Diagnostic Accuracy of 18F-FDG-PET/CT and 18F-FDG-PET/MRI in Detecting Locoregional Recurrence of HNSCC 12 Weeks after the End of Chemoradiotherapy: Single-Center Experience with PET/MRI.

Purpose: In head and neck squamous cell carcinoma (HNSCC), the early diagnosis and efficient detection of recurrences and/or residual tumor after treatment play a very important role in patient's prognosis. Positron emission tomography (PET) using 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) has become an established method for the diagnosis of suspected recurrence in head and neck carcinomas. In particular, integrated PET/MRI imaging that provides optimal soft tissue contrast and less dental implant artifacts compared to PET/CT is an intriguing technique for the follow-up imaging of HNSCC patients. The aim of this study was to evaluate the benefit of PET/MRI compared to PET/CT in post-treatment follow-up imaging of HNSCC patients. Methods: This retrospective observational cohort study consists of 104 patients from our center with histologically confirmed HNSCC. All patients received chemoradiotherapy (CRT) and underwent 18F-FDG-PET/CT (n = 52) or 18F-FDG-PET/MRI (n = 52) scan 12 weeks after the end of treatment. Image analysis was performed by two independent readers according to a five-point Likert scale analysis. Results: PET/MRI was more sensitive (1.00 vs. 0.77) than PET/CT in the detection of locoregional recurrence. PET/MRI also had better negative (1.00 vs. 0.87) predictive values. AUCs for PET/MRI and PET/CT on patient-based analysis were 0.997 (95% CI 0.989-1.000) and 0.890 (95% CI 0.806-0.974), respectively. The comparison of sensitivity, AUCs, and negative predictive values revealed a statistically significant difference, p < 0.05. In PET/CT, false-negative and positive findings were observed in the more advanced disease stages, where PET/MRI performed better. Also, false-negative findings were located in the oropharyngeal, laryngeal, and nasopharyngeal regions, where PET/MRI made no false-negative interpretations. Conclusion: Based on these results, PET/MRI might be considered the modality of choice in detecting locoregional recurrence in HNSCC patients, especially in the more advanced stages in the oral cavity, larynx, or nasopharynx.

Practical aspects of sentinel node biopsy in oral cavity cancer: all nodes that emit a signal are important.

BACKGROUND AND OBJECTIVES: Sentinel node biopsy (SNB) is a safe and effective way to examine an N0 neck in early-stage oral cavity cancer (OCC). In this study, we evaluated the variables of SNB detection, surgery, and outcome. MATERIAL AND METHODS: Ninety-two patients with N0 OCC examined with SNB were included. Number and brightness of nodes detected on preoperative imaging and during surgery were analyzed and compared with histological findings. Patients with recurrent disease were evaluated separately and the effect of smoking and alcohol consumption was analyzed. RESULTS: Eighteen patients had at least malignant cells in the sentinel lymph node (SLN); 18 patients had recurrent disease and nine patients died from the cancer. The negative predictive value of SNB was 95%. Six patients did not have metastases in the node with the strongest signal, but metastases were found in an SLN with a weaker signal. Smoking and alcohol consumption did not affect disease-specific or overall survival. CONCLUSION AND SIGNIFICANCE: SNB has been confirmed to be safe and effective in early stage N0 OCC. However, it is important to carefully harvest up to four hottest SLNs that emit a signal. Treatment of patients with only isolated tumor cells (ITC) in the SLN appears to be necessary.

Desmoid tumors of the head and neck: Two decades in a single tertiary care unit and review of the literature.

Desmoid tumors (DTs) of the head and neck have typically been classified as extra-abdominal, although the anatomic challenges of the head and neck warrant consideration of these DTs as a special entity. We present a review of DTs and describe our series of five patients with DTs of the head and neck treated within 2 decades. Altogether, 53 patients with DTs treated surgically at a tertiary care center over a 20-year period were retrospectively reviewed. Outcomes of the treatment of DTs of the head and neck (n = 5) were analyzed as a case series. DTs are rare, histologically benign, but locally aggressive tumors. In our series of 5 patients with head and neck DTs, no patient experienced a recurrence during a median follow-up of 47.5 months (range 13 to 150), although all had positive histologic margins. The functional integrity of vital structures over meticulous radicality of the tumor resection must be considered, especially in the head and neck.

Botulinum toxin alleviates dysphagia of patients with inclusion body myositis.

