Ashraf Thabet

Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations

PURPOSE To assess long-term clinical and imaging results of technically successful pulmonary arteriovenous malformation (AVM) embolization. MATERIALS AND METHODS One hundred fifty-five patients with pulmonary AVMs underwent embolization during a period of 3 years. Recommended follow-up included clinical assessment, helical computed tomography, and physiologic evaluation within 1 year and then every 5 years. RESULTS Hereditary hemorrhagic telangiectasia was present in 148 patients (95%). Four hundred fifteen pulmonary AVMs were occluded during 205 procedures. Clinical follow-up was available in all patients over 3-7 years and imaging follow-up was available in 144 patients (393 lesions) over 1-7 years (mean, 2.9 y). Problems related to pulmonary AVMs occurred in 35 patients (23%) at 42 time points: 22 patients with 23 symptomatic events and 17 patients with 19 asymptomatic events. Symptoms resulted from growth of nonembolized pulmonary AVMs (n = 19), residual embolized pulmonary AVMs (n = 5), or both (n = 2). Symptoms consisted of respiratory manifestations (n = 13), cerebral ischemia (n = 4), brain abscess (n = 5), hemoptysis (n = 3), and seizure (n = 1). Imaging showed pulmonary AVM involution in 97% of embolized lesions and 11 residual lesions (2.8%) in 10 patients (6.9%). These were caused by recanalization (n = 7), presence of an accessory feeding artery (n = 1), pulmonary collateral vessels (n = 1), and bronchial collateral vessels (n = 2). CT detected 10 of the 11 residual lesions. Imaging detected 97 previously small pulmonary AVMs that had enlarged to a significant size in 28 patients (18%), 15 of whom were symptomatic and 13 of whom were asymptomatic. CONCLUSIONS Clinical and anatomic evaluation after pulmonary AVM embolization is important to detect persistent or reperfused lesions and enlarging lesions, with the latter more common. Patients with persistent, reperfused, or enlarging lesions often have symptoms, but a significant minority of patients are asymptomatic. More frequent assessment may improve detection before the onset of symptoms.

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer

UNLABELLED How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patients progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient. SIGNIFICANCE Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.

CT-guided Celiac Plexus Neurolysis: A Review of Anatomy, Indications, Technique, and Tips for Successful Treatment

The celiac plexus is the largest visceral plexus and is located deep in the retroperitoneum, over the anterolateral surface of the aorta and around the origin of the celiac trunk. It serves as a relay center for nociceptive impulses that originate from the upper abdominal viscera, from the stomach to the proximal transverse colon. Celiac plexus neurolysis, with agents such as ethanol, is an effective means of diminishing pain that arises from these structures. Percutaneous imaging-guided celiac plexus neurolysis has been established as an invaluable therapeutic option in the management of intractable abdominal pain in patients with upper abdominal malignancy. The use of multidetector computed tomography (CT) for imaging guidance has superseded other modalities and allows direct visualization of the spread of the neurolytic agent in the antecrural space. Accurate depiction of the retroperitoneal anatomy and the position of the needle tip helps avoid crucial anatomic structures such as the pancreas, aorta, celiac artery, and superior mesenteric artery. Proper patient education, meticulous preprocedure planning, use of optimal multidetector CT techniques, adjunctive CT maneuvers, and postprocedure care are integral to successful celiac plexus neurolysis. Celiac plexus neurolysis does not completely abolish pain; rather, it diminishes pain, helping to reduce opioid requirements and their related side effects and improving survival in patients with upper abdominal malignancy.

Recent Advances in Transarterial Therapy of Primary and Secondary Liver Malignancies

The management of liver malignancies presents many challenges. Few patients with primary hepatocellular carcinoma or metastatic disease of the liver are eligible for surgery, which is the only curative therapeutic option. Because the hepatic tumor burden is often a determinant of eligibility for surgery and is a primary contributor to morbidity and mortality, an increasing number of innovative techniques based on the transarterial administration of liver-directed drug-eluting or radiation-emitting microspheres are being tested for use in cytoreductive and palliative therapy. The delivery of therapy via a transarterial route takes advantage of the fact that hepatic malignancies are primarily supplied by the hepatic artery. The early results of clinical trials are promising; the clinical effectiveness and safety of drug-eluting and yttrium-90-bearing microspheres have been demonstrated; however, further clinical investigation is needed to verify a benefit in survival. Transarterially administered gene therapy holds promise but is still in the early stages of investigation. For all transarterial therapies, the outcome depends heavily on meticulous patient selection, careful preparation and administration of therapy, and early and regular follow-up evaluations by using an interdisciplinary approach.

