Evaluation of prognostic biomarkers in a population-validated Finnish HNSCC patient cohort.

INTRODUCTION: Prognostic biomarkers and novel therapeutic approaches have been slow to emerge in the treatment of head and neck squamous cell carcinoma (HNSCC). In this study, an HNSCC patient cohort is created and performance of putative prognostic biomarkers investigated in a population-validated setting. The overall goal is to develop a novel way to combine biomarker analyses with population-level clinical data on HNSCC patients and thus to improve the carryover of biomarkers into clinical practice. MATERIALS AND METHODS: To avoid selection biases in retrospective study design, all HNSCC patients were identified and corresponding clinical data were collected from the Southwest Finland geographical area. A particular emphasis was laid on avoiding potential biases in sample selection for immunohistochemical staining analyses. Staining results were evaluated for potential prognostic resolution. RESULTS: After comprehensive evaluation, the patient cohort was found to be representative of the background population in terms of clinical characteristics such as patient age and TNM stage distribution. A negligible drop-out of 1.3% (6/476) was observed during the first follow-up year. By immunohistochemical analysis, the role of previously implicated HNSCC biomarkers (p53, EGFR, p16, CIP2A, Oct4, MET, and NDFIP1) was investigated. DISCUSSION: Our exceptionally representative patient material supports the use of population validation to improve the applicability of results to real-life situations. The failure of the putative prognostic biomarkers emphasizes the need for controlling bias in retrospective studies, especially in the heterogenous tumor environment of HNSCC. The resolution of simple prognostic examination is unlikely to be sufficient to identify biomarkers for clinical practice of HNSCC.

Whole body PET/CT in the follow-up of asymptomatic patients with stage IIB-IIIB cutaneous melanoma.

BACKGROUND: Whole body positron emission tomography (PET)/computed tomography (CT) is a sensitive imaging technique in patients with metastatic melanoma, but its role in the follow-up of asymptomatic high-risk patients is unclear. The aim was to study the role of PET/CT as a routine surveillance imaging tool in asymptomatic high-risk patients at the early stage of follow-up combined with a sufficient follow-up over several years. MATERIAL AND METHODS: A total of 110 asymptomatic patients with clinically local American Joint Committee on Cancer (AJCC) stage IIB-IIIB melanoma underwent routine whole body PET/CT scanning after a mean interval of seven months after initial surgery. Clinical data were retrospectively analyzed after a median follow-up time of 4.6 years. RESULTS: Recurrent melanoma was detected in 45 patients (41%) and 36 (33%) died of melanoma. In 11 asymptomatic patients (10%) occult disease was detected with a single PET/CT. In seven of these patients (64%), positive PET/CT finding had major influence in treatment decisions. Four patients underwent surgical metastasectomy and two of them remained disease-free. In 34 patients (31%) PET/CT revealed no disease, but recurrence was detected at a median time of 19 months after negative PET/CT scan. In 50 patients (45%) PET/CT finding was true negative. In 15 patients (14%) scan was false positive leading to additional management or repetitive imagings. CONCLUSION: A single PET/CT could detect 24% of all recurrences in asymptomatic melanoma patients at the early stage of follow-up, but an earlier detection of occult metastases did not improve survival.

Impact of deep learning-determined smoking status on mortality of cancer patients: never too late to quit.

