Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic ...option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
•Genome-wide screening identifies PTPN1 and PTPN2 as phosphatases involved in ALK inhibitor resistance in lymphoma.•PTPN1 and PTPN2 regulate ALK and SHP2 phosphorylation, and combined inhibition of ALK and SHP2 is an effective approach to treat ALCL.
Display omitted
Arteriovenous malformations (AVMs) are high-pressure, low-resistance arterial-venous shunts without intervening capillaries. Up to 60% of AVMs present with an intracranial hemorrhage; however, ...noninvasive neuroimaging has increasingly diagnosed incidental AVMs. AVM management depends on weighing the lifetime rupture risk against the risks of intervention. Although AVM rupture risk relies primarily on angioarchitectural features, measuring hemodynamic flow is gaining traction. Accurate understanding of AVM hemodynamic flow parameters will help endovascular neurosurgeons and interventional neuroradiologists stratify patients by rupture risk and select treatment plans. This review examines various neuroimaging modalities and their capabilities to quantify AVM flow, as well as the relationship between AVM flow and rupture risk. Quantitative hemodynamic studies on the relationship between AVM flow and rupture risk have not reached a clear consensus; however, the preponderance of data suggests that higher arterial inflow and lower venous outflow in the AVM nidus contribute to increased hemorrhagic risk. Future studies should consider using larger sample sizes and standardized definitions of hemodynamic parameters to reach a consensus. In the meantime, classic angioarchitectural features may be more strongly correlated with AVM rupture than the amount of blood flow.
The objective of this study was to assess the relationship of arteriovenous malformation (AVM) blood flow measured by quantitative MR angiography (QMRA) in nonruptured AVMs with MR-detected ...microhemorrhage.
All patients with unruptured AVMs who received baseline QMRA and gradient echo or susceptibility-weighted MRI were retrospectively reviewed (2004-2022). Imaging data, clinical history, and AVM angioarchitectural and flow features were collected and assessed. AVM flow was calculated from the difference of flow within primary arterial feeders from their contralateral counterparts. A review of the MR images determined the presence of microhemorrhages. Analysis of descriptive statistics, chi-square test, and binomial logistic regression were performed.
Of 634 patients with cerebral AVMs at a single center, 89 patients met the inclusion criteria (54 with microhemorrhage and 35 without microhemorrhage). The calculated AVM flow was significantly higher in the group with a microhemorrhage (447.9 ± 193.1 ml/min vs 287.6 ± 235.7 ml/min, p = 0.009). In addition, the presence of venous anomaly, arterial ectasia, and diffuse nidus was significantly associated with microhemorrhage (p = 0.017, p = 0.041, and p = 0.041, respectively). Binary logistic regression found that higher flow predicted the presence of microhemorrhage (OR 1.002, 95% CI 1.000-1.004; p = 0.031). The highest AVM flow quartile significantly predicted the presence of venous anomaly (OR 3.840, 95% CI 1.037-14.213; p = 0.044), diffuse nidus (OR 6.800, 95% CI 1.766-25.181; p = 0.005), and arterial ectasia (OR 13.846, 95% CI 1.905-122.584; p = 0.018).
This study represents the first to examine the association between flow measurements on QMRA with microhemorrhage in unruptured AVMs. Higher AVM flow, venous anomaly, arterial ectasia, and diffuse AVM nidus were related to a higher likelihood of AVM microhemorrhage. Higher AVM flow was present in AVMs with venous anomalies, a diffuse nidus, and arterial ectasia, indicating a possible interaction between these angioarchitectural findings, AVM flow, and microhemorrhage. These findings suggest a relationship between higher AVM flow and the risk of microhemorrhage.
Background
Stereotactic radiosurgery (SRS) is a current therapeutic option for treatment of arteriovenous malformations (AVMs) located in deep or eloquent brain regions. Obliteration usually occurs ...in a delayed fashion, with an expected latency of 3–5 years. Here, we assess how AVM flow correlates with volume before and after SRS treatment.
