Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations.

BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. RESULTS: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). CONCLUSIONS: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Use of minimally invasive ultrasound transducer during tubular microdiscectomy.

Minimally invasive ultrasound during tubular microdiscectomy is novel. The authors report the technique during surgery for L5-S1 herniated disc. Ultrasound provided real-time visualization of the pathology and neural elements. After discectomy and tactile assessment, ultrasound showed decompression of the thecal sac and traversing nerve root. The patient tolerated the procedure well, with resolution of preoperative pain and strength improvement. Postoperative MRI revealed a residual asymptomatic disc fragment that was retrospectively identified on ultrasonography. Minimally invasive ultrasound could become a useful supplement to direct visual and tactile assessment during tubular microdiscectomy, but further experience with surgical anatomy on ultrasound is required. The video can be found here: https://stream.cadmore.media/r10.3171/2024.1.FOCVID23206.

Real-Time Intraoperative Ultrasound Using a Minimally Invasive Transducer During Anterior Cervical Spine Surgery.

BACKGROUND AND OBJECTIVES: Intraoperative ultrasound (IOUS) during anterior cervical surgery is hindered by large transducer size and small operative corridor. We hypothesized that a linear (minimally invasive) transducer designed for transsphenoidal surgery can visualize the spinal cord, nerve roots, and surrounding structures during anterior cervical approaches, facilitating intraoperative assessment of central and foraminal decompression. METHODS: IOUS was used to evaluate 26 levels in 17 patients (15 anterior cervical discectomy and fusion, 1 corpectomy, 1 arthroplasty) with a linear probe (7 × 6-mm end-fire transducer, 150-mm length, 12-15 MHz). After pin-based distraction, discectomy, and posterior longitudinal ligament resection, IOUS assessed adequacy of cord decompression and, following proximal foraminotomy or uncinectomy, nerve root decompression. If indicated, additional decompression was completed. Criteria for adequate central and foraminal decompression were visualization of subarachnoid space around the cord and cerebrospinal fluid pulsatility along the root sleeve/absence of nerve root compression distal to the root sleeve, respectively. RESULTS: IOUS successfully visualized the cord, nerve roots, and surrounding structures in all 26 levels and influenced management in 11 levels (42.3%). IOUS indicated persistent cord and nerve root compression in 2 and 7 levels, respectively. Planned uncinectomy was aborted in 2 levels after IOUS demonstrated adequate nerve root decompression with intervertebral distraction/proximal foraminotomy alone. IOUS identified persistent nerve root compression after initial proximal foraminotomy in 4 levels and uncinectomy in 2 levels. An unplanned uncinectomy was performed in 1 level after IOUS showed persistent nerve root compression after multiple iterations of proximal foraminotomy. At follow-up (mean 3.1 months), the mean improvement in Numeric Rating Scale neck and arm pain, Neck Disability Index, and modified Japanese Orthopedic Association was 4.0%, 3.2%, 3.7%, and 0.7%, respectively. CONCLUSION: The neural elements and their relationships to surrounding bone/soft tissue can be visualized using a minimally invasive IOUS transducer during anterior cervical surgery without having to remove pin-based distraction. This allows surgeons to intraoperatively verify the extent of central and foraminal decompression.

Trans-Sternal Multilevel Corpectomy for Cervicothoracic Renal Cell Metastasis: 2-Dimensional Operative Video.

The operative management of pathological fractures at the cervicothoracic junction is a surgical challenge. Here, we present the case of a 48-year-old male patient presenting with 2 months of progressive left upper extremity weakness as well as back and bilateral arm pain (Karnofsky Performance Status 60%) who was found to have pathological fractures from C7, T1, and T2 due to metastatic renal cell carcinoma. Renal cell carcinoma is known to metastasize to bone and cause cord compression.1 Given the extensive metastasis with this highly vascular tumor, endovascular embolization was performed preoperatively to minimize intraoperative blood loss.2 Surgical management consisted of a two-stage procedure. Posterior spinal fusion from C2-T7 with C7-T2 decompression was performed during stage 1. Stage 2 consisted of a trans-sternal approach for C7, T1, and T2 corpectomy for cord decompression and placement of a cage and plate for anterior column support.3 Although prior surgeons have suggested to access upper thoracic pathology through an interaortocaval window, in this case we demonstrate a trans-sternal approach to C6-T3 that starts superior to the innominate vein and aortic arch and angles inferiorly dorsal to these vascular structures.4 When planning for a manubriotomy/trans-sternal approach, access to T1/T2 remains the most decisive factor and is most successful with a sternotomy.5 At 12-month follow-up, the patient demonstrated improvement in his left upper extremity strength and overall functional status (3/5 strength in hand grip and interossei with 5/5 in all remaining motor groups; Karnofsky Performance Status 80%). The patient consented to participate in the surgery and surgical video.

Multilevel Laminoplasty for CSM: Is C3 Laminectomy Better Than C3 Laminoplasty at the Superior Vertebra?

INTRODUCTION: In a multilevel cervical laminoplasty operation for patients with cervical spondylotic myelopathy (CSM), a partial or complete C3 laminectomy may be performed at the upper level instead of a C3 plated laminoplasty. It is unknown whether C3 technique above the laminoplasty affects loss of cervical lordosis or range of motion. METHODS: Patients undergoing multilevel laminoplasty of the cervical spine (C3-C6/C7) at a single institution were retrospectively reviewed. Patients were divided into two cohorts based on surgical technique at C3: C3-C6/C7 plated laminoplasty ("C3 laminoplasty only", N = 61), C3 partial or complete laminectomy, plus C4-C6/C7 plated laminoplasty (N = 39). All patients had at least 1-year postoperative X-ray treatment. RESULTS: Of 100 total patients, C3 laminoplasty and C3 laminectomy were equivalent in all demographic data, except for age (66.4 vs. 59.4 years, p = 0.012). None of the preoperative radiographic parameters differed between the C3 laminoplasty and C3 laminectomy cohorts: cervical lordosis (13.1° vs. 11.1°, p = 0.259), T1 slope (32.9° vs. 29.2°, p = 0.072), T1 slope-cervical lordosis (19.8° vs. 18.6°, p = 0.485), or cervical sagittal vertical axis (3.1 cm vs. 2.7 cm, p = 0.193). None of the postoperative radiographic parameters differed between the C3 laminoplasty and C3 laminectomy cohorts: cervical lordosis (9.4° vs. 11.2°, p = 0.369), T1 slope-cervical lordosis (21.7° vs. 18.1°, p = 0.126), to cervical sagittal vertical axis (3.3 cm vs. 3.6 cm, p = 0.479). In the total cohort, 31% had loss of cervical lordosis >5°. Loss of lordosis reached 5-10° (mild change) in 13% of patients and >10° (moderate change) in 18% of patients. C3 laminoplasty and C3 laminectomy cohorts did not differ with respect to no change (<5°: 65.6% vs. 74.3%, respectively), mild change (5-10°: 14.8% vs. 10.3%), and moderate change (>10°: 19.7% vs. 15.4%) in cervical lordosis, p = 0.644. When controlling for age, ordinal regression showed that surgical technique at C3 did not increase the odds of postoperative loss of cervical lordosis. C3 laminectomy versus C3 laminoplasty did not differ in the postoperative range of motion on cervical flexion-extension X-rays (23.9° vs. 21.7°, p = 0.451, N = 91). CONCLUSION: There was no difference in postoperative loss of cervical lordosis or postoperative range of motion in patients who underwent either C3-C6/C7 plated laminoplasty or C3 laminectomy plus C4-C6/C7 plated laminoplasty.