Percutaneous image-guided therapy of intra-abdominal malignancy: imaging evaluation of treatment response

The rising incidence of abdominal malignancies such as hepatocellular carcinoma (HCC) and renal cell carcinoma presents several challenges. Although surgery typically provides the best chance for cure, many patients are not surgical candidates. Innovative percutaneous therapies such as transarterial chemoembolization (TACE), radioembolization, and radiofrequency ablation (RFA) are increasingly being utilized as alternative treatment modalities, in some cases, with proven survival benefit. With the rise in interventional oncology, radiologists are being increasingly asked to interpret post-treatment imaging examinations that are critical to assessing treatment efficacy and complications. This article reviews the imaging manifestations of the most common percutaneous therapies, with special emphasis on TACE and RFA. Imaging findings of treatment-induced tumor necrosis, viable tumor, complications, and, in particular, benign ancillary findings that may be confused with viable tumor are reviewed, as manifested on computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET).

Interventional Radiology in Pregnancy Complications: Indications, Technique, and Methods for Minimizing Radiation Exposure

Complications of pregnancy, whether they occur during gestation or postpartum, often pose complex challenges because they affect two patients (mother and fetus or infant) and because both short- and long-term outcomes must be considered in management decision making. Interventional radiologists play a critical role in treating complications such as ectopic implantation, postpartum hemorrhage, symptomatic ovarian cyst, post-cesarean section fluid collection, obstructive uropathy, and vesicouterine fistula. Interventional radiology offers therapeutic options that obviate surgery, thereby minimizing morbidity and mortality and maximizing the potential for fertility preservation. Such options include chemical injection of an ectopic gestational sac, uterine artery embolization, aspiration and drainage, percutaneous nephrostomy, and suprapubic cystostomy catheter placement. All these procedures are performed with the use of radiologic imaging for guidance. The levels of radiation to which the mother and fetus may be exposed during such procedures are of concern because of potential negative effects on long-term health. However, various methods can be used to lower maternal and fetal radiation dose levels to the minimum needed to accomplish the clinical objective.

Comparative assessment of three image reconstruction techniques for image quality and radiation dose in patients undergoing abdominopelvic multidetector CT examinations

OBJECTIVE To compare image quality and radiation dose of abdominal CT examinations reconstructed with three image reconstruction techniques. METHODS In this Institutional Review Board-approved study, contrast-enhanced (CE) abdominopelvic CT scans from 23 patients were reconstructed using filtered back projection (FBP), adaptive statistical iterative reconstruction (ASiR) and iterative reconstruction in image space (IRIS) and were reviewed by two blinded readers. Subjective (acceptability, sharpness, noise and artefacts) and objective (noise) measures of image quality were recorded for each image data set. Radiation doses in CT dose index (CTDI) dose-length product were also calculated for each examination type and compared. Imaging parameters were compared using the Wilcoxon signed rank test and a paired t-test. RESULTS All 69 CECT examinations were of diagnostic quality and similar for overall acceptability (mean grade for ASiR, 3.9±0.3; p=0.2 for Readers 1 and 2; IRIS, 3.9±0.4, p=0.2; FBP, 3.8±0.9). Objective noise was considerably lower with both iterative techniques (p<0.0001 and 0.0016 for ASiR and IRIS). Recorded mean radiation dose, i.e. CTDI(vol), was 24% and 10% less with ASiR (11.4±3.4 mGy; p<0.001) and IRIS (13.5±3.7 mGy; p=0.06), respectively, than with FBP: 15.0±3.5 mGy. CONCLUSION At the system parameters used in this study, abdominal CT scans reconstructed with ASiR and IRIS provide diagnostic images with reduced image noise and 10-24% lower radiation dose than FBP. ADVANCES IN KNOWLEDGE CT images reconstructed with FBP are frequently noisy on lowering the radiation dose. Newer iterative reconstruction techniques have different approaches to produce images with less noise; ASiR and IRIS provide diagnostic abdominal CT images with reduced image noise and radiation dose compared with FBP. This has been documented in this study.

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.

BACKGROUND Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. METHODS In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. RESULTS We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. CONCLUSION Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. IMPLICATIONS FOR PRACTICE Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.

A contemporary series of patients undergoing open debridement for necrotizing pancreatitis

BACKGROUND For patients with acute pancreatitis complicated by infected necrosis, minimally invasive techniques have taken hold without substantial comparison with open surgery. We present a contemporary series of open necrosectomies as a benchmark for newer techniques. METHODS Using a prospective database, we retrospectively identified consecutive patients undergoing debridement for necrotizing pancreatitis (2006 to 2009). The primary endpoint was in-hospital mortality. RESULTS Sixty-eight patients underwent debridement for pancreatic/peripancreatic necrosis. In-hospital mortality was 8.8% (n = 6). Infection (n = 43, 63%) and failure-to-thrive (n = 13, 19%) comprised the most common indications for necrosectomy. The false negative rate (FNR) for infection of percutaneous aspirate was 20.0%. Older age (P = .02), Acute Physiology and Chronic Health Evaluation II score upon admission (P = .03) or preoperatively (P < .01), preoperative intensive care unit admission (P = .01), and postoperative organ failure (P = .03) were associated with mortality. CONCLUSIONS Open debridement for necrotizing pancreatitis results in a low mortality, providing a useful comparator for other interventions. Given the high FNR of percutaneous aspirate, debridement should not be predicated on proven infection.