Use of positron emission tomography/ computed tomography in the initial staging of head and neck squamous cell carcinoma: Accuracy in evaluation of the primary site of the tumor, metastases to cervical lymph nodes, and distant metastases.

AIM: Our study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) in the initial staging of head and neck squamous cell carcinoma (HNSCC), including assessment of local and distant spread of the disease. We also aimed to compare the accuracy of PET/CT in the evaluation of human papillomavirus (HPV) positive and HPV-negative oropharyngeal carcinoma. MATERIAL AND METHODS: This single-center, prospective study was conducted between August 2016 and September 2021. A total of 198 patients with HNSCC who underwent PET/CT within the primary staging were included. We compared PET/CT results with histological findings. We calculated the accuracy, sensitivity, specificity, and positive and negative predictive values to assess the primary tumor, cervical lymph nodes, and distant metastases. RESULTS: PET/CT showed a high success rate (32%) in revealing the primary site of carcinoma of unknown primary (CUP). The accuracy of PET/CT in displaying the primary tumor, cervical lymph node metastases, and distant metastases was 89.4%, 85.4%, and 87.4%, respectively. The method provided high sensitivity but lower specificity in all three areas. Specifically, PET/CT showed low specificity in the assessment of small tumors (75%), metastatic involvement of cervical lymph nodes (69.6%), and HPV-positive oropharyngeal carcinoma (55.6%). CONCLUSIONS: The high accuracy of PET/CT to identify distant metastases and whole-body staging in one diagnostic step accelerated primary staging and resulted in earlier commencement of therapy. However, it also led to an overestimation of clinical findings and thus to extensive surgical treatment, especially in patients with small tumors, metastatic involvement of cervical lymph nodes, and HPV- positive oropharyngeal carcinoma. PET/CT is also useful for CUP diagnostics.

Improved beta-amyloid PET reproducibility using two-phase acquisition and grey matter delineation.

PURPOSE: We investigated whether the reproducibility of standard visual reporting (STD method) in flutemetamol (FMM) PET can be improved using a newly introduced method that uses grey matter edges derived from the perfusion phase (GM-EDGE method). METHODS: Two-phase FMM PET was performed in 121 patients with mild cognitive impairment. Five nuclear medicine physicians blindly and independently evaluated all late-phase scans, initially employing the STD method and later the GM-EDGE method. A five-point scale was used to express the degree of amyloid positivity, and a binary classification (positive/negative) was used in combination with subjective confidence (five-point scale). Multirater Fleiss' kappa, intraclass correlation coefficient (ICC) and inter-rater reliability (Cohen's kappa) were determined for the STD and GM-EDGE methods. RESULTS: The weighted Cohen's kappa values for the five-point measure of amyloid positivity ranged from 0.63 to 0.73 (median 0.70) for the STD method and from 0.76 to 0.89 (median 0.80) for the GM-EDGE method (ICC 0.84, 95% CI 0.79-0.88, for the STD method; 0.91, 95% CI 0.89-0.94, for the GM-EDGE method). The nonweighted Cohen's kappa value for the binary classification ranged from 0.73 to 0.93 (median 0.82) for the STD method and 0.90 to 0.97 (median 0.93) for the GM-EDGE method (Fleiss' kappa 0.82, 95% CI 0.77-0.88, for the STD method; 0.93, 95% CI 0.87-0.99, for the GM-EDGE method). The GM-EDGE method resulted in significantly greater subjective confidence in the readings of four physicians (p < 0.010). The binary classification was concordant among all five physicians in 80.8% of the scans using the STD method and in 91.6% of the scans using the GM-EDGE method (p = 0.016). CONCLUSION: The newly introduced GM-EDGE method was associated with significantly higher inter-rater agreement among physicians and higher subjective confidence in the reading. The method is easy to implement in clinical practice, especially when the perfusion phase is utilized clinically.

Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment.

BACKGROUND: Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia. METHODS: In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher's exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression. RESULTS: We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers. CONCLUSIONS: This exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.

