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Purpose: Hypopharyngeal carcinoma (HPC) is typically diagnosed at late stages, the patients tend to have serious co-morbidities, distant relapses are frequent, and the related mortality remains high. The treatment paradigm of HPC has remarkably changed from primary surgical approach toward definitive, platinum-based concomitant chemoradiotherapy (CRT). Our aim was to analyze the HPC treatment approaches and outcome in a nationwide series and to make a comparison with a previously published corresponding nationwide patient cohort from the period 1990-1999., Methods: We retrospectively reviewed all patients diagnosed with HPC at the five university hospitals in Finland between 2005 and 2014., Results: The cohort comprised 231 patients. Treatment with curative intent was offered for 175 (76%) patients and consisted of definitive radiotherapy (RT) or CRT in 156 (89%) patients, while 20 (11%) patients had primary surgery with or without adjuvant RT or CRT. The 5-year estimates for overall survival (OS) and disease specific survival (DSS) for the whole study group were 22.7% and 36.5%, respectively. For patients treated with curative intent, the 5-year estimates for OS and DSS were 29.4% and 44.3%, respectively., Conclusions: The treatment approach of HPC in Finland has changed thoroughly, as in the 1990s, 63% of HPC patients with curative treatment intent underwent primary surgery with or without RT, while in the current study, the primary treatment approach was non-surgical in 89% of the patients. However, the survival figures have not changed and remain dismal, but most of the few surviving patients now can retain their larynx., (© 2022. The Author(s).)

A commercial deep learning (DL)-based automated segmentation tool (AST) for computed tomography (CT) is evaluated for accuracy and efficiency gain within prostate cancer patients. Thirty patients from six clinics were reviewed with manual- (MC), automated- (AC) and automated and edited (AEC) contouring methods. In the AEC group, created contours (prostate, seminal vesicles, bladder, rectum, femoral heads and penile bulb) were edited, whereas the MC group included empty datasets for MC. In one clinic, lymph node CTV delineations were evaluated for interobserver variability. Compared to MC, the mean time saved using the AST was 12 min for the whole data set (46%) and 12 min for the lymph node CTV (60%), respectively. The delineation consistency between MC and AEC groups according to the Dice similarity coefficient (DSC) improved from 0.78 to 0.94 for the whole data set and from 0.76 to 0.91 for the lymph nodes. The mean DSCs between MC and AC for all six clinics were 0.82 for prostate, 0.72 for seminal vesicles, 0.93 for bladder, 0.84 for rectum, 0.69 for femoral heads and 0.51 for penile bulb. This study proves that using a general DL-based AST for CT images saves time and improves consistency.

Background: The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC)., Methods: [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome., Results: None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = -618, p =0.019) and apoptosis with Ki-67 (rs = -638, p =0.014)., Conclusions: A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.

Purpose: In order to improve the treatment of squamous cell carcinoma of the head and neck, precise information on the treated tumour's biology is required and the prognostic importance of different biological parameters needs to be determined. The aim of our study was to determine the predictive value of pretreatment PET/CT imaging using [(18)F]FDG, a new hypoxia tracer [(18)F]EF5 and the perfusion tracer [(15)O]H₂O in patients with squamous cell cancer of the head and neck treated with radiochemotherapy., Methods: The study group comprised 22 patients with confirmed squamous cell carcinoma of the head and neck who underwent a PET/CT scan using the above tracers before any treatment. Patients were later treated with a combination of radiochemotherapy and surgery. Parametric blood flow was calculated from dynamic [(15)O]H₂O PET images using a one-tissue compartment model. [(18)F]FDG images were analysed by calculating standardized uptake values (SUV) and metabolically active tumour volumes (MATV). [(18)F]EF5 images were analysed by calculating tumour-to-muscle uptake ratios (T/M ratio). A T/M ratio of 1.5 was considered a significant threshold and used to determine tumour hypoxic subvolumes (HS) and hypoxic fraction area. The findings were finally correlated with the pretreatment clinical findings (overall stage and TNM stage) as well as the outcome following radiochemotherapy in terms of local control and overall patient survival., Results: Tumour stage and T-classification did not show any significant differences in comparison to the patients' metabolic and functional characteristics measured on PET. Using the Cox proportional hazards model, a shorter overall survival was associated with MATV (p = 0.008, HR = 1.108), maximum [(18)F]EF5 T/M ratio (p = 0.0145, HR = 4.084) and tumour HS (p = 0.0047, HR = 1.112). None of the PET parameters showed a significant effect on patient survival in the log-rank test, although [(18)F]EF5 maximum T/M ratio was the closest (p = 0.109). By contrast, tumour blood flow was not correlated with any of the clinical endpoints. There were no statistically significant correlations among [(18)F]FDG SUVmax, [(18)F]EF5 T/M ratio and blood flow., Conclusion: Our study in a limited number of patients confirmed the importance of MATV in the prognosis of locally advanced squamous cell carcinoma of the head and neck. It is of interest that high uptake of the hypoxia tracer [(18)F]EF5 showed a stronger correlation with a poor clinical outcome than [(18)F]FDG uptake. This confirms the importance of hypoxia in treatment outcome and suggests that [(18)F]EF5 may act as a surrogate marker of radioresistance.

