Derrek A. Heuveling

Sentinel node biopsy using 3D lymphatic mapping by freehand SPECT in early stage oral cancer: a new technique

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Sentinel node biopsy for early‐stage oral cavity cancer: the VU University Medical Center experience

Sentinel node biopsy (SNB) in head and neck cancer is recently introduced as the staging technique of oral squamous cell carcinoma. We report the results of SNB in patients diagnosed with a T1–T2 oral squamous cell carcinoma and clinically negative (N0) neck in a single center.

Pilot Study on the Feasibility of PET/CT Lymphoscintigraphy with 89Zr-Nanocolloidal Albumin for Sentinel Node Identification in Oral Cancer Patients

With conventional imaging techniques such as planar lymphoscintigraphy and SPECT/CT, preoperative sentinel node (SN) identification can be difficult when the SN is near the primary tumor, as is the case in floor-of-mouth carcinomas. PET/CT lymphoscintigraphy may improve the detection and localization of such SNs. Methods: In this study, the clinical feasibility of PET/CT lymphoscintigraphy using 89Zr-nanocolloidal albumin was evaluated in 5 oral cancer patients. PET/CT lymphoscintigraphy was performed after peritumoral injection of 89Zr-nanocolloidal albumin. The routine SN procedure, including SPECT/CT using 99mTc-nanocolloidal albumin, was performed on the same patients 7–9 d after the injection of 89Zr-nanocolloidal albumin. Results: Comparison of radiocolloid distribution on PET/CT and SPECT/CT showed identical drainage patterns. Moreover, PET/CT was able to identify additional foci near the primary tumor. Conclusion: This pilot PET/CT study on SN detection indicated that lymphoscintigraphy using 89Zr-nanocolloidal albumin is feasible.

Phase 0 Microdosing PET Study Using the Human Mini Antibody F16SIP in Head and Neck Cancer Patients

The aim of this microdosing phase 0 clinical study was to obtain initial information about pharmacokinetics, biodistribution, and specific tumor targeting of the antitenascin-C mini antibody F16SIP. Methods: Two milligrams of F16SIP, labeled with 74 MBq of 124I, were intravenously administered to patients with head and neck cancer (n = 4) scheduled for surgery 5–7 d later. Immuno-PET scans were acquired at 30 min and 24 h after injection. For pharmacokinetic analysis, blood samples were taken at different time points after infusion. Tissue uptake was extracted from whole-body PET scans. In addition, ex vivo radioactivity measurements of blood and of biopsies from the surgical specimens were performed. Results: 124I-F16SIP was well tolerated. Uptake was visible mainly in the liver, spleen, kidneys, and bone marrow and diminished over time. Tumor uptake increased over time, with all 4 tumors visible on 24-h PET images. The tumor-to-blood ratio was 7.7 ± 1.7 at the time of surgery. Pharmacokinetic analysis revealed good bioavailability of 124I-F16SIP. Conclusion: Performing a microdosing immuno-PET study appeared feasible and demonstrated adequate bioavailability and selective tumor targeting of 124I-F16SIP.The results of this study justify further clinical exploration of 124I-F16SIP-based therapies.

89Zr-Nanocolloidal Albumin–Based PET/CT Lymphoscintigraphy for Sentinel Node Detection in Head and Neck Cancer: Preclinical Results

Identifying sentinel nodes near the primary tumor remains a problem in, for example, head and neck cancer because of the limited resolution of current lymphoscintigraphic imaging when using 99mTc-nanocolloidal albumin. This study describes the development and evaluation of a nanocolloidal albumin–based tracer specifically dedicated for high-resolution PET detection. Methods: 89Zr was coupled to nanocolloidal albumin via the bifunctional chelate p-isothiocyanatobenzyldesferrioxamine B. Quality control tests, including particle size measurements, and in vivo biodistribution and imaging experiments in a rabbit lymphogenic metastasis model were performed. Results: Coupling of 89Zr to nanocolloidal albumin appeared to be efficient, resulting in a stable product with a radiochemical purity greater than 95%, without affecting the particle size. PET showed distinguished uptake of 89Zr-nanocolloidal albumin in the sentinel nodes, with visualization of lymphatic vessels, and with a biodistribution comparable to 99mTc-nanocolloidal albumin. Conclusion: 89Zr-nanocolloidal albumin is a promising tracer for sentinel node detection by PET.