Methods
Patients with supratentorial AVM treated with SRS at our institution between 2012–2022 were retrospectively reviewed. Patients were included if Quantitative Magnetic Resonance Angiography (QMRA) study was performed at baseline and at least at the first follow-up. Correlation between AVM flow and volume before and after treatment was evaluated. AVM flow and volume were additionally assessed for obliteration using the non-parametric receiver operating characteristic (ROC) curve.
Results
Twelve patients with radiologic follow-up imaging were included. Eight patients presented AVM rupture, one of which occurred after radiosurgical treatment. Three patients underwent embolization prior SRS. Mean AVM initial volume was 3.8 cc (0.1–12.4 cc), mean initial flow 174 ml/min (11–604 ml/min), both variables showed progressive reduction at follow-up (range 3–57 months); and flow decreased with volume reduction (p < 0.001). Area under the ROC was 0.914 for both AVM flow and volume with obliteration (p = 0.019).
Conclusions
AVM flow significantly decreased after SRS treatment, reflecting volume reduction. Baseline AVM flow and volume both predicted obliteration. QMRA provides additional non-invasive information to monitor patients after radiosurgical treatment.
Preoperative embolization of metastatic spinal tumors (MSTs) has proven advantageous in limiting intraoperative blood loss (IBL) during resection. N-butyl cyanoacrylate (nBCA) is a liquid embolic ...agent known for its rapid hemostatic effects. However, nBCA is associated with a higher risk of distal nontarget embolization. This study highlights the refinement of the embolization technique and assesses its efficacy in performing an initial distal segmental artery plug with concentrated nBCA followed by proximal diluted nBCA for MSTs.
A retrospective review of patients with MST (2018-2023) was performed. Patients who underwent preoperative nBCA endovascular embolization prior to tumor resection and spinal instrumentation were included. Baseline standard spinal angiography was performed.
Sixteen patients (13 men, 3 women; 56.0 ± 12.4 years) met inclusion criteria. And 43.75% (7 of 16) had thoracic levels, 37.5% (6 of 16) lumbar, and 18.75% (3 of 16) sacral. The most common primary tumor was renal cell carcinoma (43.75%, 7 of 16). A total of 43 pedicles were embolized (median 3), resulting in complete/near complete obliteration of the tumor blush. Most pedicles (83.7%, 36 of 43) received a single dilute concentration of nBCA; however, 16.3% (7 of 43) received two separate concentrations of nBCA, a denser concentration distally into the segmental artery and a diluted concentration proximally into the tumor bed. Mean IBL was 1150 ± 1201 mL in 3 distal plug patients distal plug patients versus 1625 ± 681 mL in 12 other patients. There were no complications related to embolization.
Performing a distal, concentrated nBCA plug during preoperative nBCA embolization of MSTs may increase tumor penetration and reduce IBL.
Background
Compared to vertebral body fusion, artificial discs are thought to lessen the risks of adjacent segment disease and the need for additional surgery by maintaining spinal mobility as they ...mimic the intervertebral disc structure. No studies have compared the rates of postoperative complications and the requirement for secondary surgery at adjacent segments among patients who have undergone anterior lumbar interbody fusions (ALIF) versus those undergoing lumbar arthroplasty.
Methods
An all-payer claims database identified 11,367 individuals who underwent single-level ALIF and lumbar arthroplasty for degenerative disc disease (DDD) between January 2010 and October 2020. Rates of complications following surgery, the need for additional lumbar surgeries, length of stay (LOS), and postoperative opioid utilization were assessed in matched cohorts based on logistic regression models. Kaplan-Meyer plots were created to model the probability of additional surgery.