An easy way to increase confidence in beta-amyloid PET evaluation.

BACKGROUND: In patients with brain atrophy, it is not easy to distinguish pathologic uptake of flutemetamol (FMM) in the gray matter from nonspecific, physiologic uptake in the white matter. In this paper we suggest an easy image processing method. MATERIAL AND METHODS: The proof-of-concept study involved three patients with mild cognitive impairment and different graphical findings at FMM-PET. Two-phase FMM-PET was acquired; the early phase represented the perfusion of gray matter, while the late phase depicted the white matter and beta-amyloid load in the gray matter. The border of the gray matter was easily extracted from the early-phase images using thresholding and the isocontour "Edges" color table. The late phase was registered with the edge images of the early phase and displayed using alpha-blending. RESULTS: Early- and late-phase image fusion displayed with appropriate color tables is presented in three different cases to illustrate the added value of the suggested approach. CONCLUSIONS: Composite late-phase images with enhanced gray matter borders strongly facilitate assessment of beta-amyloid presence in the gray matter. This is especially helpful in patients with brain atrophy.

[18F]FDG-PET scan in patients with fasting hyperglycemia.

BACKGROUND: It is generally accepted that a non-fasting state reduces [18F]FDG-PET quality, but the significance of higher levels of fasting blood glucose has aroused some doubts over time. The aim of this work was to provide further evidence to clarify this issue and its impact on the handling of hyperglycemic patients in daily routine. METHODS: Muscle and liver standardized uptake values (SUV) and their ratio, tumor SUV and the frequency of positive PET findings were retrospectively analyzed in 116 hyperglycemic (HG) patients (>11 mmol/L), in 116 patients with slightly elevated glycemia (SEG) (5.6-7.0 mmol/L) and in 116 normoglycemic (NG) patients (4.7 mmol/L). RESULTS: No significant difference was found in the muscle to liver ratio, in muscle SUV and in the frequency of positive PET findings among HG, SEG and NG patients. HG patients exhibited ~10% higher liver SUV in comparison to SEG and NG patients; a positive correlation (r=0.2849) was found between liver SUV and blood glucose levels. Significantly higher tumor SUV was present in SEG patients. CONCLUSIONS: We did not confirm that hyperglycemia in a fasting state negatively influences the diagnostic quality of [18F]FDG-PET. The positive correlation between liver SUV and blood glucose levels is clinically negligible and might be explained by increased fasting hepatic gluconeogenesis in diabetics. Our data encourage the performance of [18F]FDG-PET investigations under fasting conditions, regardless of the mild to medium elevation of fasting blood glucose level.

Characterization of 46 patient-specific BCR-ABL1 fusions and detection of SNPs upstream and downstream the breakpoints in chronic myeloid leukemia using next generation sequencing.

In chronic myeloid leukemia, the identification of individual BCR-ABL1 fusions is required for the development of personalized medicine approach for minimal residual disease monitoring at the DNA level. Next generation sequencing (NGS) of amplicons larger than 1000 bp simplified and accelerated a process of characterization of patient-specific BCR-ABL1 genomic fusions. NGS of large regions upstream and downstream the individual breakpoints in BCR and ABL1 genes, respectively, also provided information about the sequence variants such are single nucleotide polymorphisms.

Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.

