How We Do It: A Multidisciplinary Approach to 177Lu DOTATATE Peptide Receptor Radionuclide Therapy.

Lutetium 177 (177Lu) DOTA-0-Tyr3-Octreotate (DOTATATE) peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic neuroendocrine tumors. This review presents a clinical practice workflow that has been successful since 177Lu DOTATATE PRRT was approved by the U.S. Food and Drug Administration. The workflow relies heavily on the input of a multidisciplinary team and involves a nuclear medicine consultation service, tumor board, and specific preparations in advance of therapy and day-of-therapy procedures. A systematic checklist designed to ensure appropriate selection of treatment candidates and identification of any concerns to address to safely administer PRRT is provided. All patients were evaluated with gallium 68 DOTATATE PET/CT, and in cases of high-grade tumors, they were also evaluated with fluorine 18 fluorodeoxyglucose PET/CT, with imaging findings reviewed as part of the systematic checklist before PRRT. Adverse effects are discussed and imaging follow-up regimens are reviewed, including alternative diagnostic contrast materials. Approaches to multiple challenging patient scenarios are illustrated through case examples. Finally, alternative theranostic radionuclides and treatment strategies are discussed.

Intravascular Volume Profiles in Patients With Class I and II Systolic Heart Failure: Heterogeneity and Volume Overload Are Common Even in Mild Heart Failure.

BACKGROUND: Although volume overload is a commonly described clinical feature of advanced heart failure (HF), less is known regarding volume profiles of patients with less severe class I and II HF. METHODS: Intravascular volume was quantitated by radiolabeled-albumin indicator-dilution technique in clinic outpatients. RESULTS: Forty-six patients (age 61 ± 13years, left ventricular ejection fraction 30 ± 8%) were prospectively evaluated with 28 undergoing repeat evaluations at 1 year. There was no difference in averaged total blood volume (TBV) at baseline between class I (N = 26) and II (N = 20) patients (5.6 ± 1.6vs 6.0 ± 1.3 L, P = .368) and at 1-year of follow-up. However, there was marked heterogeneity in plasma volume (-13% to +69% of normal) and red cell mass (RBCM -31% to +50%) profiles with TBV expansion identified in 46% of the cohort, whereas only 48% had a normal TBV. RBCM deficit (true anemia) was common (39%), but a low hemoglobin concentration was accurate in identifying anemia in only 11% of the cohort. RBCM excess (polycythemia) also was identified in 20% of the cohort. CONCLUSIONS: Marked heterogeneity in plasma volume and RBCM volume profiles is present even in mild HF, and identifying volume overload, which was common in early HF, has the potential to help guide therapy in the reduction of HF progression. Intravascular volume as a modifiable risk factor in early HF warrants further study.

Hepatic vein tumor thrombus as a risk factor for excessive pulmonary deposition of microspheres during TheraSphere therapy for unresectable hepatocellular carcinoma.

PURPOSE: To evaluate the impact of identifiable hepatic vein tumor thrombus on the ability to safely deliver TheraSphere (yttrium 90-containing glass microspheres) for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A retrospective review was performed of 87 patients (71 men, 16 women; mean age, 64.5 years; age range, 25-83 y) referred for TheraSphere therapy for HCC during a 2-year period between April 2005 and May 2007. Evaluation included contrast-enhanced computed tomography or magnetic resonance imaging, selective mesenteric angiography, and radionuclide perfusion scintigraphy to measure the arteriovenous shunting through the tumor. RESULTS: Of the 87 patients, 83 underwent angiography and perfusion scintigraphy; 53 were ultimately treated with 65 glass microsphere infusions. Twelve of 83 were identified as having tumor thrombus in a hepatic vein or extending into the inferior vena cava. The mean lung shunt for the patients with hepatic vein tumor thrombus was 30% (range, 11%-60%), compared with 8.2% (range, 3%-23%) for patients without identifiable tumor thrombus. Two of the 12 patients were treated with reduced doses of glass microspheres, and the remaining 10 were offered alternative therapies. CONCLUSIONS: The presence of hepatic vein tumor thrombus is a risk factor for an increased lung shunt that may prohibit delivery of a therapeutic dose of TheraSphere to hepatic tumor.

