis of pseudoprogression in cases where MRI is equivocal. However, it is invasive, risky, and disruptive to patient's lives and their oncological treatment. With its increased vascularity, glioblastoma is continually shedding tumor components into the vasculature including tumor cells, genetic material, and extracellular vesicles. These elements can be isolated from routine blood draws and provide a real-time non-invasive indicator of tumor progression. Liquid biopsy therefore presents as an attractive alternative to current methods to guide treatment. While the initial evaluation of liquid biopsy for brain tumors via identification of mutations in the plasma was disappointing, novel technologies and use of alternatives to plasma cell-free DNA analytes provide promise for an effective liquid biopsy approach in brain tumors. This review aims to summarize developments in the use of liquid biopsy to monitor glioblastoma, especially in the context of immunotherapy., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

No portion of this manuscript has previously been presented. Meningiomas, the most common primary intracranial tumors, are histologically categorized by the World Health Organization (WHO) grading system. While higher WHO grade is generally associated with poor clinical outcomes, a significant subset of grade I tumors recur or progress, indicating a need for more reliable models of meningioma behavior. Several groups have developed risk scores based on molecular or immunologic characteristics. These classification schemes show promise, with several models preliminarily demonstrating similar or superior accuracy to WHO grading. Improved understanding of immune system recognition and targeting of meningioma subtypes is necessary to advance the predictive power, as well as develop new therapies. Here, we characterize meningioma molecular drivers, predictive of recurrence and progression, and describe specific aspects of the immune response to meningiomas while highlighting critical questions and ongoing research. Relevant manuscripts of interest were identified using a systematic approach and synthesized into this focused review. Finally, we summarize the ongoing and completed clinical trials for immunotherapy in meningiomas and offer perspective on future directions., Competing Interests: CJ is the co-founder and owns equity interest in Egret Therapeutics. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kannapadi, Shah, Mathios and Jackson.)

Abstract: Liquid biopsy approaches for detection of circulating biomarkers of cancer have been utilized in oncology in many clinical settings from early detection to disease monitoring. Recent approaches have focused on circulating tumor cells, circulating tumor DNA, and circulating RNAs in a variety of biofluids. However, very little progress has been made in implementing such approaches for detection of brain tumors, despite the tremendous clinical need for earlier and less invasive diagnosis, as well as more accurate assessment of disease status. In this review, we highlight the recent methodological improvements in the field of liquid biopsy technologies specifically for glioblastoma. Although many retrospective and few prospective studies have been conducted to assess the utility of circulating biomarkers for detection of brain tumors, none have yet moved forward to clinical implementation., Competing Interests: Conflicts of Interest and Source of Funding: D.M. and J.P. are inventors on patent applications submitted by Johns Hopkins University related to cell-free DNA for cancer detection. J.P. is a cofounder of Delfi Diagnostics, and Johns Hopkins University owns equity in Delfi Diagnostics. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone ( P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ ( P < .0001) and CD8+ IFN-γ ( P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain ( P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy., Competing Interests: The authors do not have any relevant conflicts of interest associated with this manuscript., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer., (© 2021. The Author(s).)

Objective: Because clinically validated biomarkers for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) have not been identified, we aimed to determine whether genotype-phenotype correlations are useful in clinical trials in NF1 and NF2., Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Biomarker Group first performed a systematic literature search and reviewed existing data on genetic biomarkers in NF1 and NF2 and in in malignant peripheral nerve sheath tumors. The group then met during a series of consensus meetings to develop a joint report., Results: We found that in NF2, the genetic severity score is clearly of potential clinical use. In NF1, despite over 3,000 constitutional variants having been described in the NF1 gene, only 4 actionable genotype-phenotype correlations exist. The diagnosis and treatment decision of these tumors should ideally include histopathology and compilation of some of the genetic markers., Conclusion: We summarized emerging clinical use of genotype-phenotype correlations in neurofibromatosis., (© 2021 American Academy of Neurology.)

Objective: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM., Methods: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry., Results: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05)., Conclusions: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Chordomas are malignant, highly recurrent tumors of the midline skeleton that arise from the remnants of the notochord. The development of systemic therapy is critically important to ultimately managing this tumor. Several ongoing trials are attempting to use molecular targeted therapies for mutated pathways in recurrent and advanced chordomas and have shown promise. In addition, immunotherapies, including brachyury-directed vaccination and checkpoint inhibition, have also been attempted with encouraging results. This article discusses the major pathways that have been implicated in the pathogenesis of chordoma with an emphasis on molecular vulnerabilities that future therapies are attempting to exploit., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The tumor-selective human adenovirus Delta24-RGD is currently under investigation in phase II clinical trials for patients with recurrent glioblastoma (GBM). To improve treatments for patients with GBM, we explored the potential of combining Delta24-RGD with antibodies targeting immune checkpoints., Methods: C57BL/6 mice were intracranially injected with GL261 cells and treated with a low dose of Delta24-RGD virus. The expression dynamics of 10 co-signaling molecules known to affect immune activity was assessed in tumor-infiltrating immune cells by flow cytometry after viral injection. The antitumor activity was measured by tumor cell killing and IFNγ production in co-cultures. Efficacy of the combination viro-immunotherapy was tested in vitro and in the GL261 and CT2A orthotopic mouse GBM models. Patient-derived GBM cell cultures were treated with Delta24-RGD to assess changes in PD-L1 expression induced by virus infection., Results: Delta24-RGD therapy increased intratumoral CD8 + T cells expressing Inducible T-cell co-stimulator (ICOS) and PD-1. Functionality assays confirmed a significant positive correlation between tumor cell lysis and IFNγ production in ex vivo cultures (Spearman r = 0.9524; P < .01). Co-cultures significantly increased IFNγ production upon treatment with PD-1 blocking antibodies. In vivo, combination therapy with low-dose Delta24-RGD and anti-PD-1 antibodies significantly improved outcome compared to single-agent therapy in both syngeneic mouse glioma models and increased PD-1 + tumor-infiltrating CD8 + T cells. Delta24-RGD infection induced tumor-specific changes in PD-L1 expression in primary GBM cell cultures., Conclusions: This study demonstrates the potential of using low-dose Delta24-RGD therapy to sensitize glioma for combination with anti-PD-1 antibody therapy., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer., (© 2019 UICC.)

