Innovation in Non-Invasive Diagnosis and Disease Monitoring for Meningiomas.

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.

Durable headache relief following endoscopic endonasal resection of sub-centimeter Rathke cleft cysts in medically refractory patients.

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.

Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden.

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.

Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types.

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.

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment.

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.

Treatment-refractory Escherichia coli subdural empyema caused by infection of a chronic subdural hematoma in an infant.

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.

Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma.

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.

Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model.

Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.

PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment.

Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.

The lateral transorbital approach to the medial sphenoid wing, anterior clinoid, middle fossa, cavernous sinus, and Meckel's cave: target-based classification, approach-related complications, and intermediate-term ocular outcomes.

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.

Genome-wide repeat landscapes in cancer and cell-free DNA.

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.

Tumor-informed deep sequencing of ctDNA detects minimal residual disease and predicts relapse in osteosarcoma.

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).

Metastatic melanoma to the brain: surgery and radiation is still the standard of care.

Malignant melanoma with brain metastases remains a difficult disease to treat. Patients presenting with disease affecting the central nervous system (CNS) have a poor prognosis. Treatment depends on a number of factors, including the size and number of lesions, performance status, comorbidities, and presenting symptoms. Physicians and patients must weigh risks and benefits of treatments, with the main goal of palliating symptoms and decreasing the risk of neurological death. Opinions throughout the country vary, but first-line treatment for brain metastases is local therapy involving either craniotomy or stereotactic radiosurgery (SRS) using CyberKnife or Gamma Knife, with or without whole brain radiation therapy (WBRT). Clinical trials remain another option for patients, with chemotherapy reserved for patients who have exhausted other options. There has been a recent surge in knowledge regarding the pathophysiology and treatment of metastatic melanoma leading to recent FDA approval in 2011 of new drugs: ipilimumab, a novel immune therapy, and vemurafenib, which blocks the MAP Kinase pathway. These drugs have the potential to treat patients with metastatic melanoma to the brain but are still undergoing clinical investigation. Despite these recent advances, the prognosis is poor, with few patients able to achieve durable and long-lasting response. Treatment for patients with brain metastases continues to lag behind treatment of other diseases, partly due to their exclusion from early clinical trials.

Lateral Transorbital Approach for Repair of Lateral Sphenoid Sinus Meningoencephaloceles in Proximity to Foramen Rotundum: Cadaveric Study and Case Report.

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.

Endoscopic odontoidectomy for brainstem compression in association with posterior fossa decompression and occipitocervical fusion.

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.

Predictors of extent of resection and recurrence following endoscopic endonasal resection of craniopharyngioma.

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.

Cell-Free DNA Fragmentomes in the Diagnostic Evaluation of Patients With Symptoms Suggestive of Lung 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.

Detecting Liver Cancer Using Cell-Free DNA Fragmentomes.

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.