OBJECTIVES: Oropharyngeal dysphagia is a disabling and undertreated symptom that often occurs in patients with sporadic inclusion body myositis (s-IBM). In this study, we examined the effect of botulinum neurotoxin A (BoNT-A) injections to the cricopharyngeus muscle (CPM) of patients with s-IBM and dysphagia. PATIENTS, MATERIALS AND METHODS: A single-center retrospective study involving 40 biopsy-proven s-IBM-patients treated in the District of Southwest Finland from 2000 to 2013. The incidence of dysphagia, rate of aspirations, rate of aspiration pneumonias and treatment results of dysphagia were analyzed. Patients treated for dysphagia were evaluated before and after surgery by video-fluoroscopy and/or using a questionnaire. RESULTS: Twenty-five of the 40 s-IBM patients (62.5%) experienced dysphagia. BoNT-A was injected a median of 2 times (range 1-7) in 12 patients with dysphagia. Before the injections 7 patients reported aspiration, none afterwards. The corresponding figures for aspiration pneumonia were 3 and 0. All of these patients had normal swallowing function 12months (median, range 2-60) after the last injection. CONCLUSION: BoNT-A injections to the CPM alleviate the dysphagia of s-IBM patients reversibly and appear to reduce the rate of aspiration effectively.

The feasibility of NBI in patients with suspected upper airway lesions: A multicenter study.

OBJECTIVE: Narrow band imaging (NBI) improves diagnosis of laryngopharyngeal cancer, but most reported NBI studies are from experienced centers. Feasibility reports on use at everyday outpatient departments are needed. STUDY DESIGN: Researcher-initiated, prospective, multicenter. METHODS: Participating physicians were instructed in NBI technique during a 4-hour meeting. Patients underwent an examination that included endoscopy with white light (WL) high-definition (HD) TV and NBI filter in the selected time period. All suspicious lesions were biopsied. The medical records of patients with NBI negative findings were evaluated 6 months after the visit to detect all possible malignant lesions coming into view at mucosal sites. These were considered as false-negative cases, enabling long-term assess to the positive predictive value (NPV) of the protocol. RESULTS: We enrolled 125 patients. Of those, 84 (67.2%) were males and the median age was 65 years (range, 35-91). In analysis of the accuracy of WL HD TV and NBI against biopsy, the sensitivity and specificity of WL HD TV were 62% and 81%, respectively; and the sensitivity and specificity of NBI were 100% and 84%, respectively. The diagnostic accuracy of NBI was significantly better (P < 0.05). When analyzing medical records 6 months after the initial examination, we found three patients who had been diagnosed with a malignant lesion (NPV of NBI of 96.8%). CONCLUSION: Narrow band imaging is readily implemented in an everyday outpatient practice, and there seems to be better detection rates of dysplastic/carcinoma lesions with HD NBI compared to HD WL. LEVEL OF EVIDENCE: 2b. Laryngoscope, 127:1821-1825, 2017.

Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo.

Bisphosphonates are standard treatments for bone metastases. When given in the adjuvant setting, they reduce breast cancer mortality and recurrence in bone but only among post-menopausal patients. Optimal drug use would require biomarker-based patient selection. Such biomarkers are not yet in clinical use. Based on the similarities in inflammatory responses to bisphosphonates and Toll-like receptor (TLR) agonists, we hypothesized that TLR9 expression may affect bisphosphonate responses in cells. We compared bisphosphonate effects in breast cancer cell lines with low or high TLR9 expression. We discovered that cells with decreased TLR9 expression are significantly more sensitive to the growth-inhibitory effects of bisphosphonates in vitro and in vivo. Furthermore, cancer growth-promoting effects seen with some bisphosphonates in some control shRNA cells were not detected in TLR9 shRNA cells. These differences were not associated with inhibition of Rap1A prenylation or p38 phosphorylation, which are known markers for bisphosphonate activity. However, TLR9 shRNA cells exhibited increased sensitivity to ApppI, a metabolite that accumulates in cells after bisphosphonate treatment. We conclude that decreased TLR9-expression sensitizes breast cancer cells to the growth inhibitory effects of bisphosphonates. Our results suggest that TLR9 should be studied as a potential biomarker for adjuvant bisphosphonate sensitivity among breast cancer patients.

Evaluation of repeated [(18)F]EF5 PET/CT scans and tumor growth rate in experimental head and neck carcinomas.

