Ablation of experimental colon cancer by intratumoral 224Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy.

PURPOSE: We developed (224)Ra-loaded wires, which release by recoil alpha emitting nuclei into solid tumors and cause tumor cell killing. This research examined if the major damage was inflicted by alpha particles emitted from these atoms or by direct gamma and beta emissions from the inserted wires. We also examined the efficacy of this treatment against colon cancer in combination with chemotherapy. MATERIALS AND METHODS: Mouse colon carcinomas (CT-26 xenografts), treated by intra-tumoral radioactive wires loaded with (224)Ra atoms were monitored for effects on tumor growth, intratumoral tissue damage and distribution of alpha emitting atoms. The effects were compared with those of (224)Ra-loaded wires coated with poly methyl methacrylate (PMMA), which blocks atom recoil. Similar experiments were performed with radioactive wires combined with systemic 5-FU. RESULTS: (224)Ra-loaded wires inhibited tumor growth and formed necrotic areas inside the tumor. PMMA coated wires did not inhibit tumor growth, and caused minor intratumoral damage. Autoradiography images of tumors treated with (224)Ra-loaded wires revealed a spread of alpha emitters over several mm, whereas PMMA-coated wires showed no such spread. Injection of 5-FU with (224)Ra-loaded wires augmented tumor growth retardation and cure. CONCLUSIONS: (224)Ra-loaded wires ablate solid tumors by the release of alpha-particle emitting atoms inside the tissue, an effect that can be enhanced by combining this method with chemotherapy.

A case and a series of published cases of esthesioneuroblastoma (ENB) in which long-standing paraneoplastic SIADH had preceded ENB diagnosis.

Esthesioneuroblastoma (ENB) is a rare tumor of the olfactory mucosa. We treated a 50-year-old man with an ENB in the right ethmoid sinus who had been diagnosed 16 years earlier with syndrome of inappropriate antidiuretic hormone secretion (SIADH) of unknown cause. When the ENB was surgically removed, the patient's osmoregulation returned to normal-that is, his SIADH resolved completely, which suggested that the SIADH was paraneoplastic in nature. These events prompted us to review the literature to determine if there is an association between our patient's ENB and his SIADH in general and between long-standing SIADH that precedes ENB in particular. Based on our review and an extrapolation of data, we have estimated that 1,300 cases of ENB have occurred since it was first described in 1924. Of these cases, SIADH was reported in 26 cases, including ours, which represents an estimated prevalence of 2% (although we believe this is actually an underestimation of the true prevalence). Of the 26 cases, SIADH had already been present in 14 patients (54%) prior to their diagnosis of EBN for a median duration of 3.5 years. We recommend that patients with newly diagnosed EBN be evaluated for SIADH. In those who are SIADH-positive, a resolution of SIADH should be expected once the ENB has been removed. If this does not occur, one should suspect that the ENB was not completely removed. If SIADH resolves but later recurs during follow-up, then a relapse should be suspected. In long-standing SIADH of unknown etiology, nasal sinus imaging should be considered.

MicroRNAs as a potential prognostic factor in gastric cancer.

AIM: To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer. METHODS: The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%). RESULTS: Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups. CONCLUSION: This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.

Interstitial wires releasing diffusing alpha emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma-bearing mice.

BACKGROUND: The objective of this study was to examine the combined effect of diffusing alpha-emitter radiation therapy (DART) together with the chemotherapeutic agent cisplatin on tumor development. METHODS: BALB/c mice bearing squamous cell carcinoma tumors were treated with radium 224 ((224)Ra-)-loaded stainless steel wires, releasing short-lived, alpha-emitting atoms from their surface. A concomitant regimen of cisplatin doses (5 mg/kg per dose) was given intravenously for the evaluation of the combined effect. Animals were monitored for tumor growth and survival. RESULTS: First, the authors observed that alpha particles and cisplatin inhibited SQ2 cell proliferation in vitro and promoted apoptosis. Treatment of tumor-bearing mice indicated that, when a regimen of 2 separate doses of cisplatin was given concomitantly with a single intratumoral (224)Ra-loaded wire, there was moderate tumor growth inhibition relative to what was observed from each treatment alone. When tumors were treated with 2 radioactive wires positioned near the tumor base and a similar drug administration, the growth arrest effect intensified, and there also was a significant increase in survival rates. The combined treatment reduced both local tumor growth and metastatic spread to the lungs. CONCLUSIONS: Antitumor activity and overall survival of metastatic tumor-bearing mice were improved significantly by the combined treatment. These results highlight the potential benefit of alpha radiation-based radiotherapy in combination with chemotherapeutic drugs for anticancer treatment.

Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms.

In the present study, we examined the antitumoral effects caused by the release of alpha emitting radioisotopes into solid squamous cell carcinoma (SCC) tumors. Using a novel method termed DART (Diffusing Alpha-emitters Radiation Therapy), we assessed the efficacy of short-lived daughters of (224)Ra releasing alpha particles, dispersing in the malignant tissue, to cause tumor growth retardation and destruction. It was carried out using specially designed wires loaded with (224)Ra activities in the range of 7-42 kBq in a set of experiments performed on BALB/c and nude mice bearing metastatic SCC tumors derived from either mouse SQ2 or human CAL27 cell lines. The insertion of a DART wire to the center of 6-7 mm primary tumors, retarded tumor growth, reduced lung metastatic load, prolonged life expectancy and in some cases caused tumor eradication. These effects were enhanced either when treating smaller tumors or treating identical tumors with 2 DART wires. Similar experiments on human-derived SCC tumors in nude mice were consistent with the outcomes of the murine model. Histological assessments revealed the tissue damage pattern, and indicated a role for the tumor vasculature in the dispersion of the atoms and the propagation of the damage. Our findings indicate that Diffusing Alpha-emitting Radiation Therapy is effective in a model system using SCC primary tumors. The in situ destruction of primary solid tumors by DART is evidently a necessary step toward curing cancer and might be augmented by chemotherapy and other modalities such as immunotherapy or antigrowth factors agents.

