Combining Melphalan Percutaneous Hepatic Perfusion with Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma: First Safety and Efficacy Data from the Phase Ib Part of the Chopin Trial.

PURPOSE: To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS. MATERIALS AND METHODS: Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs. RESULTS: Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months). CONCLUSION: Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg.

Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial.

BACKGROUND: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease. METHODS: Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves. DISCUSSION: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT04283890 . Registered as per February 2020 - Retrospectively registered. EudraCT registration number: 2018-004248-49. Local MREC registration number: NL60508.058.19.

Management of isolated nonresectable liver metastases in colorectal cancer patients: a case-control study of isolated hepatic perfusion with melphalan versus systemic chemotherapy.

BACKGROUND: To compare the median overall survival of patients with isolated nonresectable liver metastases in comparable groups of patients treated with either isolated hepatic perfusion (IHP) with melphalan or systemic chemotherapy. PATIENTS AND METHODS: Colorectal cancer patients with isolated liver metastases, who underwent IHP, were included in this study. The control group consisted of a subgroup of colorectal cancer patients with liver metastases only, who were enrolled in the randomized CApecitabine, IRinotecan, Oxaliplatin (CAIRO) phase III study. RESULTS: Ninety-nine patients were treated with IHP, and 111 patients were included in the control group. All patient characteristics were comparable except for age. Median follow-up was 78.1 months for IHP versus 54.7 months in the control group. Median overall survival was 25.0 [95% confidence interval (CI) 19.4-30.6] months for IHP and 21.7 (95% CI 19.6-23.8) months for systemic treatment and did not differ significantly (P = 0.29). Treatment-related mortality was 2% for the systemic treatment and 6% for IHP (P = 0.11). CONCLUSION: Compared with a patient group with comparable characteristics treated with systemic chemotherapy, IHP does not provide a benefit in overall survival in patients with isolated nonresectable colorectal liver metastases. Currently, the use of IHP cannot be advocated outside the scope of clinical studies.

Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients.

BACKGROUND: The aim of this study was to identify prognostic factors for local and systemic failure after isolated hepatic perfusion (IHP) with 200 mg melphalan in patients with colorectal liver metastases. PATIENTS AND METHODS: Hundred and fifty-four patients were selected for IHP and underwent laparotomy. Patients were monitored for response, toxicity and survival. Univariate and multivariate analyses were carried out to identify prognostic factors for hepatic response and progression-free and overall survival. RESULTS: Hepatic response rate was 50% with a median progression-free and overall survival of, respectively, 7.4 and 24.8 months. In multivariate analyses, absence of ability to perfuse through the hepatic artery (P = 0.003), severe postoperative complications (P = 0.048) and >10 liver metastases (P = 0.006) adversely influenced overall survival and no adjuvant chemotherapy adversely influenced progression-free survival. CONCLUSION: This is the first study to report prognostic factors for survival after IHP. Possibly, overall and disease-free survival can increase if preoperative screening is improved. In future studies on IHP, adjuvant chemotherapy should be considered.

Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: a clinical and pharmacologic evaluation.

Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery-portal vein perfusion, HI-HPP). Between December 2001 and December 2004, 30 patients with colorectal cancer liver metastases underwent HI-HPP with 200mg melphalan. Samples of the perfusate were taken for pharmacokinetic analysis. Patients were monitored for response, toxicity and survival. Perfusion was aborted prematurely in 2 patients due to leakage. During melphalan administration in the hepatic inflow cannula a mean flow rate of 121.3 mL/min and mean pressure of 62.5mm Hg were achieved. One patient died within 30 days after HI-HPP. Four patients developed veno-occlusive disease (VOD), while 2 patients showed signs of VOD. Twelve patients showed hepatic response, with a median duration of response of 11.5 months, according to WHO criteria. Although HI-HPP results in high perfusate melphalan concentration levels, it is associated with a relatively high level of hepatotoxicity and a limited response rate. We believe that the low flow and pressure rates found in this study can result in reduced drug penetration of the tumour and thus limited tumour response.

Patient and staff dose during CT guided biopsy, drainage and coagulation.

