Aron Popovtzer

Targeted gold nanoparticles enable molecular CT imaging of cancer: an in vivo study.

In recent years, advances in molecular biology and cancer research have led to the identification of sensitive and specific biomarkers that associate with various types of cancer. However, in vivo cancer detection methods with computed tomography, based on tracing and detection of these molecular cancer markers, are unavailable today. This paper demonstrates in vivo the feasibility of cancer diagnosis based on molecular markers rather than on anatomical structures, using clinical computed tomography. Anti-epidermal growth factor receptor conjugated gold nanoparticles (30 nm) were intravenously injected into nude mice implanted with human squamous cell carcinoma head and neck cancer. The results clearly demonstrate that a small tumor, which is currently undetectable through anatomical computed tomography, is enhanced and becomes clearly visible by the molecularly-targeted gold nanoparticles. It is further shown that active tumor targeting is more efficient and specific than passive targeting. This noninvasive and nonionizing molecular cancer imaging tool can facilitate early cancer detection and can provide researchers with a new technique to investigate in vivo the expression and activity of cancer-related biomarkers and molecular processes.

RADIATION DOSE-VOLUME EFFECTS IN THE LARYNX AND PHARYNX

The dose-volume outcome data for RT-associated laryngeal edema, laryngeal dysfunction, and dysphagia, have only recently been addressed, and are summarized. For late dysphagia, a major issue is accurate definition and uncertainty of the relevant anatomical structures. These and other issues are discussed.

Early Prediction of Outcome in Advanced Head-and-Neck Cancer Based on Tumor Blood Volume Alterations During Therapy: A Prospective Study

PURPOSE To assess whether alterations in tumor blood volume (BV) and blood flow (BF) during the early course of chemo-radiotherapy (chemo-RT) for head-and-neck cancer (HNC) predict treatment outcome. METHODS AND MATERIALS Fourteen patients receiving concomitant chemo-RT for nonresectable, locally advanced HNC underwent dynamic contrast-enhanced (DCE) MRI scans before therapy and 2 weeks after initiation of chemo-RT. The BV and BF were quantified from DCE MRI. Preradiotherapy BV and BF, as well as their changes during RT, were evaluated separately in the primary gross tumor volume (GTV) and nodal GTV for association with outcomes. RESULTS At a median follow-up of 10 months (range, 5-27 months), 9 patients had local-regional controlled disease. One patient had regional failure, 3 had local failures, and 1 had local-regional failure. Reduction in tumor volume after 2 weeks of chemo-RT did not predict for local control. In contrast, the BV in the primary GTV after 2 weeks of chemo-RT was increased significantly in the local control patients compared with the local failure patients (p < 0.03). CONCLUSIONS Our data suggest that an increase in available primary tumor blood for oxygen extraction during the early course of RT is associated with local control, thus yielding a predictor with potential to modify treatment. These findings require validation in larger studies.

The pattern of failure after reirradiation of recurrent squamous cell head and neck cancer: implications for defining the targets.

PURPOSE Reirradiation (re-RT) of recurrent head and neck cancer (HNC) may achieve long-term disease control in some patients, at the expense of high rates of late sequelae. Limiting the re-RT targets to the recurrent gross tumor volume (rGTV) would reduce the volumes of reirradiated tissues; however, its effect on tumor recurrence pattern is unknown. METHODS AND MATERIALS This is a retrospective review of 66 patients who underwent curative-intent re-RT for nonresectable recurrent or second primary mucosal squamous cell HNC. Treatment was delivered with three-dimensional conformal (3D) RT or intensity-modulated RT (IMRT). The targets in all patients consisted of the rGTVs with tight (0.5-cm) margins, with no intent to treat prophylactically lymph nodes or subclinical disease in the vicinity of the rGTVs. The sites of locoregional failures (LRFs) were determined using imaging at the time of failure and were compared with the rGTVs. RESULTS Median re-RT dose was 68 Gy. Forty-seven patients (71%) received concomitant chemotherapy, and 31 (47%) received hyperfractionated, accelerated RT. At a median follow-up of 42 months, 16 (23%) were alive and disease-free. Fifty patients (77%) had a third recurrence or persistent disease, including 47 LRFs. All LRFs occurred within the rGTVs except for two (4%) (95% confidence interval, 0-11%). Nineteen patients (29%) had Grade > or = 3 late complications, mostly dysphagia (12 patients). CONCLUSIONS Almost all LRFs occurred within the reirradiated rGTVs despite avoiding prophylactic RT of tissue at risk of subclinical disease. These results support confining the re-RT targets to the rGTVs to reduce reirradiated tissue volumes.