Visualization of the sentinel node in early-stage oral cancer: limited value of late static lymphoscintigraphy

ObjectiveVarious lymphoscintigraphic imaging protocols exist for sentinel node (SN) identification in early-stage oral cancer. This study aimed to evaluate the clinical value of performing additional late lymphoscintigraphic imaging. MethodsWe retrospectively analysed early (directly following injection of 99mTc-Nanocoll) and late (2–4 h after injection) imaging results of 60 early-stage (T1–T2, cN0) oral cancer patients scheduled for SN procedure. Lymphoscintigraphic results of late imaging were categorized into: (a) no visualization of additional hotspots considered to be SNs; (b) additional hotspots visualized that are considered to be SNs and (c) hotspots visualized only during late imaging. Histopathological results of the harvested SNs were related to the corresponding hotspot. ResultsIn all patients (n=60) lymphoscintigraphy was able to visualize a hotspot that was identified as an SN. In 51/60 (85%) patients, early imaging was able to visualize at least one hotspot, whereas in 9/60 (15%) patients, mostly with oral cavity tumours other than mobile tongue and floor-of-mouth tumours, only late imaging was able to visualize hotspots. In 14/51 (27%) patients, late imaging resulted in additionally visualized hotspots marked as SNs, resulting in a more extensive surgical procedure. These additionally removed SNs appeared to be of no clinical relevance, as all SNs identified during early imaging correctly predicted whether the neck was positive or negative for cancer. ConclusionResults of this study indicate that additional late lymphoscintigraphic imaging should be performed only in selected cases.

Preclinical evaluation of 89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys: Prelude to Phase 1 clinical studies.

RG7356 is a humanized antibody targeting the constant region of CD44. RG7356 was radiolabeled with 89Zr for preclinical evaluations in tumor xenograft-bearing mice and normal cynomolgus monkeys to enable study of its biodistribution and the role of CD44 expression on RG7356 uptake. Studies with 89Zr-RG7356 were performed in mice bearing tumor xenografts that differ in the level of CD44 expression (CD44+ or CD44-) and RG7356 responsiveness (resp or non-resp): MDA-MB-231 (CD44+, resp), PL45 (CD44+, non-resp) and HepG2 (CD44–, non-resp). Immuno-PET whole body biodistribution studies were performed in normal cynomolgus monkeys to determine normal organ uptake after administration of a single dose. At 1, 2, 3, and 6 days after injection, 89Zr-RG7356 uptake in MDA-MB-231 (CD44+, resp) xenografts was nearly constant and about 9 times higher than in HepG2 (CD44–, non-resp) xenografts (range 27.44 ± 12.93 to 33.13 ± 7.42% ID/g vs. 3.25 ± 0.38 to 3.90 ± 0.58% ID/g). Uptake of 89Zr-RG7356 was similar in MDA-MB-231 (CD44+, resp) and PL45 (CD44+, non-resp) xenografts. Studies in monkeys revealed antibody uptake in spleen, salivary glands and bone marrow, which might be related to the level of CD44 expression. 89Zr-RG7356 uptake in these normal organs decreased with increasing dose levels of unlabeled RG7356. 89Zr-RG7356 selectively targets CD44+ responsive and non-responsive tumors in mice and CD44+ tissues in monkeys. These studies indicate the importance of accurate antibody dosing in humans to obtain optimal tumor targeting. Moreover, efficient binding of RG7356 to CD44+ tumors may not be sufficient in itself to drive an anti-tumor response.

