Detection of metastases using circulating tumour DNA in uveal melanoma.

BACKGROUND: Approximately 50% of uveal melanoma (UM) patients will develop metastatic disease depending on the genetic features of the primary tumour. Patients need 3-12 monthly scans, depending on their prognosis, which is costly and often non-specific. Circulating tumour DNA (ctDNA) quantification could serve as a test to detect and monitor patients for early signs of metastasis and therapeutic response. METHODS: We assessed ctDNA as a biomarker in three distinct UM cohorts using droplet-digital PCR: (A) a retrospective analysis of primary UM patients to predict metastases; (B) a prospective analysis of UM patients after resolution of their primary tumour for early detection of metastases; and (C) monitoring treatment response in metastatic UM patients. RESULTS: Cohort A: ctDNA levels were not associated with the development of metastases. Cohort B: ctDNA was detected in 17/25 (68%) with radiological diagnosis of metastases. ctDNA was the strongest predictor of overall survival in a multivariate analysis (HR = 15.8, 95% CI 1.7-151.2, p = 0.017). Cohort C: ctDNA monitoring of patients undergoing immunotherapy revealed a reduction in the levels of ctDNA in patients with combination immunotherapy. CONCLUSIONS: Our proof-of-concept study shows the biomarker feasibility potential of ctDNA monitoring in for the clinical management of uveal melanoma patients.

Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression.

BACKGROUND: The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. METHODS: Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. RESULTS: ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P < 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15). CONCLUSIONS: These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.

Umbilical fissure vein, anatomical variation and potential surgical application.

BACKGROUND: The umbilical fissure vein (UFV) is a hepatic vein that travels within the umbilical fissure (or its proximity), providing venous drainage for hepatic segments 3 and 4. Its preservation carries a potential importance in extended right hemi-hepatectomy, left lateral segmentectomy and extended segment 2 resections. METHODS: Consecutive 1-mm slice thickness portovenous phase intravenous contrast computed tomography (CT) scans of the abdomen performed were retrospectively reviewed during the period of June 2019 to July 2019, with two independent investigators investigating the presence of UFV, its course, insertion and relation to the umbilical fissure. RESULTS: A total of 244 CTs were identified and 186 included. The UFV was identified on 72.8% of participants, 109 (81.4%) drained into the main left hepatic vein, while the remaining ones drained either from the main middle hepatic vein (16.4%) or the bifurcation between main left and middle hepatic vein (2.2%). The veins course lay 2 mm or less along the length of umbilical fissure in 39.5%, while 57.5% ran within 1 cm along the length of the umbilical fissure. CONCLUSION: Pre-operative identification of UFV could assist in operative planning. The vein can be used as a landmark in surgery and should be preserved in left lateral segmentectomy and extended right hepatectomy to avoid parenchymal congestion of remnant segments.

Influence of preoperative breast cancer localization techniques on rates of sentinel lymph node visualization with preoperative lymphoscintigraphy.

OBJECTIVES: The use of preoperative image-guided lesion localization for impalpable breast cancer may interfere with lymphatic drainage and cause delayed or reduced visualization of sentinel lymph nodes (SLNs) on preoperative lymphoscintigraphy. The goal of this audit was to compare rates of SLN visualization in patients undergoing preoperative breast cancer localization with either Iodine 125 seeds (radio-guided occult lesion localization using Iodine 125 seeds, ROLLIS) or hook wire and those with palpable lesions where no localization was required. PATIENTS AND METHODS: We reviewed the records of 482 patients, who underwent preoperative lymphoscintigraphy with hook wire, ROLLIS, or no localization, at three major tertiary hospitals from January 2013 to December 2017. Static lymphoscintigraphy images are performed post administration of subcutaneous periareolar Tc antimony colloid injection. The rate of SLN visualization in the three groups and time to node visualization were analyzed. RESULTS: Four hundred and eighty-two patients underwent preoperative lymphoscintigraphy: 102 after no localization, 211 in hook wire, and 169 following ROLLIS. Very high overall rates of SLN visualization on preoperative lymphoscintigraphy were noted in all three groups; no localization group: 99% [95% confidence interval (CI), 94.7-99.8%], hook wire: 98.6% (95% CI, 95.9-99.7%) and ROLLIS: 98.8% (95% CI, 95.8-99.9%). For time to node visualization, a statistically significant difference was found between the no localization versus hook-wire group (P = 0.0015) and no localization versus ROLLIS group (P = 0.00011) but no statistically significant difference between the hook-wire and ROLLIS groups (P = 0.16) was demonstrated. CONCLUSION: High rates of SLN visualization on preoperative lymphoscintigraphy were noted in all groups, with no significant reduction when breast lesion localization techniques were used. There was; however, an increased rate of delayed imaging required for SLN visualization in women who had undergone either type of preoperative localization compared with those who had not.