Purpose: A novel [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer., Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [(11)C]-acetate (n = 2) or [(18)F]-fluoromethylcholine (n = 1) PET/CT., Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [(11)C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [(18)F]-fluoromethylcholine PET/CT., Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer., (©2013 AACR.)

Unlabelled: This first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of (68)Ga-bombesin antagonist (68)Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (BAY 86-7548)., Methods: Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 ± 5 MBq). Besides total radioactivity, plasma samples were analyzed by radio-high-performance liquid chromatography for metabolism of the tracer. Dosimetry was calculated using the OLINDA/EXM software., Results: Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% ± 9% at 1 min after injection to 19% ± 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects., Conclusion: Intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.

Background: Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of capecitabine into such a regimen enhances outcome., Methods: In this open-label trial, we randomly assigned (centrally by computer; stratified by node status, HER2 status, and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done after 3 years' median follow-up. Efficacy analyses were by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT00114816., Findings: Two patients in each group were excluded from efficacy analyses because of withdrawal of consent or distant metastases. After a median follow-up of 35 months (IQR 25.5-43.6), recurrence-free survival at 3 years was better with the capecitabine regimen than with control (93%vs 89%; hazard ratio 0.66, 95% CI 0.47-0.94; p=0.020). The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and hand-foot syndrome (83/741 [11%] vs 2/741 [<1%]) and the control regimen with more occurrences of grade 3 or 4 neutropenia (368/375 [98%] vs 325/378 [86%]) and febrile neutropenia (65/741 [9%] vs 33/742 [4%]). More patients discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). Four patients in the capecitabine group and two in the control group died from potentially treatment-related causes., Interpretation: The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse effects., Funding: Roche, Sanofi-Aventis, AstraZeneca, Cancer Society of Finland.

Non-invasive detection of tumor hypoxia using radiolabeled 2-nitroimidazoles has been a major effort during the last two decades. Recent years have witnessed the introduction of several new compounds which are chemically related to [(18)F]fluoromisonidazole (FMISO) but show slight but distinct differences in biodistribution and metabolic clearance. Although [(18)F]FMISO has shown clinical potential it suffers from suboptimal oxygen dependent tissue contrast and newer agents seek to improve this essential feature. The limited data on other interesting tracers keeps the investigators busy at demonstrating the potential advantages over [(18)F]FMISO while efforts should start to concentrate on proving the clinical significance of such techniques in the form of outcome data from image-guided therapy modification. We review here our experiences with two hypoxia-avid agents [(18)F]fluoroerythronitromidazole (FETNIM) and [(18)F] 2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) and focus on the similarities and differences of these two tracers in comparison to other radiolabeled 2-nitroimidazoles. It is recognized that only [(18)F]FMISO has thus far shown clinical utility and newer tracers need to be tested against this circumstance.

Purpose: Meningiomas and schwannomas associated with neurofibromatosis 2 (NF2) are difficult to control by microsurgery and stereotactic radiotherapy alone. Boron neutron capture therapy (BNCT) is a chemically targeted form of radiotherapy requiring increased concentration of boron-10 in tumour tissue. PET with the boron carrier 4-borono-2-[(18)F]fluoro-L-phenylalanine ([(18)F]FBPA) allows investigation of whether 4-borono-L-phenylalanine (BPA) concentrates in NF2 tumours, which would make BNCT feasible., Methods: We studied dynamic uptake of [(18)F]FBPA in intracranial meningiomas (n=4) and schwannomas (n=6) of five sporadic and five NF2 patients. Tracer input function and cerebral blood volume were measured. [(18)F]FBPA uptake in tumour and brain was assessed with a three-compartmental model and graphical analysis. These, together with standardised uptake values (SUVs), were used to define tumour-to-brain [(18)F]FBPA tissue activity gradients., Results: Model fits with three parameters K (1) (transport), k (2) (reverse transport) and k (3) (intracellular metabolism) were found to best illustrate [(18)F]FBPA uptake kinetics. Maximum SUV was two- to fourfold higher in tumour as compared with normal brain and independent of NF2 status. The increased uptake was due to higher transport of [(18)F]FBPA in tumour. In multiple-time graphical analysis (MTGA, Gjedde-Patlak plot) the tumour-to-brain [(18)F]FBPA influx constant (K (i) -MTGA) ratios varied between 1.8 and 5.4 in NF2-associated tumours while in sporadic tumours the ratio was 1-1.4., Conclusion: [(18)F]FBPA PET offers a viable means to evaluate BPA uptake in meningiomas and schwannomas in NF2. Based on our results on tumour uptake of [(18)F]FBPA, some of these benign neoplasms may be amenable to BNCT.

