Extrahepatic perfusion and incomplete hepatic perfusion after hepatic arterial infusion pump implantation: incidence and clinical implications.

INTRODUCTION: This study investigates the incidence of extrahepatic perfusion and incomplete hepatic perfusion at intraoperative methylene blue testing and on postoperative nuclear imaging in patients undergoing hepatic arterial infusion pump (HAIP) chemotherapy. METHODS: The first 150 consecutive patients who underwent pump implantation in the Netherlands were included. All patients underwent surgical pump implantation with the catheter in the gastroduodenal artery. All patients underwent intraoperative methylene blue testing and postoperative nuclear imaging (99mTc-Macroaggregated albumin SPECT/CT) to determine perfusion via the pump. RESULTS: Patients were included between January-2018 and December-2021 across eight centers. During methylene blue testing, 29.3% had extrahepatic perfusion, all successfully managed intraoperatively. On nuclear imaging, no clinically relevant extrahepatic perfusion was detected (0%, 95%CI: 0.0-2.5%). During methylene blue testing, 2.0% had unresolved incomplete hepatic perfusion. On postoperative nuclear imaging, 8.1% had incomplete hepatic perfusion, leading to embolization in only 1.3%. CONCLUSION: Methylene blue testing during pump placement for intra-arterial chemotherapy identified extrahepatic perfusion in 29.3% of patients, but could be resolved intraoperatively in all patients. Postoperative nuclear imaging found no clinically relevant extrahepatic perfusion and led to embolization in only 1.3% of patients. The role of routine nuclear imaging after HAIP implantation should be studied in a larger cohort.

Adjuvant Hepatic Arterial Infusion Pump Chemotherapy After Resection of Colorectal Liver Metastases: Results of a Safety and Feasibility Study in The Netherlands.

BACKGROUND: The 10-year overall survival with adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after resection of colorectal liver metastases (CRLMs) was 61% in clinical trials from Memorial Sloan Kettering Cancer Center. A pilot study was performed to evaluate the safety and feasibility of adjuvant HAIP chemotherapy in patients with resectable CRLMs. STUDY DESIGN: A phase II study was performed in two centers in The Netherlands. Patients with resectable CRLM without extrahepatic disease were eligible. All patients underwent complete resection and/or ablation of CRLMs and pump implantation. Safety was determined by the 90-day HAIP-related postoperative complications from the day of pump placement (Clavien-Dindo classification, grade III or higher) and feasibility by the successful administration of the first cycle of HAIP chemotherapy. RESULTS: A total of 20 patients, with a median age of 57 years (interquartile range [IQR] 51-64) were included. Grade III or higher HAIP-related postoperative complications were found in two patients (10%), both of whom had a reoperation (without laparotomy) to replace a pump with a slow flow rate or to reposition a flipped pump. No arterial bleeding, arterial dissection, arterial thrombosis, extrahepatic perfusion, pump pocket hematoma, or pump pocket infections were found within 90 days after surgery. After a median of 43 days (IQR 29-52) following surgery, all patients received the first dose of HAIP chemotherapy, which was completed uneventfully in all patients. CONCLUSION: Pump implantation is safe, and administration of HAIP chemotherapy is feasible, in patients with resectable CRLMs, after training of a dedicated multidisciplinary team.

Extravasation After [ 177 Lu]Lu-HA-DOTATATE Therapy.

ABSTRACT: Extravasation of the radiopharmaceutical during peptide receptor radionuclide therapy infusion is an unwanted infrequently reported event. We present the case of a 74-year old woman with a neuroendocrine tumor who was referred for peptide receptor radionuclide therapy. During intravenous infusion of 7.4 GBq [ 177 Lu]Lu-HA-DOTATATE in the upper right arm, extravasation of the radiopharmaceutical occurred through a displaced intravenous catheter. Planar scintigraphy showed pooling of radioactivity in the right upper arm. After 24 hours, the swelling in the arm was decreased; however, erythema was increased. One week later, symptoms had disappeared, and the patient did not experience any complications during follow-up of 11 months.

Post-PRRT scans: which scans to make and what to look for.