BACKGROUND: Tumor hypoxia is linked to invasion and metastasis but whether this associates with tumor growth rate is not well understood. We aimed to study the relationship between hypoxia evaluated with the positron emission tomography (PET) tracer [(18)F]EF5 and tumor growth. Our second goal was to assess the variability in the uptake of [(18)F]EF5 in tumor between two scans. METHODS: Four human head and neck squamous cell carcinoma (UT-SCC) cell lines were xenografted in flank or neck of nude mice, and tumor size was closely monitored over the study period. The tumors were clearly visible when the first [(18)F]EF5 scan was acquired. After an exponential growth phase, the tumors were imaged again with [(18)F]EF5 and also with (18)F-fluorodeoxyglucose ([(18)F]FDG). RESULTS: There was a clear correlation between the percentage of tumor growth rate per day and the [(18)F]EF5 uptake in the latter scan (r = 0.766, p = 0.01). The uptake of [(18)F]EF5 in the first scan and the uptake of [(18)F]FDG did not significantly correlate with the tumor growth rate. We also observed considerable variations in the uptake of [(18)F]EF5 between the two scans. CONCLUSIONS: The uptake of [(18)F]EF5 in the late phase of exponential tumor growth is associated with the tumor growth rate in mice bearing HNC xenografts.

Blood pressure and free flap oxygenation in head and neck cancer patients.

CONCLUSION: This study suggests that although oxygen partial pressure in tissue (p(ti)O(2)) measurement is a feasible method for continuous postoperative monitoring of free flaps, low correlation between blood pressure (BP) and p(ti)O(2) might predict compromised overall outcome. Thus, it is of utmost importance to keep the BP optimal for adequate perfusion of re-anastomosed tissue transfers. OBJECTIVE: Optimal BP is an important factor in assuring adequate blood flow in a free flap. Tissue oxygenation in free flaps as a postoperative monitoring target is in routine clinical use in some clinics. Correlation between p(ti)O(2) and systemic BP was investigated. METHODS: Ten consecutive patients underwent resection of head and neck squamous cell carcinoma followed by microvascular reconstruction with a free microvascular flap. P(ti)O(2) of each flap was continuously monitored for 3 postoperative days with a polarographic measurement system. BP was measured invasively and continuously during the operation and during the first postoperative day at the intensive care unit. The correlation coefficient between p(ti)O(2) and BP was analysed. RESULTS: The correlation coefficient between p(ti)O(2) and BP was relatively high in all patients with uneventful flap survival (r (mean) = 0.63, n = 5). In flaps with haemodynamic problems or compromised flap vitality the correlation appeared low (r(mean) = -0.02, n = 5).

Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts.

BACKGROUND: Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. METHODS: Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG) and hypoxia ([18F]EF5), and intratumoral polarographic measurements of pO2. RESULTS: Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. CONCLUSION: FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.

Perfusion in free breast reconstruction flap zones assessed with positron emission tomography.

The aim of this pilot study was to determine the postoperative blood perfusion (BF(PET)) and perfusion heterogeneity (BF(PET) HG) in free microvascular breast reconstruction flap zones with positron emission tomography (PET). Regional BF(PET) and BF(PET) HG of the adipose tissue in medial, central, and lateral parts of 13 free flaps were assessed on the first postoperative morning with PET using oxygen-15-labeled water ([(15)O]H(2)O) in 12 patients undergoing breast reconstruction with a deep inferior epigastric perforator (DIEP) or a transverse rectus abdominis muscle (TRAM) flap. The mean BF(PET) values did not differ between DIEP and TRAM flaps (P = 0.791). The mean BF(PET) values were higher in zone III compared with zone I (P = 0.024). During follow-up, fat necrosis was identified in three patients in the medial part (zone II) of the flap. However, the adipose tissue BF(PET) assessed on the first postoperative day from all zones of the flap using PET with radiowater was normal. The BF(PET) HG was higher in the control side (i.e., in the healthy breast tissue) compared with the flap (P = 0.042). The BF(PET) HG was lower in zone III than in zone I (P = 0.03) and in zone II (P < 0.001). In this pilot study, PET was used for the first time for studying the adipose tissue perfusion in different zones in free flaps in a clinical setup, finding that the mean BF(PET) values did not differ between DIEP and TRAM flaps, and that zone II was sometimes not as well perfused as zone III supporting revisited zone division.

The use of pedicled temporal musculoperiosteal flap with or without free calvarial bone graft in maxillary reconstructions.