BACKGROUND: Persistent smoking after cancer diagnosis is associated with increased overall mortality (OM) and cancer mortality (CM). According to the 2020 Surgeon General's report, smoking cessation may reduce CM but supporting evidence is not wide. Use of deep learning-based modeling that enables universal natural language processing of medical narratives to acquire population-based real-life smoking data may help overcome the challenge. We assessed the effect of smoking status and within-1-year smoking cessation on CM by an in-house adapted freely available language processing algorithm. MATERIALS AND METHODS: This cross-sectional real-world study included 29 823 patients diagnosed with cancer in 2009-2018 in Southwest Finland. The medical narrative, International Classification of Diseases-10th edition codes, histology, cancer treatment records, and death certificates were combined. Over 162 000 sentences describing tobacco smoking behavior were analyzed with ULMFiT and BERT algorithms. RESULTS: The language model classified the smoking status of 23 031 patients. Recent quitters had reduced CM [hazard ratio (HR) 0.80 (0.74-0.87)] and OM [HR 0.78 (0.72-0.84)] compared to persistent smokers. Compared to never smokers, persistent smokers had increased CM in head and neck, gastro-esophageal, pancreatic, lung, prostate, and breast cancer and Hodgkin's lymphoma, irrespective of age, comorbidities, performance status, or presence of metastatic disease. Increased CM was also observed in smokers with colorectal cancer, men with melanoma or bladder cancer, and lymphoid and myeloid leukemia, but no longer independently of the abovementioned covariates. Specificity and sensitivity were 96%/96%, 98%/68%, and 88%/99% for never, former, and current smokers, respectively, being essentially the same with both models. CONCLUSIONS: Deep learning can be used to classify large amounts of smoking data from the medical narrative with good accuracy. The results highlight the detrimental effects of persistent smoking in oncologic patients and emphasize that smoking cessation should always be an essential element of patient counseling.

Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer.

The aim of the study is to assess the value of carbonic anhydrase isozyme IX (CA IX) expression as a predictor of disease-free survival (DFS) and disease-specific survival (DSS) in rectal cancer treated by preoperative radio- or chemoradiotherapy or surgery only. Archival tumour samples from 166 patients were analysed for CA IX expression by three different evaluations: positive/negative, proportion of positivity and staining intensity. The results of immunohistochemical analysis were confirmed by demonstrating CA IX protein in western blotting analysis. Forty-four percent of the operative samples were CA IX positive, of these 34% had weak and 66% moderate/strong staining intensity. In univariate survival analysis, intensity of CA IX expression was a predictor of DFS (P=0.003) and DSS (P=0.034), both being markedly longer in tumours with negative or weakly positive staining. In multivariate Cox model, number of metastatic lymph nodes and CA IX intensity were the only independent predictors of DFS. Carbonic anhydrase isozyme IX intensity was the only independent predictor of DSS, with HR=9.2 for dying of disease with moderate-intense CA IX expression as compared with CA IX-negative/weak cases. Negative/weak CA IX staining intensity is an independent predictor of longer DFS and DSS in rectal cancer.

Critical review of the follow-up protocol for head and neck cancer patients.

OBJECTIVE: Head and neck cancer follow-up length, interval and content are controversial. Therefore, this study aimed to evaluate the efficacy of the follow-up protocol after curative treatment in head and neck cancer patients. METHOD: Clinical data of 456 patients with new malignancy of the head and neck from a tertiary care centre district from 1999 to 2008 were analysed. Time from treatment, symptoms and second-line treatment outcomes of patients with recurrent disease were evaluated. RESULTS: A total of 94 (22 per cent) patients relapsed during the 5-year follow-up period; 90 per cent of recurrences were found within 3 years. Fifty-six per cent of the patients had subjective symptoms indicating a recurrence of the tumour. All recurrent tumours found during routine follow-up visits without symptoms were found within 34 months after completion of treatment. CONCLUSION: Routine follow up after three years is questionable; recurrent disease beyond this point was detected in only 2 per cent of patients. In this study, all late tumour recurrences had symptoms of the disease. Easy access to extra follow-up visits when symptoms occur could cover the need for late follow up.

[18F]-DOPA positron emission tomography for preoperative localization in congenital hyperinsulinism.

In recent years, considerable progress has been made in the biochemical, morphological and molecular genetic differentiation of congenital hyperinsulinism (CHI). Fluorine-18 L-3,4-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA-PET) has been introduced for differentiation between focal and diffuse CHI. The ability to take up L-DOPA and convert it into dopamine is correlated with the activity of the aromatic amino acid decarboxylase and increased in the hyperfunctional affected pancreatic area in comparison to normally functioning pancreas. The high sensitivity of this method allows the surgeon to perform a curative limited resection of a focus without the risk of long-term diabetes. The exact preoperative planning by (18)F-DOPA-PET/CT computer tomography allows laparoscopic operation in selected cases with the focus in the tail and limits necessity to open the pancreatic duct in cases with focus in the head. Patients with persistent CHI should be managed within a strong network of diagnostic, treatment, and research institutions.

Detection of residual tumours in postchemotherapy testicular cancer by FDG-PET.