AIM: The aim of this study was to evaluate the clinical utility of SPECT/CT (imaging of uptake in tumor lesions and additional findings) and the additional value of planar imaging in order to simplify clinical imaging protocols and decrease patients burden. MATERIALS AND METHODS: One hundred consecutive patients with metastatic neuroendocrine tumor (NET) treated with PRRT were included. Post-therapy imaging was performed 24 h after each PRRT cycle by both whole-body planar imaging and abdominal- and thoracic SPECT/CT. All images were evaluated for (1) the presence of new lesions, (2) discordant lesions between the two acquisitions (planar or SPECT), (3) location of lesions on SPECT (abdominal, thoracic, or both), and (4) additional findings on non-contrast enhanced CT imaging. RESULTS: In total 368 PRRT cycles including post-therapy imaging were performed in 100 patients. 45 patients had abdominal disease only, whilst in 55 patients the disease was observed on both abdominal and thoracic SPECT. 16 patients had known bone lesions that were visible only on planar imaging as these were out of range of the SPECT/CT. During PRRT, one patient developed multiple new bone metastases after the second cycle of PRRT, which were visible on both planar and SPECT/CT images. In 11 patients additional findings were found on CT images, the most common and relevant being bowel obstruction, pleural effusion, and ascites. Patients who developed ascites during PRRT appeared to do extremely poor; a post-hoc analysis showed that overall survival was 13.2 months in patients that showed ascites during PRRT at any moment and 37.9 months in patients without ascites (p < 0.001). CONCLUSION: From a clinical point of view, thoracoabdominal SPECT/CT imaging is the preferred method for post-PRRT imaging; planar imaging had no added value over SPECT/CT in this cohort. In patients with abdominal disease only on baseline imaging, SPECT/CT of the abdomen only might be sufficient for imaging during the PRRT course. All accompanying CT images should be reviewed for additional findings, especially ascites, which is suggested to be a poor prognostic factor in patients receiving PRRT.

F-18 Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography Has High Diagnostic Value for Pelvic and Distant Staging in Patients with High-risk Penile Carcinoma.

BACKGROUND: For penile cancer patients with pelvic metastases, multimodal treatment is advised, but pelvic lymph node metastases are often found upon surgical resection only. Early selection for multimodal treatment requires reliable noninvasive staging. OBJECTIVE: To evaluate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) for staging pelvic lymph nodes and distant metastases in high-risk penile cancer patients. DESIGN, SETTING, AND PARTICIPANTS: FDG-PET/CT scans performed in patients with clinically overt inguinal lymph node metastases and/or high-risk primary tumors (bulky T3 or T4) were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All scans were reviewed by two independent nuclear medicine physicians staging the pelvic nodes and distant metastases. FDG-PET/CT findings were compared with histology after node dissection if available, or with positive imaging or follow-up of at least 1 yr. RESULTS AND LIMITATIONS: Between 2006 and 2016, 61 patients met the inclusion criteria. For staging of pelvic nodes, sensitivity was 85% (specificity 75%, negative predictive value [NPV] 90%, and positive predictive value [PPV] 65%). For the detection of distant metastases, FDG-PET/CT had a PPV of 93%. Results are limited by the retrospective design and the lack of direct comparison with CT scanning alone. CONCLUSIONS: FDG-PET/CT has high sensitivity and a high NPV for staging of pelvic lymph nodes in high-risk penile cancer. It also has a high PPV for the detection of distant metastases, which were found in 23% of patients. Therefore, FDG-PET/CT enables early selection for multimodal treatment of patients with pelvic metastases and may help avoid futile treatment of patients with distant metastases. PATIENT SUMMARY: We studied whether positron emission tomography with computed tomography (PET/CT) scans in patients with advanced penile cancer can detect metastases before lymph node surgery is done. PET/CT scans can detect or rule out pelvic lymph node metastases, and can detect distant metastases. This helps in making timely treatment decisions (before surgery).

Discordant Uptake Between Diagnostic 68Ga-HA-DOTATATE PET/CT and Posttherapy 177Lu-HA-DOTATATE SPECT/CT in Patients With Neuroendocrine Tumors.

ABSTRACT: Patients with unresectable or metastasized neuroendocrine tumors are assumed eligible for PRRT (peptide receptor radionuclide therapy) with 177Lu-HA-DOTATATE if tumor uptake on somatostatin receptor imaging is higher than normal liver tissue. In our clinic, 2 patients presented with sufficient uptake of 68Ga-HA-DOTATATE in most metastases but with limited uptake in liver lesions. Posttherapy 177Lu imaging, however, showed good uptake in all neuroendocrine tumor lesions, including all liver metastases. Therefore, the presence of liver metastases in which the uptake of 68Ga-HA-DOTATATE is not or only slightly higher than in surrounding normal liver tissue should not be an absolute contraindication for PRRT.

Haematotoxicity during peptide receptor radionuclide therapy: Baseline parameters differences and effect on patient's therapy course.

