Real-World Experience with 177Lu-PSMA-617 Radioligand Therapy After Food and Drug Administration Approval.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

MEK/CDK4,6 co-targeting is effective in a subset of NRAS, BRAF and 'wild type' melanomas.

Targeted therapy has become a cornerstone for the treatment of melanoma patients. Targeting NRAS function is particularly challenging. To date, only single MEK inhibitor treatment was able to show minimal clinical efficacy. The discovery that co-targeting of MEK and CDK4,6 has antitumor activity created excitement for patients and clinicians; however, it is largely unknown if only NRAS mutant patients might benefit from MEK/CDK4,6 blockade. In this study we investigate response patterns of NRAS, BRAF mutant and 'wild type' melanoma cells in vitro and in vivo when challenged with inhibitors of MEK, CDK4,6 and the combination of both. Data revealed, that in vitro growth response patterns of cells treated with the MEK/CDK4,6 combination correspond to in vivo efficacy of MEK/CDK4,6 co-targeting in melanoma xenograft models. Strikingly, this was consistently observed in NRAS and BRAF mutant, as well as in 'wild type' melanoma cells. Additionally, cells displaying elevated p-Rb levels after single MEK inhibition, showed more effective growth reduction with MEK/CDK4,6 co-targeting compared to single MEK inhibitor treatment in vivo. Findings indicate that combined MEK/CDK4,6 inhibition could offer an effectively therapeutic modality in a subset of BRAF and NRAS mutant, as well as 'wild type' melanoma patients.

Imaging and Surgical Management of Anorectal Vaginal Fistulas.

Anorectal vaginal fistulas (ARVFs) can result in substantial morbidity and potentially embarrassing symptoms in adult women of all ages. Despite having what may be obvious clinical manifestations, the fistulas themselves can be difficult to identify with imaging. MRI is the modality of choice for the diagnosis and characterization of ARVFs. A dedicated protocol involving the use of vaginal gel and optimized imaging planes with respect to the vagina, as well as an understanding of the MRI pelvic floor anatomy, is crucial for reporting surgically relevant details. Ancillary findings such as postsurgical changes, inflammation, abscess, sphincter destruction, and neoplasm are well evaluated. Vaginography, contrast enema, endoscopic US, and CT can be highly useful complementary diagnostic examinations. The entities that result in ARVFs may be obstetric, inflammatory (eg, Crohn disease and diverticulitis), neoplastic, iatrogenic, and/or radiation induced. Surgical management is heavily dependent on the cause and complexity of the fistulizing disease, which are related to the location of the fistula in the vagina, the type and extent of fistula branching, the number of fistulas, sphincter tears, inflammation, and abscess. ©RSNA, 2018.

Association between carotid artery tortuosity and carotid dissection: a case-control study.

BACKGROUND: Carotid artery dissections have long been associated with compromise of the structural integrity of the arterial wall from heritable connective-tissue disorders, hypertension, and trauma. However, an association between spontaneous internal carotid artery dissection and tortuous or redundant carotid anatomy has not been fully explored. METHODS: Patients with CTA confirmed spontaneous cervical internal carotid artery dissections were compared to a group of age and sex matched controls who also received CTA of the neck. Patients with trauma or aortic dissections were excluded. Five radiologists reviewed the CTA images to evaluate internal carotid artery tortuosity (reported as loops, kinks or coils), retrojugular and retropharyngeal courses of the internal carotid artery, presence of fibromuscular dysplasia and presence of atherosclerotic disease. Baseline data collected included demographic characteristics (sex, age, smoking history) and cardiovascular comorbidities. RESULTS: A total of 83 cervical internal carotid artery dissection and their age and sex matched controls were included in this study. 46% of patients were female in each group and mean age was 49.2±10.6 years. The presence of any carotid tortuosity was 53% (N.=44) and 34% (N.=28) in the per-patient analysis of dissection and control groups, respectively (P=0.02). Loops were reported in 22% (N.=18) of dissection patients and 8% (N.=7) of controls (P=0.03). Retrojugular course of the internal carotid artery were seen in 23% (N.=38) of dissection patients and 9% (N.=15) of controls (P=0.0009) in the per-vessel analysis. CONCLUSIONS: Our study suggests that there is an association between the presence of tortuous carotid artery anatomy and spontaneous carotid artery dissection. This finding emphasizes the importance of the presence of tortuous arteries on CTA imaging to increase the index of suspicion for a potential dissection.