PURPOSE: Here, we studied whether amplicon next-generation deep sequencing (NGS) could improve the detection of emerging BCR-ABL1 kinase domain mutations in chronic phase chronic myeloid leukemia (CML) patients under tyrosine kinase inhibitor (TKI) treatment and discussed the clinical relevance of such sensitive mutational detection. METHODS: For NGS data evaluation including extraction of biologically relevant low-level variants from background error noise, we established and applied a robust and versatile bioinformatics approach. RESULTS: Results from a retrospective longitudinal analysis of 135 samples of 15 CML patients showed that NGS could have revealed emerging resistant mutants 2-11 months earlier than conventional sequencing. Interestingly, in cases who later failed first-line imatinib treatment, NGS revealed that TKI-resistant mutations were already detectable at the time of major or deeper molecular response. Identification of emerging mutations by NGS was mirrored by BCR-ABL1 transcript level expressed either fluctuations around 0.1 %(IS) or by slight transcript level increase. NGS also allowed tracing mutations that emerged during second-line TKI therapy back to the time of switchover. Compound mutants could be detected in three cases, but were not found to outcompete single mutants. CONCLUSIONS: This work points out, that next-generation deep sequencing, coupled with a robust bioinformatics approach for mutation calling, may be just in place to ensure reliable detection of emerging BCR-ABL1 mutations, allowing early therapy switch and selection of the most appropriate therapy. Further, prospective assessment of how to best integrate NGS in the molecular monitoring and clinical decision algorithms is warranted.

FLT-PET in previously untreated patients with low-grade glioma can predict their overall survival.

BACKGROUND: Low-grade gliomas (LGG) of the brain have an uncertain prognosis, as many of them show continuous growth or upgrade over the course of time. We retrospectively investigated the role of positron emission tomography with 3'-deoxy-3'-[18F]fluorothymidine (FLT-PET) in the prediction of overall survival and event free survival in patients with untreated LGG. No such information is yet available in the literature. MATERIAL AND METHODS: Forty-one patients with previously untreated LGG underwent 55 FLT-PET investigations during their follow-up because of subjective complaints, objective worsening of clinical conditions, equivocal findings or progression on magnetic resonance imaging. The time interval before referral for neurosurgical or radiation treatment was considered to be event free survival, the interval until death as overall survival, respectively. Standardized uptake values (SUV) were measured, and a 3-point scale of subjective assessment was also applied. ROC analysis was used to define cut-off values. The log rank test was used for comparison of Kaplan-Meier survival curves. RESULTS: Eight patients (a total of 9 FLT-PET studies performed) died during follow-up. Progression leading to referral to therapy was recorded in 24 patients (a total of 33 FLT-PET studies). With a cut-off value of SUV(mean) = 0.236, a median overall survival of 1.007 days was observed in the test positive subgroup while median overall survival for the test negative subgroup was not achieved (p = 0.0002), hazard ratio = 17.6. Subjective assessment resulted in hazard ratio 11.5 (p = 0.0001). Only marginal significance (p=0.0562) was achieved in prediction of event free survival. CONCLUSIONS: Increased FLT uptake in previously untreated patients with LGG is a strong predictor of overall survival. On the other hand, prediction of event free survival was not successful in our cohort, probably because of high prevalence of patients who needed treatment due to symptoms caused by a space-occupying lesion without respect to the proliferative activity of the tumour.

SISCOM and FDG-PET in patients with non-lesional extratemporal epilepsy: correlation with intracranial EEG, histology, and seizure outcome.

AIMS: To assess the practical localising value of subtraction ictal single-photon emission computed tomography (SISCOM) coregistered with MRI and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with extratemporal epilepsy and normal MRI. METHODS: We retrospectively studied a group of 14 patients who received surgery due to intractable epilepsy and who were shown to have focal cortical dysplasia, undetected by MRI, based on histological investigation. We coregistered preoperative SISCOM and PET images with postoperative MRI and visually determined whether the SISCOM focus, PET hypometabolic area, and cerebral cortex, exhibiting prominent abnormalities on intracranial EEG, were removed completely, incompletely, or not at all. These results and histopathological findings were compared with postoperative seizure outcome. RESULTS: Two patients underwent one-stage multimodal image-guided surgery and the remaining 12 underwent long-term invasive EEG. SISCOM findings were localised for all but 1 patient. FDG-PET was normal in 3 subjects, 2 of whom had favourable postsurgical outcome (Engel class I and II). Complete resection of the SISCOM focus (n=3), the area of PET hypometabolism (n=2), or the cortical regions with intracranial EEG abnormalities (n=7) were predictive of favourable postsurgical outcome. Favourable outcome was also encountered in: 4 of 8 patients with incomplete resection and 1 of 2 with no resection of the SISCOM focus; 4 of 7 patients with incomplete resection and 1 of 2 with no resection of the PET hypometabolic area; and 2 of 7 patients with incomplete resection of the area corresponding to intracranial EEG abnormality. No correlation between histopathological FCD subtype and seizure outcome was observed. CONCLUSION: Complete resection of the dysplastic cortex localised by SISCOM, FDG-PET or intracranial EEG is a reliable predictor of favourable postoperative seizure outcome in patients with non-lesional extratemporal epilepsy.