Patient and staff dose during CT guided coagulation of osteoid osteoma, tissue biopsy and abscess drainage were evaluated retrospectively on a conventional CT scanner and prospectively on a scanner equipped with fluoroscopic CT. The computed tomography dose index (CTDI) and the individual dose equivalent, i.e. the penetrating dose for workers at a depth of 10 mm tissue, were measured. Evaluation of CTDI enabled effective dose and maximum skin entrance doses for the patient to be determined. Doses were assessed for 96 CT guided interventions, including 16 drainages with average effective doses of 13.5 mSv and 9.3 mSv for the conventional CT scanner and the scanner with spiral CT fluoroscopy, respectively, 49 biopsies (effective doses of 8 mSv and 6.1 mSv, respectively), and 31 coagulations of osteoid osteoma (effective doses of 2.1 mSv and 0.8 mSv, respectively). Effective doses to patients were in the same range as those observed for regular diagnostic CT examinations. Entrance skin doses were well below the 2 Gy threshold for deterministic skin effects on the CT scanner equipped with fluoroscopic function (0.03-0.33 Gy), whilst skin doses on the conventional scanner were considerably higher (0.09-1.61 Gy). This is mainly owing to the fact that on the conventional scanner mAs was rarely reduced for scans evaluating needle position whereas low mAs per rotation was selected on the scanner with the fluoroscopy option. The maximum dose to a worker measured outside the lead apron was 28 microSv for one single procedure. The mean dose per procedure was below 10 microSv for radiologists and below 1 microSv for radiographers. Correcting for attenuation of the lead apron, the doses to workers are very low.

Postnatal development and structure of the neurocentral junction. Its relevance for spinal surgery.

STUDY DESIGN: The early and late development of the neurocentral junction between the vertebral arch and the vertebral body was studied, and this structure was related to spinal surgery. OBJECTIVES: Because of its strategic position within the vertebral body, its structure could be of relevance for spinal surgery. During the positioning of cannulated pedicle screws and before penetration into the cancellous bone of the vertebral body, resistance had to be overcome inside the "pedicle" of the vertebral arch. Was this point of resistance related to the neurocentral joint? SUMMARY OF BACKGROUND DATA: Data on the fate of this developmental structure after age 3-6 years, the age at which it fuses, appeared to be missing in literature. METHODS: We examined dry bone and "fresh" vertebrae from individuals ranging in age from 0 to 75 years. Observations were recorded by means of gross anatomic photographs, micrographs, radiographs, and computed tomography scans. RESULTS: After fusion of the junction at age 3-6 years, its structure persists through life as a bilateral plate of bone extending from the cranial to the caudal anular epiphyses inside the dorsolateral parts of the definitive body. CONCLUSIONS: This plate may function as a support for pedicle screw fixation. Its form explains typical burst fractures of the vertebral body. Spondylolysis at this site is unknown.

Epi- and metaphyseal changes in children caused by administration of bisphosphonates.

Nitrogen-containing bisphosphonates (NCBs) are potent inhibitors of bone resorption and are used in the treatment of adults with various skeletal disorders. Little is known about their effects on the growing skeleton. The authors retrospectively studied the skeletal radiographs obtained in nine children before, during, and after NCB administration. Bandlike metaphyseal sclerosis and concentric epi- and apophyseal sclerosis developed in all patients. The extent of sclerosis depended on the duration of treatment and was related to local, and probably general, skeletal growth activity. In the maturing spine, NCBs caused a "picture-frame" or "bone-within-bone" appearance, depending on continuation or cessation of administration. In addition, metaphyseal undertubulation of long bones was noted in five patients. After discontinuation of bisphosphonate treatment and/or closure of the growth plates, the degree of sclerosis decreased, and sclerosis tended to disappear, indicating that this is a reversible phenomenon.

MRI of tuberculous spondylitis.

Four patients with paravertebral extension of advanced tuberculous intervertebral disk-space infection were studied by CT and MRI. In one patient gadolinium-DTPA (Gd-DTPA) was administered intravenously as a paramagnetic contrast agent. MRI showed the disk-space abnormalities and extension of the inflammatory process to best advantage in the coronal plane. This plane demonstrated in one image the spinal localization and the paravertebral extension of the inflammation. Gd-DTPA assisted in delineating the communication of the vertebral and paravertebral components of inflammation. This phenomenon introduces an additional diagnostic element into the evaluation of spondylitis. Although the features of advanced tuberculous spondylitis are conspicuously well shown with MRI, further experience is needed to evaluate the potential of MRI in detecting early tuberculous spondylitis in relation to nontuberculous spondylitis.

MRI of liver metastases: limitation of spleen-liver model in optimizing pulse sequences.

The spleen-liver model, as a predictor for contrast-to-noise ratio (C/N) in liver metastases, was verified for seven sequences in 22 patients with 70 colorectal metastases. Optimization of conventional spin-echo, T1-magnetization-prepared gradient-echo and fat frequency-selective presaturation inversion-recovery fast spin echo can be done using the spleen-liver model. C/N of liver-spleen and liver-metastases, however, differed significantly on our T1 gradient-echo and T2-weighted fast spin-echo images, with and without fat-selective saturation.

Accuracy of helical CT for acute pulmonary embolism: ROC analysis of observer performance related to clinical experience.