Longitudinal Monitoring of ctDNA in Patients with Melanoma and Brain Metastases Treated with Immune Checkpoint Inhibitors.

PURPOSE: Brain involvement occurs in the majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation. EXPERIMENTAL DESIGN: This study examined circulating BRAF, NRAS, and c-KIT mutations in patients with melanoma with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analyzed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/mL plasma). RESULTS: Of a total of 72 patients, 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (P < 0.01). Undetectable ctDNA on-therapy was associated with extracranial response (P < 0.01) but not intracranial response. The median overall survival in patients with undetectable (n = 34) versus detectable (n = 38) ctDNA at baseline was 39.2 versus 10.6 months [HR, 0.51; 95% confidence interval (CI), 0.28-0.94; P = 0.03] and on-therapy was 39.2 versus 9.2 months (HR, 0.32; 95% CI, 0.16-0.63; P < 0.01). CONCLUSIONS: ctDNA remains a strong prognostic biomarker in patients with melanoma with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.

Monitoring melanoma recurrence with circulating tumor DNA: a proof of concept from three case studies.

BACKGROUND: A significant number of melanoma patients experience recurrence to distant sites, despite having had surgical treatment of the primary lesion, with curative intent. Monitoring of patients for early evidence of disease recurrence would significantly improve management of the disease, allowing timely therapeutic intervention. Circulating tumor DNA (ctDNA) is becoming a well-recognized biomarker for monitoring malignancies and has, in a few studies, been shown to signify disease recurrence earlier than conventional methods. METHODS: We performed a retrospective analysis of plasma ctDNA using droplet digital PCR (ddPCR) in 30 primary melanoma patients with tumors harboring BRAF, NRAS or TERT promoter mutations. Mutant specific ctDNA, measured during clinical disease course, was compared with disease status in patients with confirmed disease recurrence (n = 3) and in those with no evidence of disease recurrence (n = 27). RESULTS: Mutant specific ctDNA was detected in all three patients with disease recurrence at the time of clinically confirmed progression. In one case, plasma ctDNA detection preceded clinical identification of recurrence by an interval of 4 months. CtDNA was not detected in patients who were asymptomatic and had no radiological evidence of recurrence. CONCLUSIONS: This study demonstrates promising results for the use of ctDNA as an informative monitoring tool for melanoma patients having undergone tumor resection of an early stage primary tumor. The clinical utility of ctDNA for monitoring disease recurrence warrants investigation in prospective studies as it may improve patient outcome.

Locus-specific concordance of genomic alterations between tissue and plasma circulating tumor DNA in metastatic melanoma.

Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for noninvasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70%) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80% of the mutations found in tumor tissue were also detected in ctDNA. However, TERT promoter mutations were only detected by ddPCR, and promoter mutations were consistently found at lower concentrations than other driver mutations in longitudinal samples. In vitro experiments revealed that mutations in promoter regions of TERT and DPH3 are underrepresented in ctDNA. While the results underscore the utility of using ctDNA as an alternative to tissue biopsy for genetic profiling and surveillance of the disease, our study highlights the underrepresentation of promoter mutations in ctDNA and its potential impact on quantitative liquid biopsy applications.

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients.

BACKGROUND: Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB). METHODS: Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR). RESULTS: CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (p < 0.001). CtDNA was not detectable in patients with an MTB of ≤10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR. CONCLUSIONS: We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.

Humerus photon starvation streak artefact.

INTRODUCTION: The reduced (attenuated) number of photons passing through the arm can result in a combination of fine and thick streak artefacts, particularly with the use of thin CT slices and lower radiation dose parameters. This phenomenon is known as photon starvation. We noted an abnormal appearance of the humerus when imaged with certain arm position. This appearance was thought to be artefact due to photon starvation. METHODS: A human radius bone was imaged in different positions and the kV and mA were varied in an attempt to reproduce the artefact, which would support the hypothesis that the artefact may be caused by bone attenuation. RESULTS: Scanning the bone in a different angle and radiation dose parameters reproduced the artefactual appearance of the bone. CONCLUSION: Performing a chest CT scan with arms up can occasionally result in an abnormal appearance to the humerus due to photon starvation artefact. Familiarity with this artefact is essential to avoid misinterpretation.

Impact of same day vs day before pre-operative lymphoscintigraphy for sentinel lymph node biopsy for early breast cancer (local Australian experience).