The aim of this study was to investigate whether 2-(F-18)-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) could reliably detect testicular cancer in patients following chemotherapy. Twenty FDG-PET studies were performed on 15 patients with metastatic seminoma or non-seminoma. Tracer uptake in the PET study was measured by calculating the standardised uptake value (SUV) for the tracer. Nine lesions out of 20 were judged to be positive based on high FDG uptake. Three proved to represent inflammatory changes in non-cancerous tissue. Eleven PET studies were negative. In one of these, viable tumour was found at retroperitoneal lymphadenectomy. The median SUV values of metastatic tumours and benign residual tumours were 2.7 (range 1.6-9.5, n = 10) and 1.7 (range 0.7-5.5, n = 15), respectively. The large overlap of SUVs between these groups was due to the relatively high FDG uptake in inflammatory tissue (median 4.2, range 2.0-5.5, n = 4). The results indicate that FDG imaging of metastatic testicular cancer after chemotherapy has limited value because of a potentially high accumulation of FDG in inflammatory tissues.

Cerebral blood flow and glucose metabolism in long-term survivors of childhood acute lymphoblastic leukaemia.

Central nervous system treatment for childhood acute lymphoblastic leukaemia (ALL) has been reported to cause changes in cerebral blood flow and glucose metabolism. Little is known about the association of these functional changes with neuropsychological defects and structural changes. The aim of the present study was to assess the relationship between changes in regional cerebral blood flow and glucose utilisation in long-term survivors of ALL, and the association of these functional abnormalities with neurocognitive and structural defects. 8 survivors of childhood ALL were studied with single photon emission tomography (SPECT) using Tc99m-ethyl cysteinate dimer (ECD) as tracer and with positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) as tracer. 8 healthy controls also underwent FDG-PET. All subjects also underwent magnetic resonance imaging and neuropsychological assessment 5 years after cessation of the therapy. Focal cerebral blood flow abnormalities were found in ECD-SPECT in 5 of the 8 survivors. Glucose utilisation appeared normal in the corresponding regions. However, glucose utilisation was decreased in thalamus and cerebellum in the survivors of ALL as compared with healthy controls. 3 patients had severe and 5 patients mild neurocognitive difficulties. The changes in cerebral blood flow and FDG uptake did not correspond neuroanatomically with the neurocognitive defects. Focal defects in cerebral blood flow in long-term survivors of ALL are not associated with changes in local cerebral glucose utilisation. Neurocognitive difficulties are not consistently associated with either changes in cerebral blood flow or with decreased glucose utilisation. Therefore, based on the present set of studies FDG-PET and ECD-SPECT cannot yet be recommended for the evaluation of long-term neurocognitive defects associated with treatment of ALL.

Experience in qualitative and quantitative FDG PET in follow-up of patients with suspected recurrence from head and neck cancer.

We evaluated positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in the detection of recurrent head and neck cancer, and compared visual and quantitative interpretation of PET images for their accuracy in the identification of tumour recurrence. Sixty-two FDG PET studies were performed in 56 patients having a total of 81 lesions, which were clinically suspected for recurrent carcinoma of the head and neck. The PET images were interpreted visually, and tracer uptake was quantitated as the standardised uptake value adjusted to body weight (SUV). Sensitivity of visual interpretation of the PET images for the presence of malignancy ranged from 84 to 95%, and specificity from 84 to 93%, respectively, depending on the selected scheme for grading of the lesions. Malignant lesions accumulated significantly more FDG than the benign ones (the median SUVs were 6.8 and 3.3, respectively, P<0.001). However, there was a wide overlap of the FDG uptake values between these two groups. Hence, the highest accuracy of quantitative analysis in correct identification of tumour recurrence (75% at Receiver Operating Curve analysis) was inferior to that of visual analysis (89%). FDG PET is feasible for the detection of recurrent head and neck cancer. Although quantitation of FDG uptake using SUV shows significantly higher tracer concentrations for malignant than benign lesions, the wide overlap of individual SUVs between these two groups is a serious concern in diagnostic evaluation. Therefore, in clinical practice it may be preferable to identify the presence of tumour recurrence within this patient group by qualitative interpretation of the PET images.

