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.

Acute Upper-Limb Complications Following Radial Artery Catheterization for Coronary Angiography.

PURPOSE: The radial artery is becoming the vessel of choice for performing cardiac catheterization. Transradial catheterization can impose risks on the upper extremity, and hand surgeons should be aware of the most frequent complications. The purpose of this study was to determine the frequency, timing, and scope of upper-limb complications shortly after transradial catheterization. METHODS: A retrospective review was conducted of the medical records of patients who underwent catheterization between 2009 and 2016. Complications were assessed for up to 60 days. The Cox model was used to assess risk factors for complications. RESULTS: A total of 10,540 patients were included in the analysis (68.5% male), median age 67 years. There were 79 patients who experienced at least one complication within 60 days (0.84% of procedures; 95% confidence interval, 0.65% to 1.02%). The most common complications were hematoma (n = 39) and radial artery occlusion (n = 28). Other complications included pseudoaneurysm (n = 7), arteriovenous fistula (n = 3), carpal tunnel syndrome (n = 4), arterial perforation (n = 3), persistent vasospasm (n = 2), and compartment syndrome (n = 1). The complications were diagnosed a median of 1 day after catheterization. Female sex was at increased risk for developing a complication. Diabetes, age, body mass index, and catheter size were not associated with an increased risk for developing a complication. Ten patients underwent surgical management of a complication. Reasons for surgery included symptomatic radial artery occlusions, pseudoaneurysm formation, arteriovenous fistulas, and compartment syndrome. No identifiable risk factors were associated with patients who underwent surgical intervention. CONCLUSIONS: The frequency of upper-limb complications after radial artery catheterization is small. They include arterial occlusion, bleeding, compartment syndrome, arteriovenous fistula, and pseudoaneurysm. Most complications presented within 1 week of the procedure and occurred more frequently in the female sex. Operative management of complications was infrequent. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

The evolving role of imaging for small bowel neuroendocrine neoplasms: estimated impact of imaging and disease-free survival in a retrospective observational study.

PURPOSE: To determine how small bowel neuroendocrine neoplasms (SBNEN's) are diagnosed and examine the effect of CT enterography (CTE) on diagnosis and rates of disease-free survival. METHODS: Histopathologically-confirmed SBNEN's diagnosed at our institution between 1996 and 2016 were identified. Clinical presentation, radiology, endoscopy, surgery, and pathology reports were reviewed and compared between consecutive 5-year periods. RESULTS: Of the 178 SBNEN initially diagnosed at our institution, the incidence increased 12-fold from 9 (during 1996-2000) to 114 (during 2011-2016). Comparing the first 5 to the last 5 years, GI bleeding and abdominal pain increased significantly as indications (with both increasing from 0 to > 25%, p ≤ 0.023). Initial diagnosis by radiology increased 2-fold [from 33% (n = 3) to 66% (n = 75); p = 0.263]. Detection of a small bowel mass and the suggestion that SBNEN was present varied significantly between imaging modalities (p < 0.0001; CTE - 95% (52/55) and 91% (50/55) vs. abdominal CT 45% (37/85) and 35% (29/85), respectively). Recurrence rates increased with SBNEN size (p = 0.012; e.g., of SBNEN diagnosed by endoscopy, 18% of SBNEN measuring 0.6 ± 0.3 cm recurred vs. 75% measuring 3.7 ± 1.0 cm). Rates of disease-free survival, and the incidence of local and liver metastases were decreased when tumors were first identified by CTE rather than other CT/MR imaging modalities (p = 0.0034, 0.0475, and 0.0032, respectively). CONCLUSION: There has been a dramatic increase in SBNENs detected by CTE and endoscopy over the last 20 years. SBNEN's detected by CTE and small tumors detected at endoscopy have longer disease-free survival after surgical resection.

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.

Melanoma immunotherapy.

Immunotherapy is a cornerstone in the treatment of melanoma, and is intended to modulate the host immunity against the tumor. Immunotherapy can be used in an adjuvant setting, after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages. Development of novel therapeutic approaches and the optimization of existing therapies hold a great promise in the field of melanoma therapy research. Different clinical trials are ongoing, and immunotherapy is showing the ability to confirm durable clinical benefits in selected groups of melanoma patients. The aim of this review is to summarize different types of immunotherapy agents, as well as to discuss different strategies, complementary regimens, and possible biomarkers of response to the treatment.