David Loose

Quantitative Tumor Apoptosis Imaging Using Technetium-99m–HYNIC Annexin V Single Photon Emission Computed Tomography

PURPOSE Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m- (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. PATIENTS AND METHODS Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. RESULTS Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P =.012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. CONCLUSION In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.

The Immune System and Cancer

Cancer patients mount adaptive immune responses against their tumor. However, while tumor-infiltrating lymphocytes and natural-killer (NK) cells try to detect and eliminate malignant cells, they eventually fail when these malignant cells develop mechanisms to evade effective immunosurveillance. First, malignant cells produce immunosuppressive cytokines and prostaglandins that skew the immune response toward a Th2 response, resulting in a humoral response with significantly less antitumor capacities, generating a low interleukin-2 environment blocking NK cell division, T-helper cell proliferation, and T-cytotoxic cell proliferation and function. Second, immunoresistant malignant cell variants emerge through selection of major histocompatibility class I and II and antigen-processing mutants reducing antigenicity. Finally, malignant cells may actively eliminate T-cells via activation-induced cell death or by mounting a counterattack through Fas ligand expression.

Nuclear medicine imaging for the assessment of primary and recurrent head and neck carcinoma using routinely available tracers

This article reviews the literature on the use of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) and thallium-201, technetium-99m sestamibi and technetium-99m tetrofosmin single-photon emission tomography (SPET) for the diagnosis and staging of primary and recurrent squamous cell carcinoma of the head and neck (SCCHN). A search of the MEDLINE and CancerLit databases covering articles entered between 1989 and February 2003 was performed. In the case of FDG PET, only full-ring PET studies that included comparison with conventional morphological imaging were considered. Due to the wide variation in methodology, a straightforward meta-analysis of FDG PET literature was impossible. Instead, indicative summary receiver-operating curves of FDG PET and morphological imaging techniques were generated and a paired comparison of the sensitivities and specificities of FDG PET and morphological imaging performed. Compared with conventional morphological imaging, FDG PET proved as sensitive and specific for the detection of primary SCCHN but more sensitive and specific for the detection of cervical lymph node involvement (CLNI) and recurrence of SCCHN. Additional studies addressing the role of FDG PET in screening for distant metastases and synchronous primary tumours are mandatory. Following negative conventional evaluations, FDG PET identifies occult primary tumours in 20–50% of patients presenting with CLNI. As regards the use of 201Tl, 99mTc-sestamibi and 99mTc-tetrofosmin, more studies are required to define whether these imaging agents could form part of the current diagnostic armamentarium in SCCHN patients. It is concluded that FDG PET either is superior to or offers added value when compared with conventional morphological imaging techniques for the purpose of diagnosis and staging of primary and recurrent SCCHN.

Prognostic value of CD25 expression on lymphocytes and tumor cells in squamous-cell carcinoma of the head and neck

CD4(+) CD25(+) T-cells play a central role in initiating and maintaining anticancer immune response. On the other hand, CD25(+) is also expressed on tumor cells, the meaning of which is currently unclear. Therefore, this study was designed to determine the prognostic value of the presence of CD4(+) CD25(+) T-cells in squamous-cell carcinoma of the head and neck (SCCHN) and of CD25 on SCCHN tumor cells. Thirty-five (35) patients diagnosed with a primary untreated SCCHN were included in this study. Instantly snap-frozen resection or biopsy specimens were analyzed by immunohistochemistry. Histologic results obtained were related to overall, disease-free survival. On univariate analysis, both lymph-node status and the number of CD25(+) lymphocytes were associated with disease-free survival (p=0.039 and 0.04). On multivariate analysis, only the number of CD25(+) lymphocytes showed an association with disease-free survival (p=0.036), whereas both factors showed an independent association with overall survival (p=0.007 and 0.003). Contrarywise, the CD25 expression on SCCHN tumor cells was not associated with disease-free survival nor with overall survival. The presence of a high number of SCCHN-infiltrating CD4(+) CD25(+) lymphocytes is associated with a good prognosis in SCCHN patients. Contrarywise, the CD25 expression on SCCHN tumor cells is not associated with a prognosis in SCCHN patients, and its role and meaning remains to be elucidated.

99mTc-HYNIC Annexin-V imaging of primary head and neck carcinoma.

In this study, the potential of 99mTc-HYNIC Annexin-V scintigraphy to visualize primary head and neck carcinoma was assessed and compared with computed tomography (CT) findings and histology. Eighteen patients suspected of having primary head and neck carcinoma underwent a spiral CT scan and 99mTc-HYNIC Annexin-V scintigraphy within 1 week of each other, followed by resection of the suspected lesion. Results obtained by CT and scintigraphy were compared vs. histopathology. The diagnosis was primary head and neck carcinoma in 18 patients, accompanied by lymph node involvement in seven patients. 99mTc-HYNIC Annexin-V uptake was identified in five patients on planar images and in 17 patients on tomographic images (single-photon emission computed tomography, SPECT), corresponding to the pathological regions identified by CT. In the remaining patient, CT and 99mTc-HYNIC Annexin-V scintigraphy were false negative. In 11 patients, SPECT and CT scan were concordant, identifying all primary lesions and two sites of lymph node involvement. In the six remaining patients, CT and SPECT accurately identified the primary lesion, but were discordant with regard to the existence of lymph node involvement. In five of six patients, SPECT failed to identify lymph node involvement, whereas CT scan did not. In the remaining patient, CT scan was false positive for lymph node involvement, whereas SPECT was not. In this series, 99mTc-HYNIC Annexin-V allowed for the visualization of all primary head and neck tumours identified by CT scan, but failed to identify most of the sites of lymph node involvement.