Squamous cell carcinoma of the oral tongue in young patients.

Objectives/Hypothesis: Cancer of the tongue is reported with increasing frequency in young people. The objective of this work was to study the biologic and clinical course of the disease in this group. The clinical course of the disease in this patient group remains controversial.

Nanomedicine for Cancer Immunotherapy: Tracking Cancer-Specific T-Cells in Vivo with Gold Nanoparticles and CT Imaging

Application of immune cell-based therapy in routine clinical practice is challenging due to the poorly understood mechanisms underlying success or failure of treatment. Development of accurate and quantitative imaging techniques for noninvasive cell tracking can provide essential knowledge for elucidating these mechanisms. We designed a novel method for longitudinal and quantitative in vivo cell tracking, based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with state-of-the-art nanotechnology. Herein, T-cells were transduced to express a melanoma-specific T-cell receptor and then labeled with gold nanoparticles (GNPs) as a CT contrast agent. The GNP-labeled T-cells were injected intravenously to mice bearing human melanoma xenografts, and whole-body CT imaging allowed examination of the distribution, migration, and kinetics of T-cells. Using CT, we found that transduced T-cells accumulated at the tumor site, as opposed to nontransduced cells. Labeling with gold nanoparticles did not affect T-cell function, as demonstrated both in vitro, by cytokine release and proliferation assays, and in vivo, as tumor regression was observed. Moreover, to validate the accuracy and reliability of the proposed cell tracking technique, T-cells were labeled both with green fluorescent protein for fluorescence imaging, and with GNPs for CT imaging. A remarkable correlation in signal intensity at the tumor site was observed between the two imaging modalities, at all time points examined, providing evidence for the accuracy of our CT cell tracking abilities. This new method for cell tracking with CT offers a valuable tool for research, and more importantly for clinical applications, to study the fate of immune cells in cancer immunotherapy.

Anatomical changes in the pharyngeal constrictors after chemo-irradiation of head and neck cancer and their dose–effect relationships: MRI-based study

PURPOSE Dysfunction of pharyngeal constrictors (PCs) after chemo-irradiation of head and neck (HN) cancer has been proposed as major cause of dysphagia. We conducted prospective MRI study to evaluate anatomical changes in the PCs after chemo-irradiation, to gain insight of the mechanism of their dysfunction and their dose-effect relationships. The PCs were compared to the sternocleidomastoid muscles (SCMs), which receive high doses but do not relate to swallowing. PATIENTS AND METHODS Twelve patients with stage III-IV HN cancer underwent MRI before and 3 months after completing chemo-irradiation. T1- and T2-weighted signals and muscle thickness were evaluated for PCs (superior, middle, and inferior), and SCMs. Mean muscle doses were determined after registration with the planning CT. RESULTS T1-weighted signals decreased in both PCs and SCMs receiving >50 Gy (p<0.03), but not in muscles receiving lower doses. T2-weighted signals in the PCs increased significantly as the dose increased (R(2)=0.34, p=0.01). The T2 signal changes in the PCs were significantly higher than the T2 changes in the SCMs (p<0.001). Increased thickness was noted in all PCs, with muscles receiving >50 Gy gaining significantly more thickness than PCs receiving lesser doses (p=0.02). In contrast, the SCM thickness decreased post-therapy (p=0.002). CONCLUSIONS These MRI-based findings, notably the differences between PCs and SCMs, suggest that underlying causes of PC dysfunction are inflammation and edema, likely consequential to acute mucositis affecting the submucosa-lying PCs. These results support reducing mean PC doses to 50 Gy, as well as reducing acute mucositis, to improve long-term dysphagia.