Various techniques have been used to repair maxillary defects. The aim of this study was to evaluate the suitability of pedicled temporal musculoperiosteal flap (PTMF) and free calvarial bone graft for the reconstruction of maxillary defects. In this retrospective series, 34 patients operated on from 1995 to 2006 at Turku University Central Hospital because of defects of maxilla reconstructed using PTMF with or without free calvarial bone graft were evaluated. The diagnosis, the indication for surgery, the location and staging of the tumours, and the type of radiotherapy used were reviewed. The classification of the maxillary defects was performed according to the classification of Brown (Br J Oral Maxillofac Surg 40:183-190, 2002) and the success rates of the reconstructions were evaluated. Of the patients, 32 had been operated on due to a malignant tumour, one due to a benign tumour and one due to posttraumatic palatal defect. Preoperative radiotherapy (n = 14), preoperative chemoradiotherapy (n = 2) or postoperative radiotherapy (n = 11) had been used in the tumour group. As a reconstructive method, PTMF had been used with (n = 21) or without (n = 13) free calvarial bone graft. The use of free calvarial bone graft did not have a significant effect on flap survival. At 1-month follow-up, the flap survival in the 32 patients was 71.9%, whereas 28.1% of the patients suffered from partial flap loss, but there was no total flap loss. At 6-month follow-up, the flap survival in 26 patients was 76.9%, whereas 7.7% of the patients suffered from partial flap loss, and there were four (15.4%) total flap losses. If unilateral alveolar maxillectomy had been performed (Brown classification a), at 1-month follow-up, the flap survival was 82.6%, 17.4% of the patients suffered from partial flap loss, and there was no total flap loss. At 6-month follow-up, the flap survival was 89.5%, while 10.5% of the patients suffered from partial flap loss, and there was no total flap loss. The application of PTMF with or without free calvarial bone graft for reconstruction of limited palatal and maxillary defects appears to be feasible.

The limitations of tissue-oxygen measurement and positron emission tomography as additional methods for postoperative breast reconstruction free-flap monitoring.

Twelve patients who underwent breast reconstruction with a microvascular flap were monitored postoperatively with continuous partial tissue oxygenation (p(ti)O(2)) measurement. The regional blood flow (BF) of the entire flap was evaluated with positron emission tomography (PET) using oxygen-15-labelled water on the first postoperative (POP) morning to achieve data of the perfusion of the entire flap. A re-exploration was carried out if the p(ti)O(2) value remained lower than 15 mmHg for over 30 min. The mean p(ti)O(2) value of the flaps was 52.9+/-5.5 mmHg, whereas the mean BF values were 3.3+/-1.0 ml per 100 g min(-1). One false-positive result was detected by p(ti)O(2) measurement, resulting in an unnecessary re-exploration. Another re-operation suggested by the low p(ti)O(2) results was avoided due to the normal BF results assessed with PET. Totally, three flaps were re-explored. This prospective study suggests that continuous tissue-oxygen measurement with a polarographic needle probe is reliable for monitoring free breast flaps from one part of the flap, but assessing perfusion of the entire flap requires more complex monitoring methods, for example, PET. Clinical examination by experienced personnel remains important in free-breast-flap monitoring. PET could be useful in assessing free-flap perfusion in selected high-risk patients as an alternative to a re-operation when clinical examination and evaluation by other means are unreliable or present controversial results.

Monitoring microvascular free flaps with tissue oxygen measurement and PET.

Tissue oxygen measurement and positron emission tomography (PET) were evaluated as methods for predicting ischemia in microvascular free flaps of the head and neck. Ten patients with head and neck squamous cell cancer underwent resection of the tumour followed by microvascular reconstruction with a free flap. Tissue oxygenation of the flap (P(ti)O(2)) was continuously monitored for three postoperative (POP) days and the blood flow of the flap was assessed using oxygen-15 labelled water and PET. In three free flaps a perfusion problem was suspected due to a remarkable drop in P(ti)O(2)-values, due to two anastomosis problems and due to POP turgor. No flap losses occurred. During the blood flow measurements with PET [mean 8.5 mL 100 g(-1) min(-1 )(SD 2.5)], the mean P(ti)O(2) of the flaps [46.8 mmHg (SD 17.0)] appeared to correlate with each other in each patient (p<0.05, n=10). Tissue oxygenation measurement is a feasible monitoring system of free flaps. The perfusion-study with PET correlates with P(ti)O(2)-measurement.

Functional evaluation of microvascular free flaps with positron emission tomography.