BACKGROUND: Mainly severe (CTCAE grade 3-4) haematotoxicity during peptide receptor radionuclide therapy (PRRT) is reported in literature due to major clinical impact, however moderate (CTCAE grade 2) haematotoxicity is common and could affect therapy management. The aim of this study was to evaluate the haematotoxicity course during PRRT and to compare baseline parameters between haematotoxicity grades. METHODS: In this retrospective study, 100 patients with a neuroendocrine tumour treated with PRRT were included. Patients were treated with an aimed number of four cycles with 7.4 GBq [177Lu]Lu-DOTA-TATE administered every 10 weeks. Haematological assessment was performed at baseline and frequently up to 10 weeks after the fourth cycle. The lowest haematological value was graded according to CTCAE v5.0, and patients were classified using the highest observed grade. Differences in baseline parameters, including [68Ga]Ga-DOTA-TATE positive tumour volume, were evaluated between CTCAE grades. RESULTS: Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed. CONCLUSIONS: The incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values.

Arteriovenous fistulae as an alternative to central venous catheters for delivery of long-term home parenteral nutrition.

BACKGROUND & AIMS: The success of home parenteral nutrition (HPN) programs is compromised by complications of central venous catheters (CVCs), such as occlusions and bloodstream infections. We performed a retrospective analysis of complication rates of arteriovenous fistulae versus CVCs in patients on long-term HPN. METHODS: Data were collected from 127 consecutive patients who received HPN between January 2000 and October 2006, comprising 344 access years of CVCs and 194 access years of arteriovenous fistulae. We evaluated access-related bloodstream infection and occlusion incidence rates (number of complications per access year) using Poisson-normal regression analysis. Complication incidence rate ratios were calculated by dividing complication incidence rates of CVCs by those of arteriovenous fistulae, adjusting for HPN frequency, medication use, infusion fluid composition, and underlying diseases. RESULTS: Bloodstream infection incidence rates were 0.03/year for arteriovenous fistulae, 1.37/year for long-term CVCs (Port-a-Caths and tunneled catheters), and 3.12/year for short-term CVCs (nontunneled catheters). Occlusion incidence rates were 0.60/year for arteriovenous fistulae, 0.35/year for long-term CVCs, and 0.93/year for shortterm CVCs. Adjusted incidence rate ratios of long-term CVCs over arteriovenous fistulae were 47 (95% confidence interval, 19-117) for bloodstream infections and 0.53 (95% confidence interval, 0.31-0.89) for occlusions. CONCLUSIONS: The occlusion incidence rate was higher for arteriovenous fistulae than for certain types of CVCs. The incidence rate of the most serious access-related complication (bloodstream infections) was much lower for arteriovenous fistulae than for all types of CVCs. Thus, arteriovenous fistulae are safe and valuable alternatives to CVCs for patients requiring long-term HPN.

Early response assessment and prediction of overall survival after peptide receptor radionuclide therapy.

BACKGROUND: Response after peptide receptor radionuclide therapy (PRRT) can be evaluated using anatomical imaging (CT/MRI), somatostatin receptor imaging ([68Ga]Ga-DOTA-TATE PET/CT), and serum Chromogranin-A (CgA). The aim of this retrospective study is to assess the role of these response evaluation methods and their predictive value for overall survival (OS). METHODS: Imaging and CgA levels were acquired prior to start of PRRT, and 3 and 9 months after completion. Tumour size was measured on anatomical imaging and response was categorized according to RECIST 1.1 and Choi criteria. [68Ga]Ga-DOTA-TATE uptake was quantified in both target lesions depicted on anatomical imaging and separately identified PET target lesions, which were either followed over time or newly identified on each scan with PERCIST-based criteria. Response evaluation methods were compared with Cox regression analyses and Log Rank tests for association with OS. RESULTS: A total of 44 patients were included, with median follow-up of 31 months (IQR 26-36 months) and median OS of 39 months (IQR 32mo-not reached)d. Progressive disease after 9 months (according to RECIST 1.1) was significantly associated with worse OS compared to stable disease [HR 9.04 (95% CI 2.10-38.85)], however not compared to patients with partial response. According to Choi criteria, progressive disease was also significantly associated with worse OS compared to stable disease [HR 6.10 (95% CI 1.38-27.05)] and compared to patients with partial response [HR 22.66 (95% CI 2.33-219.99)]. In some patients, new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging. After 3 months, new lesions on [68Ga]Ga-DOTA-TATE PET/CT which were not visible on anatomical imaging, were detected in 4/41 (10%) patients and in another 3/27 (11%) patients after 9 months. However, no associations between change in uptake on 68Ga-DOTA-TATE PET/CT or serum CgA measurements and OS was observed. CONCLUSIONS: Progression on anatomical imaging performed 9 months after PRRT is associated with worse OS compared to stable disease or partial response. Although new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging, [68Ga]Ga-DOTA-TATE uptake, and serum CgA after PRRT were not predictive for OS in this cohort with limited number of patients and follow-up time.