Increased Prevalence of Cerebrovascular Disease in Hospitalized Patients with Marfan Syndrome.

BACKGROUND AND PURPOSE: Small studies have suggested that Marfan syndrome is associated with a number of cerebrovascular complications. We sought to determine whether a clinical diagnosis of Marfan syndrome is associated with a higher prevalence of cerebrovascular diseases than the general population by performing a case-control study of hospitalized patients in the Nationwide Inpatient Sample (NIS). METHODS: Using the 2000-2012 NIS, we performed a case-control study matching cases of Marfan syndrome to controls without such a diagnosis. The prevalence of various cerebrovascular diseases between the 2 groups were compared, and multivariate logistic regression was used to adjust for suspected comorbidities. RESULTS: Between 2000 and 2012, there were a total of 13,883 discharges carrying a diagnosis of Marfan syndrome. On univariate analysis, patients with Marfan syndrome were more likely to have a primary or secondary diagnosis of hemorrhagic stroke (0.5% versus 0.3%, odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.06-2.29, P = 0.02) as well as intracranial hemorrhage (subarachnoid hemorrhage [SAH] and hemorrhagic stroke) (0.3% versus 0.2%, OR = 1.72, 95% CI = 1.05-2.82, P = 0.03). Patients hospitalized with Marfan syndrome were significantly more likely to have carotid dissection (0.3% versus 0.0%, OR = 11.69, 95% CI = 3.60-38.08, P <. 0001) and cerebral aneurysms (0.2% versus 0.1%, OR = 3.67, 95% CI = 1.76-7.68, P = 0.0002). On multivariate analysis adjusted for age, race, and comorbidities, patients with Marfan syndrome had significantly higher odds of ischemic stroke (OR = 1.20, 95% CI = 1.02-1.43, P = 0.03), hemorrhagic stroke (OR = 1.75, 95% CI = 1.18-2.63, P = 0.005), carotid artery dissection (OR = 11.94, 95% CI = 4.23-50.03, P < 0.0001), and cerebral aneurysm (OR = 3.95, 95% CI = 1.95-8.90, P <0.0001). CONCLUSIONS: There is a modestly increased prevalence of ischemic stroke, hemorrhagic stroke, and cerebral aneurysms in hospitalized patients with Marfan syndrome when compared with controls.

Increased Prevalence of Cerebrovascular Disease in Hospitalized Patients with Ehlers-Danlos Syndrome.

BACKGROUND AND PURPOSE: Small studies have suggested that Ehlers-Danlos syndrome (EDS) is associated with a number of cerebrovascular complications. We sought to determine whether a clinical diagnosis of EDS is associated with a higher prevalence of cerebrovascular diseases than the general population by performing a case-control study of hospitalized patients in the Nationwide Inpatient Sample (NIS). METHODS: Using the 2000-2012 NIS, we performed a case-control study matching cases of EDS to controls without such a diagnosis. The prevalence of various cerebrovascular diseases between the 2 groups was compared, and multivariate logistic regression was used to adjust for suspected comorbidities. RESULTS: Between 2000 and 2012, there were a total of 9067 discharges carrying a diagnosis of EDS. On univariate analysis, patients with EDS were more likely to be hospitalized for carotid dissection (.2% versus .01%, odds ratio [OR] = 18.0, confidence interval [CI] = 2.41-135.12, P < .0001), vertebral dissection (.1% versus 0%, P = .008), cervical artery aneurysm (.1% versus .01%, OR = 9.01, CI = 1.14-71.11, P < .0001), cerebral aneurysm (.4% versus .09%, OR = 4.89, CI = 2.28-10.47, P < .0001), and cerebrovascular malformation (.1% versus .02%, OR = 5, CI = 1.10-22.85, P = .021), compared to the controls. On multivariate analysis adjusted for age, race, and comorbidities, EDS patients had significantly higher odds of carotid dissection (OR = 15.02, CI = 3.08-270.87, P < .0001), vertebral dissection (OR = 2406539.5, P = .0037), cervical artery aneurysm (OR = 11.75, CI = 2.11-220.71, P = .0026), cerebral aneurysm (OR = 5.59, CI = 2.69-13.18, P < .0001), and cerebrovascular malformation (OR = 4.67, CI = 1.20-30.87, P = .0243). CONCLUSIONS: Carotid and vertebral dissections, cervical and cerebral aneurysms, as well as other cerebrovascular malformations are more common in hospitalized patients with EDS compared to controls.