Purpose: The outcome of locally advanced head-and-neck cancer often is poor. An important determinant of treatment failure is tumor hypoxia arising from an inappropriate blood supply. Quantitation of the hypoxic fraction and blood flow in vivo may provide prognostic information and a means to target specifically tumor cells resistant to conventional treatment., Methods and Materials: Twenty-one patients with head-and-neck cancer underwent multitracer positron emission tomography (PET) before the start of preoperative or definitive radiotherapy (RT). Tumor blood flow was measured using the [(15)O]H(2)O autoradiographic technique followed by evaluation of oxygenation status using [(18)F]fluoroerythronitroimidazole ([(18)F]FETNIM). [(18)F]fluorodeoxyglucose PET was performed on a separate day to calculate the metabolically active tumor volume. The definition of the fractional hypoxic volume (FHV) in the tumor was determined by multiple voxel-wise measurements of the uptake of [(18)F]FETNIM in well-oxygenated tissues and tumor. PET findings were then correlated with the RT outcome and survival., Results: High blood flow was associated with poor local control after RT (p = 0.021) and with poor survival (p = 0.018). Patients with a FHV greater or equal to the median had significantly worse survival than those with a FHV less than the median (p = 0.036). The relationship between tumor hypoxia and FHV was supported in 3 patients who underwent invasive measurement of the tissue O(2) partial pressure., Conclusion: High tumor blood flow predicted for a poor response to RT in head-and-neck cancer. The use of [(18)F]FETNIM for assessment of radiobiologic hypoxia requires a study with greater statistical power. PET with [(15)O]H(2)O or [(18)F]FETNIM may become useful in clinical trials in which novel therapeutic agents targeting tumor vasculature or hypoxia are evaluated.

Fluorine-18 fluoroerythronitroimidazole ([(18)F]FETNIM) is a nitroimidazole compound that is potentially useful as a hypoxia marker in positron emission tomography (PET) studies of oncological patients. Our aim was to develop a simple protocol to quantitate uptake of [(18)F]FETNIM in hypoxic tumours. Dynamic imaging data from ten patients with head and neck cancer undergoing [(18)F]FETNIM PET was used in simulations and model fits to assess hypoxia marker uptake under different levels of blood flow. The distribution volume determined from dynamic PET study was compared with simple tumour to plasma and tumour to muscle ratios at 90-120 min. In skeletal muscle having a low but variable blood flow [2-6 ml/(100 gxmin)], differences in hypoxia-specific uptake of [(18)F]FETNIM remain small and may be hard to detect with PET. At higher blood flow [>20 ml/(100 gxmin)], the retention of [(18)F]FETNIM reflects the oxygenation status well and results in satisfactory contrast between hypoxic and well-oxygenated tissue. A good estimate of tissue hypoxia is accomplished by measuring the tissue to plasma [(18)F]FETNIM activity ratio using only a few late time points. The increased hypoxia-specific retention of [(18)F]FETNIM in tissues with high blood flow, such as malignant tumours, may facilitate application of [(18)F]FETNIM as a hypoxia marker in oncological patients. In the assessment of the tumour to non-target uptake ratio, plasma is the preferred reference tissue rather than muscle, which may show a more heterogeneous tracer uptake not easily controlled for.

Unlabelled: 18F-Fluoroerythronitromidazole (FETNIM) is a new promising PET tracer for imaging tumor hypoxia. Accurate radiation dosimetry is important for estimating absorbed radiation doses to patients and for calculating the allowable injected dose., Methods: Radiation absorbed doses were estimated from PET scans obtained on cancer patients on the basis of the MIRD procedure. Dynamic acquisition data was obtained from the thorax, abdomen, and head and neck regions. The tracer was injected intravenously and mean injected activity was 366 MBq (range, 288-385 MBq). Arterial blood was continuously assayed over dynamic PET imaging. The bladder wall dose was evaluated from the voided urine activity measurements., Results: The effective dose to a 70-kg adult was 0.015 or 0.019 mSv/MBq, calculated on 2- or 4-h voiding intervals, respectively. The critical organ proved to be the urinary bladder wall, with a highest absorbed dose of 0.062 or 0.127 mGy/MBq depending on the voiding schedule as described above. Absorbed doses in all other organs were at least 5-fold smaller than the bladder wall doses., Conclusion: With an injected activity of 370 MBq (18)F-FETNIM, the radiation doses are generally comparable with those of other related radionuclide imaging procedures. Specifically, in comparison with (18)F-fluoromisonidazole, the absorbed doses of (18)F-FETNIM are equal. However, special attention should be given to adequate hydration and voiding to limit the relatively high exposure of the critical organ, bladder wall, to (18)F-FETNIM.

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.