Granulocyte macrophage-colony stimulating factor (GM-CSF) and sucralfate in prevention of radiation-induced mucositis: a prospective randomized study.

PURPOSE: To compare subcutaneously given molgramostim (GM-CSF) and sucralfate mouth washings to sucralfate mouth washings in prevention of radiation-induced mucositis. METHODS AND MATERIALS: Forty head and neck cancer patients were randomly assigned to use either GM-CSF and sucralfate (n = 20) or sucralfate alone (n = 20) during radiotherapy. Sucralfate was used as 1.0 g mouth washing 6 times daily after the first 10 Gy of radiotherapy, and 150-300 microg GM-CSF was given subcutaneously. The grade of radiation mucositis and blood cell counts were monitored weekly. Salivary lactoferrin was measured as a surrogate marker for oral mucositis. RESULTS: We found no significant difference between the molgramostim and the control groups in the oral mucositis grade, oral pain, use of analgesic drugs, weight loss, or survival. The median maximum neutrophil counts (median, 9.2 x 10(9)/L vs. 5.9 x 10(9)/L, p = 0.0005), eosinophil counts (median, 1.3 x 10(9)/L vs. 0.2 x 10(9)/L, p = 0.0004), and salivary lactoferrin concentrations were higher in patients who received GM-CSF. The most common toxicities in the GM-CSF plus sucralfate group were skin reactions at the GM-CSF injection site (65%), fever (30%), bone pain (25%), and nausea (15%), whereas the toxicity of sucralfate given alone was minimal. CONCLUSION: We found no evidence indicating that subcutaneously given GM-CSF reduces the severity of radiation-induced mucositis.

Radiotherapy treatment planning and long-term follow-up with [(11)C]methionine PET in patients with low-grade astrocytoma.

PURPOSE: To evaluate the feasibility of [(11)C]-methionine positron emission tomography (MET PET) in radiotherapy (RT) treatment planning and long-term follow-up in patients with low-grade glioma. PATIENTS: Thirteen patients with low-grade astrocytoma and 1 with anaplastic astrocytoma underwent sequential MET PET and magnetic resonance imaging (MRI) before and 3, 6, 12, and 21-39 months after RT, respectively. Ten patients were studied after initial debulking surgery or biopsy and 4 in the recurrence phase. METHODS: A total of 58 PET scans were performed. After transmission scanning, a median dose of 425 MBq of MET was injected intravenously and emission data was acquired 20 min after injection for 20 min. The uptake of MET in tumor area was measured as standardized uptake value (SUV) and tumor-to-contralateral brain SUV ratios were generated to assess irradiation effects on tumor metabolism. Functional imaging with PET was compared with concurrent MRI in designing the RT planning volumes and in assessment of response to RT during a median follow-up time of 33 months. RESULTS: In 12 patients (86%), tumor area was clearly discernible in the baseline PET study. In the remaining 2 patients with a suspected residual tumor in MRI, PET showed only a diffuse uptake of MET interpreted as negative in the original tumor area. In the dose planning of RT, MET PET was helpful in outlining the gross tumor volume in 3 of 11 cases (27%), whereas PET findings either coincided with MRI (46%) or were less distinctive (27%) in other cases. In quantitative evaluation, patients with a low tumor SUV initially had significantly better prognosis than those with a high SUV. Tumor-to-contralateral brain uptake ratios of MET discriminated well patients remaining clinically stable from those who have since relapsed or died of disease. CONCLUSION: Quantitative MET PET has prognostic value at the time of initial treatment planning of low-grade glioma. Some patients may benefit of RT volume definition with MET PET, which seems to disclose residual tumor better than MRI in selected cases. Stable or decreasing uptake of MET in tumor area after RT during follow-up seems to be a favorable sign.

Evaluation of treatment response to radiotherapy in head and neck cancer with fluorine-18 fluorodeoxyglucose.