Radiolabeled Annexin-V for Monitoring Treatment Response in Oncology

Because of its potential to allow for noninvasive, repetitive, and selective in vivo identification of the site and extent of apoptotic cell death and for monitoring cell death kinetics without the need for invasive biopsy, radiolabeled annexin-V is of major clinical relevance. This paper reviews available preclinical and clinical data on radiolabeled annexin-V pertaining to the domain of monitoring response to radiotherapy and chemotherapy, focusing especially on advantages and drawbacks of the different labeling procedures for the radiolabeling of annexin-V.

Prognostic value of FDG uptake by the bone marrow in squamous cell carcinoma of the head and neck.

BackgroundThe appearance of natural suppressor cells and circulating endothelial progenitor cells in tumour tissue has been associated with myelopoetic stimulation by growth factors that may increase fluorodeoxyglucose (FDG) uptake by the bone marrow and high FDG uptake by bone marrow in patients suffering from human malignancies is a not uncommon finding. MethodsThis study looked at the relationship between bone marrow FDG uptake, biochemical (Hb level, RBC count, WBC count and platelet count), clinical and radiological findings and outcome in a series of 35 patients suffering from squamous cell carcinoma of the head and neck (SCCHN), consecutively referred for FDG PET as part of their routine staging procedure. Results and conclusionIn SCCHN, mean FDG standardized uptake values (SUVs) of the primary tumour correlate significantly with blood WBC count (r=0.44; P=0.011, Bonferroni corrected P=0.04) and mean FDG SUVs of bone marrow are significantly correlated to the maximum FDG SUVs of the primary tumour (r=0.523; P=0.002). Finally, FDG uptake by the bone marrow is related to disease-free and overall survival. These findings warrant confirmation in a larger patient series.

Effect of a buccal bioadhesive nystatin tablet on the lifetime of a Provox™ silicone tracheoesophageal voice prosthesis

Conclusion. Daily application of a buccal bioadhesive slow-release nystatin tablet (100 000 IU per tablet) significantly increased the voice prosthesis lifetime in laryngectomized patients compared to conventional local cleaning of the prosthesis with an antimicrobial agent on a brush. Objective. To investigate the effect of a buccal bioadhesive nystatin tablet on the lifetime of a Provox™ tracheoesophageal voice prosthesis in post-laryngectomy patients. Material and methods. A buccal bioadhesive tablet, based on a spray-dried Amioca®/Carbopol® 974P mixture containing 10% (w/w) Carbopol® 974P, was loaded with 100 000 IU of nystatin. Patients were included in the study when replacement of their voice prosthesis was required and were divided into three groups. Conventional daily local cleaning of the voice prosthesis by means of an oral nystatin suspension on a brush (Group 1; n=7) was compared with application of one nystatin buccal bioadhesive tablet per day, after breakfast, on the gingiva above the upper canine (Group 2; n=7). The control group (n=5) used no antimicrobial agents. The lifetime of the prosthesis was followed and expressed in days. Results. The lifetime of the voice prosthesis was significantly increased in Group 2 compared to Group 1 (p<0.05; paired t-test), indicating that sustained release of nystatin in the oral cavity, by means of erosion of the tablet over a period of ≈8 h, is more effective at preventing microbial colonization of the prosthesis than local cleaning.

Acquired atresia of the external auditory canal: long-term clinical and audiometric results after surgery.

Objective Acquired atresia of the external auditory canal is a rare condition in which the medial part of the external auditory canal is obliterated by a soft fibrous plug, mostly as a result of chronic inflammation of the outer ear canal. In this study, the clinical and audiometric long-term postsurgical results were assessed. Patients Records of patients with acquired atresia, surgically treated in a tertiary referral center during the period 2000–2009, were retrospectively reviewed. Preoperative and postoperative clinical and audiometric data were collected. Intervention All patients underwent the same surgical technique, consisting of a maximal bony canaloplasty with coverage of the bony ear canal using full-thickness skin graft and a meatoplasty. Eligible patients were reinvited for objective and subjective evaluation. Main Outcome Measures The primary outcome was the long-term postoperative status, based on clinical (patency and condition of the external auditory canal) and audiometric findings (mean air-bone gap). Results The analysis comprised 17 operated ears (14 different patients). Mean follow-up time was 5.14 years. True recurrence occurred in 3 ears (17.6%), whereas another 4 ears had episodic otorrhea (23.5%). At early (<0.5 yr), but also at late follow-up (>4y), the air-bone gap in the operated ears was significantly smaller. Conclusion Surgical treatment for acquired atresia leads to beneficial results. Patients should be informed of the possibility of recurrence of disease. Nevertheless, they seem to be satisfied with the surgical intervention. Preoperative dermatologic referral is required, given the high prevalence of an underlying dermatologic disease.