Purpose
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is used for (re)staging prostate cancer (PCa) and as a biomarker for evaluating response ...to therapy, but lacks established response criteria. A panel of PCa experts in nuclear medicine, radiology, and/or urology met on February 21, 2020, in Amsterdam, The Netherlands, to formulate criteria for PSMA PET/CT-based response in patients treated for metastatic PCa and optimal timing to use it.
Methods
Panelists received thematic topics and relevant literature prior to the meeting. Statements on how to interpret response and progression on therapy in PCa with PSMA PET/CT and when to use it were developed. Panelists voted anonymously on a nine-point scale, ranging from strongly disagree (1) to strongly agree (9). Median scores described agreement and consensus.
Results
PSMA PET/CT consensus statements concerned utility, best timing for performing, criteria for evaluation of response, patients who could benefit, and handling of radiolabeled PSMA PET tracers. Consensus was reached on all statements. PSMA PET/CT can be used before and after any local and systemic treatment in patients with metastatic disease to evaluate response to treatment. Ideally, PSMA PET/CT imaging criteria should categorize patients as responders, patients with stable disease, partial response, and complete response, or as non-responders. Specific clinical scenarios such as oligometastatic or polymetastatic disease deserve special consideration.
Conclusions
Adoption of PSMA PET/CT should be supported by indication for appropriate use and precise criteria for interpretation. PSMA PET/CT criteria should categorize patients as responders or non-responders. Specific clinical scenarios deserve special consideration.
Background
Most validations of paediatric glomerular filtration rate (GFR) estimating equations using standardized creatinine (CR) and cystatin C (CYS) assays have comprised relatively small cohorts, ...which makes accuracy across subgroups of GFR, age, body mass index (BMI) and gender uncertain. To overcome this, a large cohort of children referred for GFR determination has been established from several European medical centres.
Methods
Three thousand four hundred eight measurements of GFR (mGFR) using plasma clearance of exogenous substances were performed in 2218 children aged 2–17 years. Validated equations included Schwartz-2009
CR
/2012
CR/CYS/CR+CYS
, FAS
CR/CYS/CR+CYS
, LMR
CR
, Schwartz-Lyon
CR
, Berg
CYS
, CAPA
CYS
, CKD-EPI
CYS
, Andersen
CR+CYS
and arithmetic means of the best single-marker equations in explorative analysis. Five metrics were used to compare the performance of the GFR equations: bias, precision and three accuracy measures including the percentage of GFR estimates (eGFR) within ± 10% (P
10
) and ± 30% (P
30
) of mGFR.
Results
Three of the cystatin C equations, Berg
CYS
, CAPA
CYS
and CKD-EPI
CYS
, exhibited low bias and generally satisfactory accuracy across all levels of mGFR; CKD-EPI
CYS
had more stable performance across gender than the two other equations. Among creatinine equations, Schwartz-Lyon
CR
had the best performance but was inaccurate at mGFR < 30 mL/min/1.73 m
2
and in underweight patients. Arithmetic means of the best creatinine and cystatin C equations above improved bias compared to the existing composite creatinine+cystatin C equations.
Conclusions
The present study strongly suggests that cystatin C should be the primary biomarker of choice when estimating GFR in children with decreased GFR. Arithmetic means of well-performing single-marker equations improve accuracy further at most mGFR levels and have practical advantages compared to composite equations.
Objectives
PSMA-PET has become the PET technique of choice to localise the site of biochemically recurrent prostate cancer (PCa). With hybrid PET/MRI, the advantages of MRI are added to molecular ...characteristic of PET. The aim of this study was to investigate the incremental value of PET/MR versus PET/CT in patients with biochemically recurrent PCa by head-to-head comparison.
Methods
Thirty-four patients with biochemically recurrent PCa were prospectively included. They underwent
68
GaGa-PSMA-11 PET/CT, followed by simultaneous PET/MR. All PET (PET
CT
, PET
MR
), CT and MR images were evaluated for number of lesions and location. The number of lesions at specific sites was compared using Wilcoxon-sign-rank test. For PET, the maximum and mean standardised uptake values (SUVs) were calculated for each lesion compared using a two-sided paired t test.