The study of survival outliers of glioblastoma can provide important clues on gliomagenesis as well as on the ways to alter clinical course of this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of glioblastoma. Although the two classical molecular markers of glioblastoma including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are associated with overall survival rate of glioblastoma patients, they are not specific to the survival outliers. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the glioblastoma patients who lived longer than 3 years (n = 17) and the patients who lived less than 1 year (n = 12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of DNA methylation patterns specific to long-term survivors of glioblastoma were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of long-term survivors of glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the long-term survival glioblastoma-specific sites distant from CGI, somatic mutations of glioblastoma are enriched with higher DNA methylation, suggesting that the hypomethylation in long-term survival glioblastoma can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type glioblastoma, we also showed that these two patterns of DNA methylation can be used as molecular markers of long-term survival glioblastoma. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of glioblastoma.

Background: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model., Methods: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry., Results: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines., Conclusions: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

Introduction: Subdural empyema (SDE) is a neurosurgical emergency that is typically treated with surgical drainage, either by burr hole or by craniotomy. Escherichia coli is an uncommon cause of SDE and is associated with infection of a pre-existing subdural hematoma., Case Report: We report the case of an otherwise healthy, immunocompetent 4-month-old infant girl with an E. coli-infected subdural hematoma. The infection persisted despite aggressive neurosurgical treatment that included drainage of the subdural space through burr holes and, subsequently, a wide craniotomy was performed. Ultimately, after 30 days, the SDE resolved with good neurological outcome. A review of prior literature indicates that infected subdural hematomas (including those caused by E. coli) are typically less aggressive and respond to burr hole drainage., Conclusion: We illustrate the fulminant progression of the SDE in the face of neurosurgical treatment. Our experience suggests lowering the threshold for wide craniotomy in these incompletely understood cases.

Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma., (© 2018 UICC.)

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc + tumors, we found that TIGIT expression was upregulated on CD8 + and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45 + immune cells and the percentage of active CD8 + T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer., Competing Interests: Conflict of interest statement: S.B.B. and C.A.Z. have a collaborative research agreement with Janssen. V.B., K.R.W., G.S.C., and K.E.B. are employed by Janssen.

OBJECTIVE Trigeminal neuralgia (TN) is characterized by intermittent, paroxysmal, and lancinating pain along the distribution of the trigeminal nerve. Microvascular decompression (MVD) directly addresses compression of the trigeminal nerve. The purpose of this study was to determine whether patients undergoing MVD as their first surgical intervention experience greater pain control than patients who undergo subsequent MVD. METHODS A retrospective review of patient records from 1998 to 2015 identified a total of 942 patients with TN and 500 patients who underwent MVD. After excluding several cases, 306 patients underwent MVD as their first surgical intervention and 175 patients underwent subsequent MVD. Demographics and clinicopathological data and outcomes were obtained for analysis. RESULTS In patients who underwent subsequent MVD, surgical intervention was performed at an older age (55.22 vs 49.98 years old, p < 0.0001) and the duration of symptoms was greater (7.22 vs 4.45 years, p < 0.0001) than for patients in whom MVD was their first surgical intervention. Patients who underwent initial MVD had improved pain relief and no improvement in pain rates compared with those who had subsequent MVD (95.8% and 4.2% vs 90.3% and 9.7%, respectively, p = 0.0041). Patients who underwent initial MVD had significantly lower rates of facial numbness in the pre- and postoperative periods compared with patients who underwent subsequent MVD (p < 0.0001). The number of complications in both groups was similar (p = 0.4572). CONCLUSIONS The results demonstrate that patients who underwent other procedures prior to MVD had less pain relief and a higher incidence of facial numbness despite rates of complications similar to patients who underwent MVD as their first surgical intervention.

Purpose: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS., Experimental Design: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed., Results: Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples., Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124-36. ©2016 AACR., (©2016 American Association for Cancer Research.)

The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8 + cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types., (Copyright © 2016, American Association for the Advancement of Science.)

[This corrects the article DOI: 10.1186/s40425-016-0132-2.].