A head-to-head comparison between two commercial software packages for hybrid dosimetry after peptide receptor radionuclide therapy.

BACKGROUND: Dosimetry after peptide receptor radionuclide therapy (PRRT) is increasing; however, comparing or pooling of dosimetric results can be challenging since different approaches are used. The aim of this study was to perform a head-to-head comparison of post-PRRT curve fitting and dosimetry obtained from two commercial software Hybrid Viewer Dosimetry and PLANET Dose. METHODS: Post-therapy imaging included planar scintigraphy at 0.5, 4, 24 and 72 h post-injection of [177Lu]Lu-DOTA-TATE for kinetics and SPECT/CT at 24 h for quantification. On planar imaging, 2 cm regions-of-interest were positioned within the inferior pole of the kidneys and kidney cortex was segmented on low-dose CT. On both planar and SPECT/CT, 2 cm spheres were positioned in the proximal humerus (red marrow equivalent) and in the region with the highest uptake in tumour lesions. TACs were estimated with mono- and bi-exponential fits in both software systems, after which tissue absorbed (kidney, red marrow, tumour) and biological effective doses (kidney) were calculated. Agreement-ICC, Spearman correlation and Bland-Altman plots were used to compare results. RESULTS: Mono-exponential fits showed the most comparable correlation between the measured and fitted data between both software. The ICC between absorbed dose outcomes was > 0.7 in tumour lesions and kidneys, but negative for the red marrow. Spearman correlation was > 0.9 for mono-exponential fits in kidneys and tumour lesions, and -0.7 in red marrow. Bi-exponential fits resulted in lower correlations and agreement values. Concordance between both software packages concerning the number of PRRT cycles with 7.4 GBq was observed based on a biological effective dose limit of 27 Gy to the kidneys. CONCLUSION: [177Lu]Lu-DOTA-TATE dosimetry results of two software packages were comparable in the same dataset, despite the limited number of imaging time-points. However, these results should be verified in a larger cohort before pooling of clinical data, as the obtained results will depend on acquisition protocol, timing and lesions definition.

Avastin scintigraphy in surveillance of bevacizumab treatment in a patient with neurofibromatosis type 2: a case report.

A patient with neurofibromatosis type 2 (bilateral vestibular schwannomas) was treated with bevacizumab (anti-vascular endothelial growth factor [VEFG] monoclonal antibody). The left-sided tumor showed intense uptake on pretreatment In-bevacizumab scintigraphy, indicating VEGF production in the tumor, and no uptake 4 weeks later, demonstrating effective binding of nonradiolabeled bevacizumab to the VEGF produced in the tumor. The right-sided tumor showed no tracer uptake at any time point. Significant tumor volume reduction (assessed with MRI) and hearing improvement were observed on the left side. In-bevacizumab scintigraphy may be a promising upfront patient selection tool to identify patients who may benefit from expensive bevacizumab treatment.

Parenteral medium-chain triglyceride-induced neutrophil activation is not mediated by a Pertussis Toxin sensitive receptor.

BACKGROUND & AIMS: Lipid-induced immune modulation might contribute to the increased infection rate that is observed in patients using parenteral nutrition. We previously showed that emulsions containing medium-chain triglycerides (LCT/MCTs or pure MCTs), but not pure long-chain triglycerides (LCTs), impair neutrophil functions, modulate cell-signaling and induce neutrophil activation in vitro. It has recently been shown that medium-chain fatty acids are ligands for GPR84, a pertussis toxin (PT)-sensitive G-protein-coupled receptor (GPCR). This finding urged us to investigate whether MCT-induced neutrophil activation is mediated by PT-sensitive GPCRs. METHODS: Neutrophils isolated from blood of healthy volunteers were pre-incubated with PT (0.5-1 microg/mL, 1.5 h) and analyzed for the effect of this pre-incubation on LCT/MCT (2.5 mmol/L)-dependent modulation of serum-treated zymosan (STZ)-induced intracellular Ca(2+) mobilization and on LCT/MCT (5 mmol/L)-induced expression of cell surface adhesion (CD11b) and degranulation (CD66b) markers and oxygen radical (ROS) production. RESULTS: PT did not inhibit the effects of LCT/MCT on the STZ-induced increase in cytosolic free Ca(2+) concentration. LCT/MCT increased ROS production to 146% of unstimulated cells. However, pre-incubation with PT did not inhibit the LCT/MCT-induced ROS production. Furthermore, the LCT/MCT-induced increase in CD11b and CD66b expression (196% and 235% of unstimulated cells, respectively) was not inhibited by pre-incubation with PT. CONCLUSION: LCT/MCT-induced neutrophil activation does not involve the action of a PT-sensitive G-protein-coupled receptor.