Prognostic and diagnostic accuracy of [18F]FDG-PET/CT in 190 patients with carcinoma of unknown primary.

PURPOSE: The aim of the study was to determine the accuracy of [(18)F]fluorodeoxyglucose (FDG) PET/CT in the search for the primary and the presence of a malignancy. The prognostic value of FDG-PET/CT information was tested. METHODS: A total of 190 patients were retrospectively analysed: 82 with histologically proven metastases (HPM) and 108 with clinical suspicion of the presence of a malignancy (CSM). The sensitivity and specificity were determined. Overall survival was calculated to evaluate the prognostic value of the FDG-PET/CT findings. RESULTS: In the search for the primary, the sensitivity and specificity were 62.0% and 81.9%, respectively. In the search for the presence of a malignancy, the sensitivity and specificity were 93.6% and 85.7%, respectively. Between the HPM and CSM groups, no significant difference in sensitivity and specificity was found either in the search for the primary or in the search for the presence of a malignancy. No significant difference in the sensitivity and specificity was found between 78 patients who were investigated by contrast-enhanced FDG-PET/CT and the remaining patients. A significantly shorter overall survival was found among patients with positive FDG-PET/CT findings compared with patients with negative findings (p = 0.00001); no significant difference in survival was found between the HPM and the CSM group (p = 0.770). CONCLUSION: FDG-PET/CT imaging is very helpful in the search for the presence of a malignancy in patients with carcinoma of unknown primary syndrome. FDG-PET/CT is less accurate in identifying exactly the site of a primary. Discovery of a hypermetabolic lesion was associated with the worst survival rate.

The role of FDG-PET/CT in the detection of recurrent colorectal cancer.

PURPOSE: The conventional diagnostic techniques used to assess recurrence of colorectal cancer (CRCR) often yield unspecific findings. Integrated FDG-PET/CT seems to offer promise for the differential diagnosis of benign and malignant lesions. The aim of this study was to compare the value of FDG-PET and PET/CT in the detection of CRCR subsequent to colonic resection or rectal amputation. METHODS: The population for this retrospective study comprised 84 patients with suspected CRCR. The sensitivity, specificity and accuracy of PET and PET/CT were calculated for (a) intra-abdominal extrahepatic recurrences, (b) extra-abdominal and/or hepatic recurrences and (c) all recurrences, and tumour marker levels were analysed. RESULTS: The sensitivity, specificity and overall accuracy of PET in detecting intra-abdominal extrahepatic CRCR were 82%, 88% and 86%, respectively, compared with 88%, 94% and 92%, respectively, for PET/CT. The corresponding figures for detection of extra-abdominal and/or hepatic CRCR were 74%, 88% and 85% for PET and 95%, 100% and 99% for PET/CT. Considering the entire population, the sensitivity, specificity and overall accuracy of PET were 80%, 69% and 75%, respectively, compared with 89%, 92% and 90%, respectively, for PET/CT. FDG-PET/CT examination correctly detected 40 out of a total of 45 patients with CRCR. Two of five patients with falsely negative FDG-PET/CT findings had local microscopic recurrences and one had miliary liver metastases. Of 39 patients without CRCR, three showed false positive FDG-PET/CT results. Two of these cases were due to increased accumulation in inflammatory foci in the bowel wall, while one was due to haemorrhaging into the adrenal gland. CONCLUSION: FDG-PET/CT appears to be a very promising method for distinguishing a viable tumour from fibrous changes, thereby avoiding unnecessary laparotomy.