Results
PET
CT
and PET
MR
scans were positive in 19 and 20 patients, detecting 73 and 79 lesions respectively. All lesions detected on PET
CT
were also detected on PET
MR
. CT and MRI only were positive in 14 and 17 patients, detecting 38 and 50 lesions, respectively, which was significantly lower than PET
CT
and PET
MR
respectively. Combined interpretation showed more lesions on PET/MR than on PET/CT (88 vs 81). No significant difference in detection of presence of local recurrence nor distant metastases was found. SUV
mean
and SUV
max
values were significantly higher on PET
MR
than on PET
CT
in local recurrence and lymph node metastases.
Conclusions
68
GaGa-PSMA-11 PET/MR was able to detect biochemically recurrent PCa at least as accurately as PET/CT for local recurrence, lymph node metastasis and distant metastasis.
Key Points
• PSMA PET/MRI detects the location of biochemical recurrence at least as accurately as PET/CT.
• Substitution of PET/CT by PET/MRI adds sensitivity in PSMA lesion detection also in the setting of distant recurrence due to both the MR and TOF PET components.
Pirfenidone may attenuate the decline of pulmonary function in restrictive allograft syndrome (RAS) after lung transplantation. We retrospectively assessed all lung transplant recipients with RAS who ...were treated with pirfenidone for at least 3 months (n = 11) in our lung transplant center and report on their long‐term outcomes following initiation of pirfenidone. Main outcome parameters included evolution of pulmonary function and overall survival. Pirfenidone appears to attenuate the decline in forced vital capacity and forced expiratory volume in 1 second. Notably, 3 patients were bridged to redo‐transplantation with pirfenidone for 11 (5‐12) months and are currently alive, while 3 other patients demonstrate long‐term stabilization of pulmonary function after 26.6 (range 18.4‐46.6) months of treatment. Median overall 3‐year survival after RAS diagnosis was 54.5%. Subjective intolerance, mainly anorexia and nausea, necessitating pirfenidone dose de‐escalation in 55% of patients, as well as calcineurin dose increase requirements with about 20% are important complications during pirfenidone treatment after lung transplantation. Our findings provide further evidence that pirfenidone appears to be safe and may attenuate the rate of decline in lung function in patients with RAS, but the actual clinical benefit cannot be assessed in the context of this study design and requires further investigation in a larger randomized trial.
This case series of lung transplant recipients treated with pirfenidone for restrictive allograft syndrome demonstrates that pirfenidone may attenuate the rate of pulmonary function decline.
Summary
Objective
We investigated changes in the endocannabinoid system and glucose metabolism during temporal lobe epileptogenesis.
Methods
Because it is rarely possible to study epileptogenesis in ...humans, we applied the electrical amygdala kindling model in nonhuman primates to image longitudinal changes in type 1 cannabinoid receptor (CB1R) binding and cerebral glucose metabolism. Two rhesus monkeys received 18F‐MK‐9470 and fluorodeoxyglucose–positron emission tomography (18F‐FDG ‐PET) scans in each of the 4 kindling stages to quantify relative changes over time of CB1R binding and cerebral glucose metabolism in vivo. We constructed z‐score images relative to a control group (n = 8), and considered only those changes measured in both kindled animals by calculating the binary conjunction image per kindling stage.
Results
The seizure‐onset zone exhibited an increased CB1R binding and a decreased glucose metabolism, which both aggravated gradually in extent and intensity throughout kindling. The ipsilateral thalamus and insula showed hypometabolism that coincided with an increase and a decrease in CB1R binding, respectively. These changes also became gradually more severe throughout kindling and overlapped with ictal perfusion changes during the final stage of amygdala kindling, with hyperperfusion in the ipsilateral thalamus and hypoperfusion in the ipsilateral insula.