Thyroid Cancer in Children: Management and Outcome Experience of a Referral Center

OBJECTIVE: To shed light on the discrepancy between the advanced stage at presentation and high recurrence rate of well-differentiated thyroid cancer in children and the overall good survival. DESIGN AND METHODS: The files of 75 children with well-differentiated thyroid cancer treated from 1954 to 2001 in a major tertiary-care hospital were reviewed for disease course, management, and outcome. RESULTS: Sixty patients (80%) had positive neck metastases with involvement of central compartment lymph nodes in all, lateral neck nodes in 36, and distant metastases in 4. Sixty-seven patients underwent total thyroidectomy with adjuvant radioiodine treatment and 8 underwent hemithyroidectomy; all had concomitant neck treatment. The rate of local (5%) and neck (9%) recurrence was similar to the total rate reported in adults. Total thyroidectomy led to a significantly lower recurrence rate (7.5%) than hemithyroidectomy (38%; P < 0.005). Type of neck dissection did not affect recurrence or appearance of distant metastases. All deaths (n = 2) were due to distant metastases, whereas 30% of adult deaths are due to local or neck disease. CONCLUSIONS: The treatment of choice for well-differentiated thyroid cancer in young patients is total thyroidectomy. Neither regional disease at presentation nor recurrences affect survival.

Invasive well-differentiated thyroid carcinoma: effect of treatment modalities on outcome.

OBJECTIVE: Well-differentiated thyroid carcinoma is considered an indolent malignant disease. Although rare, extrathyroidal invasion is associated with a worse prognosis and increased risk of morbidity. Management remains controversial, with some authors advocating conservative treatment with preservation of midline structures and others, aggressive extensive en bloc resection. The aim of this study was to report our 40-year experience with invasive thyroid carcinoma, with emphasis on the clinical characteristics and the effect of different treatment modalities on survival. STUDY DESIGN AND SETTING: A retrospective study including a file review of 1,200 patients with a diagnosis of well-differentiated thyroid carcinoma of whom 49 (5%) showed involvement of an adjacent structure (larynx, trachea and esophagus) (study group). Type of surgery, radiation treatment, radioiodine treatment, and patient demographics were evaluated. RESULTS: Compared to the rest of the patients, the study group was characterized by a higher rate of male patients (39% vs 25%), and older average age (58 vs 45 years). Average size of the primary tumor was 3.7 cm. Sixteen patients underwent radical surgery and 33 conservative surgery followed by radio-iodine treatment. Five-year survival and recurrence rates for the whole group were 78% and 52%, respectively. The only statistically significant factor for survival was large tumor size. Distant metastases developed in 46% of patients, all in the lungs. Ten of 14 deaths were due to distant metastases. External radiation, used in 52% of the patients, was associated with worse prognosis. CONCLUSION: Conservative procedures followed by radioiodine treatment are associated with similar survival rates as aggressive techniques, with less perioperative mortality and lower overall morbidity. SIGNIFICANCE: This study provides further evidence that in cases of invasive thyroid tumors the extent of the primary surgery seems to have no influence on survival. EBM rating: C-4

Complications of Mastoiditis in Children at the Onset of a New Millennium

The aim of the present study was to review our recent experience in the diagnosis and treatment of acute mastoiditis and its complications in a single tertiary-care, university-affiliated pediatric center. Ninety-eight children with 101 episodes of acute mastoiditis were included in the study. The mean interval from onset of illness to mastoiditis was 4.5 days. Ear cultures most often grew Streptococcus pneumoniae and Pseudomonas aeruginosa (23.7% each). Complications occurred in 15.8% of episodes. The only factor differentiating children with and without complications was white blood cell count. These findings indicate that acute mastoiditis not only is a complication of prolonged infection of the middle ear, but may also present as an acute infection of the mastoid bone that can progress within 48 hours. The complication rate remains high, and antibiotic treatment at the onset of symptoms does not prevent complications. A high white blood cell count on admission may serve as a predictive factor of complicated cases.