Non-invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: a pilot study.

Early in the course of immunotherapy there is frequently a transient enlargement of tumor masses (pseudo-progression) due to tumor infiltration by TILs. Current clinical imaging modalities are not able to distinguished pseudo-progression from true tumor progression. Thus, patients often remain on treatment 4-8 weeks longer to confirm disease progression. Nuclear medicine offers the possibility to image immune cells and potentially discriminate pseudo-progression and progression. We conducted a pilot study in patients with metastatic melanoma receiving ipilimumab (IPI) or pembrolizumab (PEMBRO) to assess safety and feasibility of SPECT/CT imaging with 99mTc- interleukin-2 (99mTc-HYNIC-IL2) to detect TILs and distinguish between true progression from pseudo- progression. Scans were performed prior to and after 12w treatment. After labelling,99mTc-HYNIC-IL2 was purified and diluted in 10 mL of 5% glucose with 0.1% human serum albumin. Of the 5 patients (2 treated with IPI and 3 with PEMBRO) enrolled, two failed to complete the second scan as they discontinued IPI due grade 3 colitis (1 patient) or patient refusal after developing multiple toxicities attributed to IPI (1 patient). Following the first scan, one patient reported to have a grade 1 pruritus with grade 1 pain. No other toxicities attributed to the radiopharmaceutical infusion were reported. Metastatic lesions could be visualized by 99mTc-IL2 imaging and there was positive correlation between size and 99mTc-HYNIC-IL2 uptake, both before and after 12 weeks of therapy. The results of this pilot study demonstrate the safety and feasibility of 99mTc-IL2 imaging and has led to a number of hypotheses to be tested in future studies.

A phase I multiple dose, dose escalation study of cG250 monoclonal antibody in patients with advanced renal cell carcinoma.

The chimeric monoclonal antibody cG250 recognises the G250/CAIX/MN antigen found on 95% of clear cell renal cell carcinomas (RCCs). We performed a phase I clinical trial to evaluate the safety, blood pharmacokinetics (PK), and biodistribution of repeated doses of cG250. The primary endpoint was toxicity. Secondary endpoints were cG250 biodistribution and PK; measurement of human anti-chimeric-antibodies (HACA); and tumour response rates. Eligible patients had unresectable or metastatic clear cell RCC. Doses of 5, 10, 25, or 50 mg/m(2) were given weekly by intravenous infusion for six weeks. Three patients were treated at each dose level. Trace (131)I-labelled cG250 was administered on weeks 1 and 5. Thirteen patients participated and were evaluable. One patient developed brain metastases and was replaced. No grade 3 or 4 toxicities and no dose-limiting toxicity occurred. One patient died due to progressive disease within 30 days of receiving the study drug. One patient developed HACA during the second six-week cycle. PK analysis showed mean whole body and blood alpha and beta half-lives of cG250 of 18.99 +/- 6.84 and 180.19 +/- 86.68 hours, respectively. All patients had cG250 tumour localization by gamma camera imaging in week 1 and 5. One patient had a complete response, nine patients had stable disease, and three had progressive disease. One patient received 11 six-week cycles of treatment with no toxicity or HACA. In conclusion, repeated intravenous doses of up to 50 mg/m(2) of cG250 are safe. Furthermore cG250 has a long half-life and targets clear cell RCC effectively.

A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer.