BACKGROUND: The aim of this study was to assess blood flow (BF) of microvascular free flaps studied with positron emission tomography (PET) in patients with head and neck squamous cell cancer (HNSCC) undergoing major radical surgery 3-4 weeks after high-dose radiotherapy. METHODS: Five patients underwent resection of the HNSCC of the oral cavity followed by microvascular reconstruction with a radial forearm flap. Regional BF in oral and neck tissues was measured with PET using radiolabelled water ([15O]H2O) twice (1-2 and 12-14 days, respectively) following radical surgery. RESULTS: In the first postoperative PET study, the median BF in the cutaneous flap area was 5.1 mL/100 g/min, and in the muscle contra-lateral to the recipient site 19.9 mL/100 g/min. A low flap-to-muscle BF ratio appeared to correlate with circulatory incongruity, and thus with poorer flap success. The follow-up study on the second postoperative week supported the results of the primary PET scan. CONCLUSIONS: This pilot study suggests that PET using [15O]H2O is a feasible method to quantitatively evaluate BF of the whole free flap in patients operated on for oral

Ultrasonically activated scalpel compared with electrocautery in tonsillectomy.

The occurrence of postoperative bleeding, the quantity of operative bleeding and the duration of operation were retrospectively evaluated in 407 patients who underwent tonsillectomy within a 32-month period. They were operated on with either an ultrasonically activated scalpel (UAS), bipolar diathermy (BPD) or blunt dissection with monopolar diathermy (MPD) with the following results. (1) Primary bleeding was more common with MPD: MPD 7.1% vs. BPD 2.4% (p < 0.01) vs. UAS 1.0% (p < 0.001). Secondary bleeding was more common with UAS: UAS 19.6% vs. MPD 14.5% (p < 0.001) vs. BPD 14.5% (p < 0.01). There was no statistical significance in the differences between overall postoperative bleeding rates. (2) There was statistically significantly less operative bleeding with UAS:UAS 24.8 ml vs. MPD 58.7 ml vs. BPD 43.8 ml. (3) On the other hand, the operation time was on average longer with UAS: UAS 32.3 min vs. MPD 18.4 min vs. BPD 22.1 min. Our results suggest that UAS offers no significant advantage over MPD or BPD in tonsillectomy other than minimal operative bleeding possibly due to longer duration of operation.

Effect of blood loss on vascular responsiveness in pedicled groin flaps in a rat model.

Using the clamping method (closing and opening the flap feeding artery) and continuous laser Doppler flowmetry, the effects of blood withdrawals on flap blood flow and on active and passive mechanisms regulating it were investigated in 12 Sprague-Dawley rats. Measurements were made during stable normovolemic conditions, during hypovolemia (after 3 ml/kg and after 6 ml/kg blood withdrawal), and after retransfusion of the shed blood. The continuous blood flow responses during and after the clamping procedure were analyzed. After clamp release, the increase in blood flow, duration of overshoot, and peak flow of overshoot were significantly greater (the level of significance was set equal to 0.05) in the registrations performed after blood withdrawals than before them. The post-ischemic response curves indicating significantly increased flap hyperemia during reperfusion in the registrations after blood withdrawals may be associated with decreased vascular resistance in the flap. Thus, the authors conclude that a short-term decrease in blood pressure caused by blood loss may prepare the flap microcirculation for tolerating more ischemia.

Effect of acute ischemic preconditioning on blood-flow response in the epigastric pedicled rat flap.

Research in the field of microvascular surgery has shown that ischemic preconditioning (repeated brief episodes of feeding artery occlusions followed by reperfusion) improves flap survival. The authors used a custom-designed clamping method and laser Doppler flowmetry to investigate changes in blood flow (BF) responses, either with acute ischemic preconditioning or without it. The animal model used was the partially elevated epigastric flap of adult Sprague-Dawley rats. In the preconditioned group (n=12), the flaps underwent preconditioning with three cycles of 10-min of feeding artery clamping, followed by 10 min of reperfusion, for a total preconditioning period of 1 hr. In the control group (n=12), the flaps were perfused without clamping for 1 hr. All the flaps underwent occlusion of the feeding artery for 15, 30, 60, 120 and 180 sec to observe the changes in the BF responses, 60 min and 150 min after flap elevation. To compare the responses between preconditoned and control groups the BF responses were analyzed during the overshoot period (i.e., BF being above the baseline after different feeding artery occlusion periods). Statistical analysis of the responses showed that the magnitude of increase in BF after clamp release (p<0.001), the duration of overshoot (p=0.014), and the amplitude of overshoot after clamp release (p=0.002) were statistically significantly greater in the preconditioned group than in the control group. The results suggest that vessels and their responses to change in perfusion pressure are involved in the multifactorial process of the ischemia-protective effect caused by acute ischemic preconditioning. As far as is known, this is the first report showing changes in flap vascular responses after acute ischemic preconditioning.