The potential role of non-FDG-PET in the management of head and neck cancer

Positron emission tomography (PET) is a functional imaging modality that is widely used in oncology. The integration of PET with CT (PET-CT) provides at the same time also detailed morphological information, which is especially attractive for the anatomically complex head and neck region. The most widely used PET-tracer for imaging the enhanced metabolism of tumours is ¹⁸F-fluorodeoxyglucose (¹⁸FDG), but several new tracers for imaging of metabolic features other than glucose consumption (non-FDG tracers) have been developed with the aim to perform better than ¹⁸FDG in specific indications. For initial staging of head and neck squamous cell carcinoma (HNSCC) these tracers until now did not show a better performance than ¹⁸FDG. Most data suggest a potential role for non-FDG metabolic tracers for treatment response prediction and surveillance of HNSCC. This information may provide a guide for further individualized treatment decisions. The possibility of PET to image biologic features and molecular targets as key drivers of malignant growth and survival provides another important tool for treatment guidance. The presence of the biologic feature hypoxia, a common phenomenon in head and neck cancer, is associated with a poor response to (chemo) radiotherapy. Therefore, knowledge of hypoxia may influence treatment decisions. Several candidate hypoxia PET tracers are discussed. With the increasing knowledge of critical molecular targets in head and neck cancer (e.g. the epidermal growth factor receptor), many novel targeted anticancer therapeutics become available among which monoclonal antibodies and small molecular tyrosin kinase inhibitors. Upon labelling of these drugs with a positron emitter, their distribution within the human body can be quantitatively imaged by PET. In this way, PET can be used for better understanding of in vivo tumour biology, guidance of drug development, and appropriate treatment selection for the individual patient (personalized medicine). Altogether, the potential role of non-FDG-PET in the management of HNSCC seems to be guidance and surveillance of treatment of the individual patient.

Fusion of Freehand SPECT and Ultrasound to Perform Ultrasound-Guided Fine-Needle Aspiration Cytology of Sentinel Nodes in Head and Neck Cancer

BACKGROUND AND PURPOSE: Criteria for ultrasound-guided fine-needle aspiration cytology (USgFNAC) for the detection of occult lymph node metastasis in patients with clinically negative head and neck cancer are based on the morphology of cervical lymph nodes. To improve the selection of lymph nodes for USgFNAC, we examined the feasibility of fused freehand single-photon emission tomography ultrasound-guided fine-needle cytology (freehand SPECT-USgFNAC) of sentinel nodes in patients with early stage oral and head and neck skin cancer. MATERIALS AND METHODS: Six patients with early-stage head and neck cancer (4 oral and 2 head and neck skin cancers) and a clinically negative neck who were scheduled for transoral or local excision and a sentinel node procedure underwent USgFNAC and freehand SPECT-USgFNAC preoperatively. RESULTS: All freehand SPECT sonographic examinations were technically successful in terms of identifying sentinel nodes. All aspirates of sentinel nodes obtained by freehand SPECT-USgFNAC contained substantial radioactivity, confirming puncture of the sentinel nodes. USgFNAC evaluated 13 lymph nodes; freehand SPECT-USgFNAC, 19 nodes; and sentinel node biopsy, 13 nodes. Three sentinel nodes were histopathologically positive and were selected for aspiration cytology by freehand SPECT-USgFNAC, but not by conventional ultrasound. The cytologic examination findings of the aspirations were negative or inconclusive. CONCLUSIONS: Freehand SPECT ultrasound can identify sentinel nodes and could potentially improve USgFNAC in patients with head and neck cancer by better selection of lymph nodes at highest risk of having metastases (sentinel nodes), but its sensitivity is limited by sampling error and insufficient aspirated material for cytology.

Evaluation of vascular features of vocal cords proposed by the European Laryngological Society

A newly proposed classification by the European Laryngological Society (ELS) of glottic lesions by narrow-band imaging (NBI) divides their vascular patterns into longitudinal and perpendicular ones. The latter are further subdivided into the wide and narrow patterns. The longitudinal, wide, and narrow patterns are characteristic of benign disease, papilloma, and malignancy, respectively. The aim of the study was to investigate the diagnostic effectiveness of the classification. Forty patients with glottic lesions underwent microlaryngoscopy. The vascular patterns of all vocal cords were defined with NBI. The affected vocal cords were histologically analysed and comprised the arm (A). Unaffected vocal cords were not histologically analysed but followed-up and comprised the arm (B) and were regarded as true negatives if no suspicious changes appeared during the follow-up. The vocal cords from the arm A were categorised into the benign and malignant group according to the histologic result. The ratio of vascular patterns was determined and the groups were statistically compared using the Chi-square test and Fisher’s exact test. Perpendicular changes were observed in 36.6% (9/26) of benign diseases and in 100% (23/23) of cancer conditions (p < 0.001). Wide perpendicular changes appeared only in papillomas (6/6) while narrow ones mostly in malignancies (23/26) and also in benign conditions (3/26) (p < 0.001). The sensitivity, specificity, positive and negative predictive values, and accuracy were 100, 95, 88, 100 and 96%, respectively. The new ELS classification can be used effectively and safely to differentiate malignant from benign disease.