PURPOSE: The purpose of this research was to determine the safety, immunogenicity, pharmacokinetics, biodistribution, and tumor uptake of repeat infusions of a complementarity-determining region grafted humanized antibody (sibrotuzumab) directed against human fibroblast activation protein (FAP). EXPERIMENTAL DESIGN: A Phase I open-label dose escalation study was conducted in patients with cancers epidemiologically known to be FAP positive. Patients were entered into one of four dosage tiers of 5, 10, 25, or 50 mg/m(2) sibrotuzumab, administered weekly for 12 weeks, with trace labeling with 8-10 mCi of (131)I in weeks 1, 5, and 9. RESULTS: A total of 26 patients were entered into the trial (15 males and 11 females; mean age, 59.9 years; age range, 41-81 years). Twenty patients had colorectal carcinoma, and 6 patients had non-small cell lung cancer. A total of 218 infusions of sibrotuzumab were administered during the first 12 weeks of the study, with 24 patients being evaluable. One patient received an additional 96 infusions on continued-use phase for a total of 108 infusions over a 2-year period, and 1 patient received an additional 6 infusions on continued use. There were no objective tumor responses. Only one episode of dose-limiting toxicity was observed. Therefore, a maximum tolerated dose was not reached. Treatment-related adverse events were observed in 6 patients during the infusional monitoring period. Four of the 6 patients, 3 of whom had associated positive serum human antihuman antibody, were removed from the study because of clinical immune responses. Gamma camera images of [(131)I]sibrotuzumab demonstrated no normal organ uptake of sibrotuzumab, with tumor uptake evident within 24-48 h after infusion. Analysis of pharmacokinetics demonstrated a similar mean terminal t(1/2) of 1.4-2.6 days at the 5, 10, and 25 mg/m(2) dose levels, and with a longer mean t(1/2) of 4.9 days at the 50 mg/m(2) dose level. CONCLUSION: Repeat infusions of the humanized anti-FAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer.

Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma.

PURPOSE: Intermediate-stage hepatocellular carcinoma (HCC) is usually treated with locoregional therapy using transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using ß-emitting yttrium-90 integral to the glass matrix of the microspheres is an alternative to TACE. This retrospective case-control study compared the outcomes and safety of TARE versus TACE in patients with unresectable HCC. MATERIALS AND METHODS: Patients with unresectable HCC without portal vein thrombosis treated with TARE between 2005 and 2008 (n = 61) were retrospectively frequency-matched by age, sex, and liver dysfunction with TACE-treated patients (n = 55) in the Mayo Clinic Hepatobiliary Neoplasia Registry. Imaging studies were reviewed, and clinical and safety outcomes were abstracted from the medical records. RESULTS: Complete tumor response was more common after TARE (12 %) than after TACE (4 %) (p = 0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the two groups (15.0 months for TARE and 14.4 months for TACE; p = 0.47). Two-year survival rates were 30 % for TARE and 24 % for TACE. TARE patients received fewer treatments (p < 0.001). Fifty-nine (97 %) TARE patients received outpatient treatment. In contrast, 53 (98 %) TACE patients were hospitalized for ≥1 day (p < 0.001). Compared with TACE, TARE was more likely to induce fatigue (p = 0.003) but less likely to cause fever (p = 0.02). CONCLUSION: There was no significant difference in efficacy between TARE and TACE. TARE patients reported more fatigue but had less fever than TACE patients. Treatment with TARE required less hospitalization than treatment with TACE. These findings require confirmation in randomized trials.

Liver transplantation after radioembolization in a patient with unresectable HCC.

BACKGROUND: A 58-year-old white man who was being followed by his hepatologist for nonalcoholic steatohepatitis-related liver cirrhosis and portal hypertension and who had been found to have a biopsy-proven hepatocellular carcinoma (HCC) on routine screening, self-referred to our center for a second opinion on the management of his HCC. INVESTIGATIONS: Laboratory investigations, CT scan of the abdomen and chest, bone scan and technetium macroaggregated albumin scan. DIAGNOSIS: The patient had unresectable HCC. MANAGEMENT: The patient underwent two treatments with Yttrium-90 glass microspheres, which were performed as outpatient procedures 1 month and 3 months after diagnosis. He underwent orthotopic liver transplantation (OLT) 1 year after the initial diagnosis of HCC. The post-OLT immunoregimen included OKT3 plus rituximab and high-dose steroids. On discharge from hospital he was on immunosuppressive treatment with tacrolimus. He had de novo autoimmune hepatitis 6 months post-OLT, which was treated with a short course of low-dose steroids and addition of mycophenolate mofetil.