Nineteen patients with malignant head and neck tumors were imaged before and during radiation therapy with 18F-2-fluoro-2-deoxy-D-glucose (FDG) to study the effect of radiotherapy (RT) on FDG uptake. All tumor images were FDG-positive before treatment. After RT, a decrement of tumor FDG uptake was found in all but two patients; these were nonradioresponders. There was a significant decrement (p less than 0.001) in uptake ratios after irradiation of 30 +/- 5 Gy among the radioresponsive (CR + PR) but not among the radioresistant (NC + PD) tumors. The administered dose of RT correlated (r = 0.47, p less than 0.05) with the decrement in FDG activity among the CR + PR but not among the NC + PD patients. The biologic half-life of FDG radioactivity in tumor tissue was evaluated by dynamic scintigraphy. A change in the half-life of FDG toward the value observed in normal tissue was associated with treatment response. The results suggest that FDG imaging can be used for follow-up of RT in patients with head and neck cancer.

In vitro comparison of cell proliferation kinetics and uptake of tritiated fluorodeoxyglucose and L-methionine in squamous-cell carcinoma of the head and neck.

UNLABELLED: Estimation of tumor proliferative activity is important for the optimal management of head and neck cancer. Noninvasive metabolic imaging with PET may complement currently used cytopathologic methods to study tumor proliferation. METHODS: Fluorodeoxyglucose (FDG) and L-methionine (MET) were studied for their potential to assess in vitro the growth characteristics of three squamous-cell carcinoma (SCC) cell lines established recently in patients with head and neck cancer. A time-course uptake of tritiated FDG and MET was measured over the complete growth cycle of one rapidly growing (UT-SCC-5) and two relatively slower growing (UT-SCC-1A and UT-SCC-9) cell lines. DNA flow cytometry was used for assessment of proliferative activity. RESULTS: There was a strong linear relationship for both FDG and MET uptake versus the viable cell number although absolute MET uptake was consistently lower than that of FDG in the exponential and plateau phases of growth (p < 0.01), leading MET to underestimate cell number. The pattern of MET uptake followed the flow cytometric changes in the proliferation index (% of S + G2/M cells) in two of three cases (UT-SCC-1A and UT-SCC-5) while a similar, although clearly weaker, relationship was seen with FDG and flow cytometry findings in only one case (UT-SCC-5). CONCLUSION: In these three human SCC cell lines assessed in vitro, FDG is a better marker of cell viability than MET, whereas MET is superior for estimating proliferative activity. Extrapolations of these in vitro data to the interpretation of PET images should be made with caution since tumors may have confounding factors that may affect in vivo tracer uptake.

Nodal staging of lymphoma with whole-body PET: comparison of.

UNLABELLED: Accurate staging is elementary for optimal management of malignant lymphoma. Advanced cases may be curable with multidrug chemotherapy combined with radiotherapy, whereas limited disease can sometimes be cured by local radiotherapy only. Recently, FDG imaging with whole-body PET (WB PET) has been introduced as an accurate method for staging lymphoma. We evaluated the usefulness of L-[methyl-11C]methionine (MET) in comparison with FDG as a tracer for nodal staging of lymphoma with WB PET. METHODS: Nineteen patients with untreated, histologically proven malignant lymphoma underwent WB PET imaging with MET and FDG within 1 wk before treatment. Fourteen patients had non-Hodgkin's lymphoma (NHL), and 5 had Hodgkin's disease (HD). Two of these 19 patients were excluded from the final analysis because of hyperglycemia. WB PET images using FDG and MET were visually compared by 3 independent interpreters, and the PET findings were correlated with the data on the basis of conventional staging studies. RESULTS: Fifty-five of 178 lymph node regions were classified as diseased both by FDG PET and by CT, and 54 of 178 were classified as diseased both by MET PET and by CT. In addition, 11 lymph node regions that CT showed to be normal avidly accumulated FDG. Ten of these lymph node regions also had clear uptake of MET. Another 4 and 5 lymph node regions were enlarged at CT but were judged to be normal by FDG and MET PET, respectively. In nodal staging, both FDG PET and MET PET would have upstaged the disease in 3 patients. MET PET would also have downstaged the disease in 1 patient. CONCLUSION: FDG and MET seem to be comparable in the detection of lymphoma by WB PET. However, visual interpretation of the images tends to be hampered more by physiologic accumulations of MET than by normal accumulations of FDG, and MET may be preferable to FDG in hyperglycemic patients undergoing staging studies with PET.

Influence of the blood glucose concentration on FDG uptake in cancer--a PET study.