INTRODUCTION: To assess the impact of delayed vs immediate pre-operative lymphoscintigraphy (LSG) for sentinel lymph node biopsy in a single Australian tertiary breast cancer centre. METHODS: Retrospective cohort study analysing patients with breast cancer or DCIS who underwent lumpectomy or mastectomy with pre-operative LSG and intra-operative sentinel lymph node biopsy from January 2015 to June 2016. RESULTS: A total of 182 LSG were performed. Group A patients had day before pre-operative LSG mapping (n = 79) and Group B had LSG mapping on the day of surgery (n = 103). The overall LSG localisation rate was 97.3% and no statistical difference was detected between the two groups. The overall sentinel lymph node biopsies (SLN) were identified in 99.6% of patients. The number of nodes excised was slightly higher in Group A (1.90 vs 1.72); however, this was not statistically significant. In addition, the number of nodes on histopathology and the incidence of second echelon nodal detection were also similar between the two groups without statistical significance. CONCLUSION: In conclusion, the 2-day LSG protocol had no impact on overall SLNB and LSG detection rates although slightly higher second tier nodes but this did not translate to any difference between the number of harvest nodes between the two groups. The 2-day LSG allows for greater flexibility in theatre planning and more efficient use of theatre time. We recommend a dose of 40 Mbq of Tc99 m pertechnetate-labelled colloid be given day prior to surgery within a 24-hour timeframe.

Voltage-gated potassium channel antibody limbic encephalitis: a case illustrating the neuropsychiatric and PET/CT features with clinical and imaging follow-up.

OBJECTIVE: To illustrate the neuropsychiatric and imaging findings in a confirmed case of voltage-gated potassium channel antibody limbic encephalitis. METHOD: Case report and review of the literature. RESULTS: A 64-year-old man presented with several months' history of obsessive thoughts and compulsions associated with faciobrachial dystonic seizures. He had no significant past medical and psychiatric history. Physical examinations revealed only mildly increased tone in the left upper limb. Bedside cognitive testing was normal. Positron-emission tomography showed intense symmetrical uptake in the corpus striatum. No underlying malignancy was identified on whole body imaging. Magnetic resonance imaging, lumbar puncture and electroencephalogram were normal. Serum voltage-gated potassium channel antibodies were strongly positive. The patient had a favourable response to antiepileptic drugs, oral steroids and immunotherapy. CONCLUSIONS: Voltage-gated potassium channel limbic encephalitis characteristically presents with neuropsychiatric symptoms and temporal lobe seizures. Positron-emission tomography-computed tomography can be a useful adjunct to the clinical and biochemical work-up.

68Ga DOTATATE PET/CT of Non-FDG-Avid Pulmonary Metastatic Hemangiopericytoma.

We present the FDG and Ga DOTATATE PET/CT findings of a 68-year-old woman with pulmonary metastases 28 years after her initial diagnosis of central nervous system hemangiopericytoma. The largest of the pulmonary lesions showed prominent Ga DOTATATE uptake with comparatively minimal FDG avidity. Hemangiopericytoma is a rare mesenchymal tumor that arises from malignant pericytes, cells that form the walls of capillaries and postcapillary venules. This case demonstrates the potential of radiolabeled somatostatin analogs as a therapeutic option in the setting of widespread metastatic disease.

Novel CT and scintigraphic findings of bone metastasis from invasive lobular breast cancer.

INTRODUCTION: The aim of this study is to identify and describe the computed tomography and scintigraphic imaging patterns of osseous metastasis from invasive lobular breast cancer (ILC). MATERIALS AND METHODS: CT and skeletal scintigraphy (SS) studies of 23 patients with diagnosis of ILC and osseous metastasis on their initial presentation were reviewed. RESULTS: Osseous metastases in 14 patients (60.8%) appear as uniform small sclerotic lesions (USSL) on CT scan. The SS in these patients were interpreted as negative for metastasis (either normal or with some equivocal findings not typical for metastasis). CONCLUSION: Osseous metastasis from ILC can have a characteristic imaging pattern on CT and SS. The pattern of USSL on CT scan with negative SS is highly suggestive of osseous metastasis from ILC.

Primary aspergillosis of bilateral laryngoceles.

Laryngocele is an abnormal dilatation of the saccule of laryngeal ventricle, which is usually unilateral and filled with air or fluid. We present a case of bilateral laryngoceles colonized by Aspergillus species.

CT pulmonary angiography during veno-arterial extracorporeal membrane oxygenation in an adult.

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) causes changes in the filling and blood flow of the cardiac chambers and pulmonary vessels as well as alterations in the path of intravenous contrast injected during CT. We present a patient with a potentially misleading CT pulmonary angiogram while on full VA ECMO. We demonstrate circulatory changes as well as alterations in contrast flow when ECMO flows are reduced.