Results
Following 1:1 exact matching, 846 records of patients who had undergone ALIF or lumbar arthroplasty were analyzed. All-cause readmission within 30–30 days following surgery was significantly higher in patients undergoing ALIF versus arthroplasty (2.6% vs. 0.71%,
p
= 0.02). LOS was significantly lower among the patients who had undergone ALIF (1.043 ± 0.21 vs. 2.17 ± 1.7,
p
< .001).
Conclusions
ALIF and lumbar arthroplasty procedures are equally safe and effective in treating DDD. Our findings do not support that single-level fusions may biomechanically necessitate revisional surgeries.
Reversible cerebral vasoconstriction syndrome is a complex neurovascular syndrome that presents with varying neurological deficits as well as segmental vasoconstriction of the small and medium ...cerebral arteries. There is limited literature on pathologies that mimic reversible cerebral vasoconstriction syndrome, so this study aims to understand what factors may impact the angiographic confirmation of reversible cerebral vasoconstriction syndrome on follow-up and play a role in establishing the diagnosis.
The Clinical Research Data Warehouse at this institution was employed to search the medical records for patients with diagnosis and treatment of reversible cerebral vasoconstriction syndrome between January 2010 and May 2021. After screening, 32 patients met the inclusion criteria for a presumed diagnosis of reversible cerebral vasoconstriction syndrome with both angiography on presentation and at three-month follow-up after treatment. Patients were divided into two categories: those with complete angiographic resolution, versus partial or no improvement on follow-up. Clinical and radiographic data were analyzed.
Patients who had partial or no resolution were more likely to have a history of hypertension (
= 0.001), higher systolic blood pressure on admission (
= 0.047), and present with a recurrent thunderclap headache (
= 0.038). Binary logistic regression selected for hypertension (odds ratio OR 18.35 95% CI, 1.37-245.1) as predictive of not having reversible cerebral vasoconstriction syndrome, as can be seen by partial or no resolution on follow-up angiography (
= 0.028).
Complete resolution on follow-up angiography is a distinguishing factor of reversible cerebral vasoconstriction syndrome. Our analysis revealed that a history of hypertension is the most significant predictor of confirming that a patient may not have reversible cerebral vasoconstriction syndrome. This is due, in part, to increased atherosclerotic or hypertensive cerebral arterial changes, which can mimic reversible cerebral vasoconstriction syndrome and present as partial or no resolution on angiography.
Embolization of brain arteriovenous malformations (bAVMs) is often used as adjuvant therapy to microsurgical resection to reduce the high-risk features of bAVMs such as large size and high flow. ...However, the effect of preoperative embolization on surgical performance and patient outcome has shown mixed results. Heterogeneity in treatment goals, selection criteria, and unpredictable changes in bAVM hemodynamics after partial embolization may account for these uncertain findings. In this study we use an objective quantitative technique to assess the impact of preoperative embolization on intraoperative blood loss (IBL).
Patients with bAVM treated with microsurgical resection only or in combination with preoperative embolization from 2012 to 2022 were retrospectively reviewed. Patients were included if quantitative magnetic resonance angiography was performed prior to any treatment. Correlation of baseline bAVM flow, volume, and IBL was evaluated between the two groups. Additionally, bAVM flow prior to and after embolization was compared.
Forty-three patients were included, 31 of whom required preoperative embolization (20 had more than one session). Mean bAVM initial flow (362.3 mL/min vs 89.6 mL/min, p=0.001) and volume (9.6 mL vs 2.8 mL, p=0.001) were significantly higher in the preoperative embolization group; flow decreased significantly after embolization (408.0 mL/min vs 139.5 mL/min, p<0.001). IBL was comparable between the two groups (258.6 mL vs 141.3 mL, p=0.17). Linear regression continued to show a significant difference in initial bAVM flow (p=0.03) but no significant difference in IBL (p=0.53).
Patients with larger bAVMs who underwent preoperative embolization had comparable IBL to those with smaller bAVMs undergoing only surgical treatment. Preoperative embolization of high-flow bAVMs facilitates surgical resection, reducing the risk of IBL.