The aim of this study was to test the influence of observer experience on the accuracy for interpreting helical CT for acute pulmonary embolism (PE) and to identify sources of observer errors. Three observers of different expertise blindly assessed 147 helical CT scans for suspected PE (true status regarding absence or presence of PE known from independent reference studies). These observers were (a) an experienced CT radiologist, (b) a fellow in CT, and (c) a second-year resident without any formal training in CT. None of them had prior experience with CT for PE. Firstly, 70 CT scans were scored without revealing true PE status. Afterwards, feedback was provided and another 77 CT scans were evaluated. The CT scans were scored on a 5-point confidence scale and receiver-operator-characteristic analysis was performed. Different sources of interpretation errors were analyzed. The two observers with CT experience were significantly more accurate than the unexperienced observer. Their performance was not influenced by feedback training. Certain observer errors were identified, but there was no clear difference among the three observers considering the type of errors. There is significant influence of observer experience on accuracy of reading helical CT for PE: A basic working experience with whole-body CT seems to be a prerequisite. These results suggest that with this experience any radiologist should be able to achieve good accuracy; helical CT thus might become a suitable technique for acute PE in routine clinical practice.

Comparison of inversion-recovery gradient- and spin-echo and fast spin-echo techniques in the detection and characterization of liver lesions.

PURPOSE: To compare respiratory-triggered inversion-recovery (IR) gradient- and spin-echo (GRASE) magnetic resonance (MR) imaging with respiratory-triggered T2-weighted fast spin-echo (SE) imaging in the diagnosis of liver metastases. MATERIALS AND METHODS: In this prospective study, two radiologists independently identified focal hepatic lesions on respiratory-triggered IR GRASE and respiratory-triggered fast SE MR images in 28 consecutive patients with 186 (135 malignant and 51 benign) proved lesions. A combination of findings at surgery, intraoperative ultrasonography (US), and histologic examination served as the standard of reference. Contrast-to-noise ratios (CNRs) were obtained from 86 lesions larger than 10 mm. RESULTS: The sensitivity in the detection of liver metastases was, independent of lesion size and observer, higher for IR GRASE imaging (55%) than for fast SE imaging (44%-50%) (observer 1, P = .014; observer 2, P = .21). Confidence levels with IR GRASE imaging were higher, but not significantly so, than those with fast SE imaging (P < .098). Both observers characterized liver lesions better with IR GRASE than with fast SE imaging (observer 1, P = .04; observer 2, P = .48). The metastasis-liver CNR was significantly higher (P = .012) with IR GRASE imaging. CONCLUSION: The respiratory-triggered IR GRASE sequence is a fast alternative to the respiratory-triggered fast SE sequence in the evaluation of suspected liver metastases.

Magnetic resonance imaging of the genitourinary tract.

This is an overview of the current applications of magnetic resonance imaging (MRI) in the genitourinary tract based on the experience with the 0.5-Tesla MR scanner (Gyroscan, Philips) at the Leiden University Hospital and on reports in the literature. MRI appears to share some of the limitations of CT. MRI cannot reliably differentiate between a malignant and a benign tumor. In the staging of ovarian malignancies by means of MRI, bowel preparation would be desirable. On the other hand, the soft-tissue contrast resolution of MRI is superior to that of CT and images can be obtained in any plane. Thus MRI promises to be an accurate method for staging malignancies. The results in the examination of transplant kidneys are encouraging. We expect that there will be a place for MRI as a complementary technique to ultrasonography in the diagnosis of scrotal disease.

Focal liver lesions: evaluation of the efficacy of gadobenate dimeglumine in MR imaging--a multicenter phase III clinical study.

PURPOSE: To evaluate gadobenate dimeglumine (Gd-BOPTA) for dynamic and delayed magnetic resonance (MR) imaging of focal liver lesions. MATERIALS AND METHODS: In 126 of 214 patients, MR imaging was performed before Gd-BOPTA administration, immediately after bolus administration of a 0.05- mmol/kg dose of Gd-BOPTA, and 60-120 minutes after an additional intravenously infused 0.05-mmol/kg dose. In 88 patients, imaging was performed before and 60-120 minutes after a single, intravenously infused 0.1-mmol/kg dose. T1- and T2-weighted spin-echo and T1-weighted gradient-echo images were acquired. On-site and blinded off-site reviewers prospectively evaluated all images. Intraoperative ultrasonography, computed tomography (CT) during arterial portography, and/or CT with iodized oil served as the reference methods in 110 patients. RESULTS: Significantly more lesions were detected on combined pre- and postcontrast images compared with on precontrast images alone (P <. 01). All reviewers reported a decreased mean size of the smallest detected lesion and improved lesion conspicuity on postcontrast images. All on-site reviewers and two off-site reviewers reported increased overall diagnostic confidence (P <.01). Additional lesion characterization information was provided on up to 109 (59%) of 184 delayed images and for up to 50 (42%) of 118 patients in whom dynamic images were assessed. Gd-BOPTA would have helped change the diagnosis in 99 (47%) of 209 cases and affected patient treatment in 408 (23%) of 209 cases. CONCLUSION: Gd-BOPTA increases liver lesion conspicuity and detectability and aids in the characterization of lesions.