Radiolabeled [11F]-2-fluoro-2-deoxy-D-glucose (FDG) is a glucose analogue widely used to study tumor metabolism by means of positron emission tomography (PET). Little is known about the effect of hyperglycemia on FDG uptake and PET imaging of tumors. Five patients with head and neck cancer underwent two PET studies prior to cancer therapy, first in the fasting state and then 2-5 days later after oral glucose loading. FDG uptake was measured with standardized uptake values (SUV) and Ki values according to Patlak et al. The fasting SUVs ranged from 4.1 to 10.9 and Kis from 0.021 min-1 to 0.067 min-1, whereas after loading both the SUVs (range 2.2-5.9, p < 0.02) and Ki values (range 0.006-0.042 min-1, p < 0.05) decreased significantly, and the quality of the PET images became markedly poorer. The FDG metabolic rate (Ki x P-Gluc) remained similar in different plasma glucose concentrations in tumors, but increased clearly in muscles after loading. Therefore, patients entering PET-FDG studies should fast and their blood glucose concentration needs to be taken into account when evaluating FDG accumulation.

Comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine in head and neck cancer.

The positron emission tomography (PET) tracer 2-18F-fluoro-2-deoxy-D-glucose (FDG) is the most widely used tracer in oncology. PET tracer. Another radiotracer, L-methyl-11C-Methionine (11C-methionine), also has been used successfully for PET imaging of brain and lung tumors, non-Hodgkin's lymphoma, breast cancer and head and neck cancer. This study compared FDG and 11C-methionine as tumor-detecting agents in head and neck cancer. Prior to cancer therapy, fourteen patients underwent a PET study with FDG and one with 11C-methionine. Nineteen of 21 malignant lesions that could be evaluated were visible with both tracers. Tracer uptake was measured as standardized uptake values (SUV) and Ki values according to Patlak et al. The mean SUV in FDG studies was 7.7 +/- 4.2 and in 11C-methionine studies 7.7 +/- 2.5, whereas the Ki values in 11C-methionine studies (mean, 0.128 +/- 0.068 min-1) were always higher than in FDG studies (mean, 0.036 +/- 0.023 min-1). A good correlation was found between the SUVs (r = 0.79, p < 0.0001) and the Ki values (r = 0.82, p < 0.001) between the two tracers. Both FDG and 11C-methionine are effective in PET imaging of head and neck cancer, and the uptake rates of the tracers seem to be closely related.

Pharmacokinetics of [18F]FETNIM: a potential marker for PET.

UNLABELLED: 18F-labeled fluoroerythronitroimidazole (FETNIM) has been suggested as a marker of tumor hypoxia for use with PET. Our goal was to evaluate the pharmacokinetic properties of [18F]FETNIM in rats and analyze metabolites in human, dog, and rat plasma and urine. Metabolites in liver and tumor homogenates from tumor-bearing rats, as well as the biodistribution of the tracer, were also studied. METHODS: Radio-thin-layer chromatography and digital autoradiography were used to distinguish metabolites from the parent drug in urine and plasma from 8 patients, 3 dogs, and 18 rats, as well as in liver and tumor homogenates from Sprague-Dawley rats bearing 7,12-dimethylbenzanthracene-induced rat mammary carcinoma. Biodistribution of [18F]FETNIM was also studied in rats at 15, 30, 60, 120, and 240 min after tracer injection. RESULTS: Most of the radioactivity in plasma and urine was the unchanged tracer, whereas rat liver homogenates contained almost only metabolites of [18F]FETNIM. None of the species studied showed binding of tracer to plasma proteins. A large variation-3%-70%-in the radioactivity represented by unchanged [18F]FETNIM was found in rat tumor. A negative correlation was found between the percentage of radioactivity represented by unchanged [18F]FETNIM in tumor tissue and tumor uptake (percentage injected dose per gram of tissue) at later times. The highest radioactivity was seen in urine and kidney; the lowest uptake was in fat, cerebellum, and bone matrix. In contrast to matrix, bone marrow had high uptake of 18F. The tumor-to-blood ratio reached a maximum of 1.80 +/- 0.64 at 2 h. CONCLUSION: We conclude that [18F]FETNIM shows low peripheral metabolism, little defluorination, and possible metabolic trapping in hypoxic tumor tissue. These suggest a potential use for this tracer in PET studies on hypoxia of cancer patients.