Cross-sectional imaging in refractory celiac disease.

PURPOSE: The purpose of this study is to identify unique imaging findings of refractory celiac disease (RCD) including Type I RCD, Type II RCD versus healed celiac disease (CD). METHODS: A retrospective study of patients with known CD and refractory symptoms with cross-sectional imaging was performed. We included patients who underwent T cell receptor rearrangement or T-cell immunophenotyping studies on small bowel (SB) biopsies to classify patients into: healed CD, Type I RCD, or Type II RCD. GI radiologists performed a blinded review of the imaging studies. RESULTS: One-hundred eighteen patients (32 healed; 67 Type I RCD; 19 Type II RCD) were included (mean age 53 ± 6 years; 62% female). The presence of any fold pattern abnormality was more likely to be found in Type II and Type I RCD than healed CD (53% vs. 43% vs.16%; p = 0.009). Type II RCD patients were more likely than Type I RCD and healed CD to have imaging findings of ulcerative jejunitis (26% vs. 6% vs. 3%; p = 0.009), SB wall thickening (37% vs. 16% vs. 0%; p = 0.002) and SB dilation (26% vs. 7% vs. 6%; p = 0.04). Type II RCD demonstrated non-significant trends for decreased number of jejunal folds only, SB mass, mesenteric lymphadenopathy, localized peri-mural edema, and intramural duodenal edema. CONCLUSIONS: Fold pattern abnormalities, ulcerative jejunitis, SB wall thickening, and SB dilation are more likely to be identified in cross-sectional imaging of RCD than healed CD. SB dilatation and ulcerative jejunitis are more likely to be found in Type II than Type I RCD.

Neurovascular manifestations of connective-tissue diseases: A review.

Patients with connective tissue diseases are thought to be at a higher risk for a number of cerebrovascular diseases such as intracranial aneurysms, dissections, and acute ischemic strokes. In this report, we aim to understand the prevalence and occurrences of such neurovascular manifestations in four heritable connective tissue disorders: Marfan syndrome, Ehlers-Danlos syndrome, Neurofibromatosis Type 1, and Loeys-Dietz syndrome. We discuss the fact that although there are various case studies reporting neurovascular findings in these connective tissue diseases, there is a general lack of case-control and prospective studies investigating the true prevalence of these findings in these patient populations. Furthermore, the differences observed in the manifestations and histology of such disease pathologies encourages future multi-center registries and studies in better characterizing the pathophysiology, prevalence, and ideal treatment options of neurovascular lesions in patents with connective tissue diseases.

Phosphoproteomic Analyses of NRAS(G12) and NRAS(Q61) Mutant Melanocytes Reveal Increased CK2α Kinase Levels in NRAS(Q61) Mutant Cells.

In melanoma, mutant and thereby constantly active neuroblastoma rat sarcoma (NRAS) affects 15-20% of tumors, contributing to tumor initiation, growth, invasion, and metastasis. Recent therapeutic approaches aim to mimic RAS extinction by interfering with critical signaling pathways downstream of the mutant protein. This study investigates the phosphoproteome of primary human melanocytes bearing mutations in the two hot spots of NRAS, NRAS(G12) and NRAS(Q61). Stable isotope labeling by amino acids in cell culture followed by mass spectrometry identified 14,155 spectra of 3,371 unique phosphopeptides mapping to 1,159 proteins (false discovery rate < 2%). Data revealed pronounced PI3K/AKT signaling in NRAS(G12V) mutant cells and pronounced mitogen-activated protein kinase (MAPK) signaling in NRAS(Q61L) variants. Computer-based prediction models for kinases involved, revealed that CK2α is significantly overrepresented in primary human melanocytes bearing NRAS(Q61L) mutations. Similar differences were found in human NRAS(Q61) mutant melanoma cell lines that were also more sensitive to pharmacologic CK2α inhibition compared with NRAS(G12) mutant cells. Furthermore, CK2α levels were pronounced in patient samples of NRAS(Q61) mutant melanoma at the mRNA and protein level. The preclinical findings of this study reveal that codon 12 and 61 mutant NRAS cells have distinct signaling characteristics that could allow for the development of more effective, mutation-specific treatment modalities.