Significance
The observed changes in CB1R binding may reflect a combination of a protective mechanism of neurons against seizure activity that becomes stronger over time to combat more severe seizures, and on the other hand, a process of epileptogenesis that facilitates seizure activity and generalization, depending on the cell type involved in those specific regions. This study provides unique evidence that the CB1R is dynamically and progressively involved from the start of mesial temporal lobe epileptogenesis.
Pilocarpine administration to rats results in status epilepticus (SE) and after a latency period to the occurrence of spontaneous seizures. The model is commonly used to investigate mechanisms of ...epileptogenesis as well as the antiepileptic effects of novel compounds. Surprisingly, there have been no video-EEG studies determining the duration of latency period from SE to the appearance of the first spontaneous seizures or the type and frequency of spontaneous seizures at early phase of pilocarpine-induced epilepsy even though such information is critical for design of such studies. To address these questions, we induced SE with pilocarpine in 29 adult male Wistar rats with cortical electrodes. Rats were continuously video-EEG monitored during SE and up to 23 days thereafter. The first spontaneous seizures occurred 7.2
±
3.6 days after SE. During the follow-up, the mean daily seizure frequency was 2.6
±
1.9, the mean seizure duration 47
±
7 s, and the mean behavioral seizure score 3.2
±
0.9. Typically first seizures were partial (score 1–2). Interestingly, spontaneous seizures occurred in clusters with cyclicity, peaking every 5 to 8 days. These data show that in the pilocarpine model of temporal lobe epilepsy the latency period is short. Because many of the early seizures are partial and the seizures occur in clusters, the true phenotype of epilepsy triggered by pilocarpine-induced SE may be difficult to characterize without continuous long-term video-EEG monitoring. Finally, our data suggest that the model can be used for studies aiming at identifying the mechanisms of seizure clustering.
We present the case of a 67-year-old woman who suffered recurrent episodes of angioedema of the face and larynx. After thorough biochemical investigations, an acquired deficiency of C1-INH was ...suspected. To evaluate a potential underlying malignancy, a whole-body FDG-PET/CT was performed and showed solely a marked splenomegaly pointing towards a splenic marginal zone lymphoma, which was confirmed by pathological examination.With this case, we discuss the pathophysiology, diagnosis and management of recurrent acquired angioedema attacks as the first presentation of an underlying lymphoproliferative disease.
Background
Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours ...(PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with
18
FFDG PET/CT in a subgroup of patients.
Methods
SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available,
18
FFDG PET/CT images were also evaluated. The maximum standardized uptake (SUV
max
) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUV
max
values were related to the tumour type (TC versus AC) for both SSTR and
18
FFDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUV
max
values were compared to the pathological status (N
+
versus N
−
) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed.
Results
A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed.
18
FFDG PET/CT was available in 46 patients. Analysis of the SUV
max
values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUV
max
18.4 vs 3.8;
p
= 0.003) and significantly higher
18
FFDG uptake in AC compared to TC (median SUV
max
5.4 vs 3.5;
p
= 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on
18
FFDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/
18
FFDG SUV
max
values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for
18
FFDG PET/CT (difference 0.17; 95% confidence interval − 0.03 to 0.38;
p
= 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed.
Conclusion
Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for
18
FFDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines.
Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific ...peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose-effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.
We report the case of a 27-year-old woman who underwent an F-FDG PET/CT, after administration of 20 mg propranolol, 20 minutes preinjection, to investigate B-symptoms as well as right-sided shoulder ...pain. Unilateral hypermetabolism was seen in the left cervical, thoracic, and paravertebral brown fat, without any uptake on the contralateral side. The patient was born with neuroblastoma in the right thoracic area. She underwent surgery a few days after birth. As brown fat activation is under sympathetic control, we hypothesize that a surgical lesion to the right orthosympathetic trunk resulted in sympathetic denervation, responsible for this distribution.
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