Prediction of survival with fluorine-18-fluoro-deoxyglucose and PET in head and neck cancer.

UNLABELLED: The aim of this prospective study was to investigate if high uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) is associated with aggressiveness in head and neck cancer and low probability of survival. METHODS: Thirty-seven patients with squamous-cell carcinoma of the head and neck underwent FDG-PET in the fasting state before cancer treatment. FDG uptake in primary tumor was quantitated as the standardized uptake value of FDG normalized to the predicted lean body mass (SUVlean, n = 37) and as the graphically determined metabolic rate for FDG (rMR[FDG], n = 34). Paraffin-embedded tumor samples were used for histologic evaluation, and expression of cytokeratin and Ki-67 antigen were assessed by immunohistochemistry. RESULTS: Interobserver agreement for the determination of quantitative uptake of FDG in tumors was excellent (r2 = 0.996, p < 0.00001), and all 37 primary tumors were visualized. A high uptake of FDG as assessed by SUVlean was associated with a higher than the median mitotic count (p = 0.01), absence of keratinization (p = 0.03), low or moderate histological grade of differentiation (p = 0.046) and advanced stage (p = 0.03), but not with Ki-67 expression (p = 0.11). The overall survival of patients with a SUVlean lower than or equal to the median value (9.0) was clearly better in univariate analysis than that of patients with a SUVlean higher than the median (3-yr survival 73% versus 22%, relative risk of death (RR) 4.2, 1.6-11.0). However, in a multivariate analysis the only independent predictors of survival were the mitotic count (RR 4.0, 1.4-11.7) and stage (3.8, 1.2-12.2). CONCLUSION: High uptake of FDG in untreated head and neck cancer is associated with advanced disease, and may portend poor survival. Aggressive treatment approaches should be considered for patients presenting with a tumor with high uptake of FDG.

Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET.

UNLABELLED: Hypoxia is a characteristic feature of malignant tumors that should be evaluated before the start of therapy. (18)F-labeled fluoroerythronitroimidazole (FETNIM) is a possible candidate for imaging tumor hypoxia with PET. Quantitative analysis of [(18)F]FETNIM uptake in vivo is necessary before proceeding to assays predicting hypoxia. METHODS: Eight patients with untreated head and neck squamous cell carcinoma were enrolled in the study. All patients underwent dynamic PET imaging with [(18)F]FETNIM, coupled with measurements of blood flow with [(15)O]H(2)O and blood volume with [(15)O]CO. The metabolically active tumor volume was determined from [(18)F]FDG PET performed on a separate day. [(18)F]FETNIM uptake in the tumor was correlated with that in neck muscles and arterial plasma and compared with the findings of other PET studies. RESULTS: Blood flow in tumor was 5- to 30-fold greater than in muscle, in contrast to blood volume, which did not significantly differ in the 2 tissues. With [(18)F]FETNIM PET, muscle activity remained invariably less than plasma activity, whereas activity in whole tumors was always greater than that in muscle. In 4 instances, the maximum tumor uptake of [(18)F]FETNIM was 1.2-2.0 times higher than plasma activity in the late dynamic phase. A kinetic model developed for calculation of distribution volume of reversibly trapping tracers was successfully applied in the [(18)F]FETNIM studies. Tumor distribution volume correlated strongly with the standardized uptake value of [(18)F]FETNIM between 60 and 120 min and with blood flow but not with the standardized uptake value of [(18)F]FDG. The relationship between [(18)F]FETNIM uptake and the blood flow of the tumor was less obvious on a pixel-by-pixel level. CONCLUSION: Uptake of [(18)F]FETNIM in head and neck cancer is highly variable and seems to be governed by blood flow at least in the early phase of tissue accumulation. Maximum tumor-to-muscle tracer uptake ratios > 180 min were in the range of 1-4, comparing favorably with those reported previously for [(18)F]fluoromisonidazole. Assessment of the distribution volume of [(18)F]FETNIM after the initial blood-flow phase is feasible for subsequent evaluation of hypoxia-specific retention.