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 radioiodine 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.

Is there any significant reduction of patients' outcome following delay in commencing postoperative radiotherapy?

PURPOSE OF REVIEW: Postoperative radiation treatment is a key factor in the outcome of advanced head and neck cancer. The start of postoperative radiation treatment may be delayed in a substantial number of patients for medical or technical reasons. The aim of this review is to evaluate clinical implications of a delay in postoperative radiation treatment, further our understanding of the biological mechanisms involved, and discuss ways to minimize these effects. RECENT FINDINGS: Some studies have shown that an interval between surgery and postoperative radiation treatment of more than 6 weeks may impair outcome. Others, however, reported that this delay was not associated with lower survival or decreased local control, and still others reported an increase in local recurrence, but no difference in overall survival. Because the cell repopulation induced by the postoperative presence of microscopic residual tumor mass varies in rate and timing by the aggressiveness of the particular type of head and neck cancer, a delay in postoperative radiation treatment may have a different effect in different disease subsites. The methods proposed to date to reduce the influence of postoperative radiation treatment delay are based mainly on the principle of shortening the overall treatment time. SUMMARY: It remains uncertain if outcome is significantly worsened by a delay in commencing postoperative radiation treatment in patients with advanced head and neck cancer tumors. The data accrued in the last 5 years indicate that the use of advanced treatment techniques such as altered fractionation, reduction of overall treatment time, and combined postoperative radiation treatment and chemotherapy may minimize any adverse effects of delay.

Adenoid cystic carcinoma of the salivary glands: a 20-year review with long-term follow-up.

The behavior of adenoid cystic carcinoma (ACC) of the salivary glands has been shown to be unpredictable in terms of local and distant spread and mortality. We retrospectively studied 35 operations in 34 patients who had had a pathologic diagnosis of ACC of the salivary glands and who had been treated over a 20-year period and followed for a minimum of 10 years. We analyzed the effect that different factors had on outcomes. The site of origin appeared to be an important factor in survival rates; survival among patients with tumors that had originated in the parotid gland was fairly good, while survival among those with tumors that originated in the minor salivary glands was significantly worse. TNM staging was another significant factor in survival. Other poor prognostic indicators were local spread, nodal positivity, distant metastasis, and local and regional recurrence. Radiation and chemotherapy did not appear to be beneficial for patients with advanced disease. We recommend radical surgery with complete resection for all patients with ACC of the salivary glands and a careful assessment of the neck in patients with minor salivary gland tumors.

Is the delay in starting postoperative radiotherapy a key factor in the outcome of advanced (T3 and T4) laryngeal cancer?

OBJECTIVE: To identify factors influencing the outcome of postoperative radiotherapy in patients with advanced laryngeal cancer. DESIGN: The files of 44 patients with advanced laryngeal cancer who were treated by surgery followed by radiotherapy (24 with pT3 and 20 with pT4) were reviewed. Median delay in starting radiotherapy was 50 days (range, 19-150 days). Treatment variables, in addition to certain patient and tumor characteristics, were analyzed in terms of locoregional control and survival. SETTING: Major referral tertiary center in central Israel. RESULTS: Locoregional control rates were 86% and 81% at 2 and 5 years, respectively, and corresponding survival rates were 82% for both. Only nodal involvement retained statistical significance for both locoregional control as well as survival on multivariate analysis (P = 0.0009 and P = 0.0004, respectively). CONCLUSIONS: This is the first study showing that delay in postoperative radiotherapy in advanced laryngeal cancer is not a significant predictor of locoregional control or survival in advanced laryngeal cancer. Only lymphatic spread was found to have a significant influence on treatment outcome.

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. STUDY DESIGN: A retrospective 30-year review was made from data from a tertiary academic medical center. METHODS: A chart review was performed for 48 patients with oral tongue cancer. The following variables were compared: age, sex, tobacco and alcohol use, treatment, and outcome. RESULTS: Stage (T1,2-N0) and treatment modality were similar in the two age groups, as was disease-specific outcome. However, in the younger group, the clinical course followed two distinct patterns: extremely aggressive appearance with a 40% mortality rate within 2 years compared with 10.7% in the older group (P <.05) or indolent with freedom from disease for over 15 years. CONCLUSIONS: Squamous cell carcinoma (SCC) of the oral tongue may be associated with a variable clinical course in younger patients. Although, in general, the disease-specific outcome is similar to that of the older patients, some of the patients have an exceptionally aggressive disease. An extensive therapeutic regimen should be used in all cases.

Basaloid squamous carcinoma of the larynx.

BACKGROUND: Basaloid squamous cell carcinoma (BSCC) is a distinct variant of squamous cell carcinoma that was first described by Wain et al in 1986. Since then, about 160 cases have been reported in the literature. Only 40 cases have been described in the larynx. METHODS: Four cases of BSCC of the larynx treated in our department between 1986 and 2000 are presented. The clinical features, biological behavior, and histopathological and immunohistochemical characteristics of this uncommon tumor are described, and the relevant literature is reviewed. RESULTS: The main clinical presentation did not differ from other histological types of laryngeal carcinoma. The clinical course, however, was much more aggressive. All the patients received aggressive therapy including radical surgery and radiation. Two patients received chemotherapy. Two of the 4 patients presented died of distant metastasis shortly after diagnosis and treatment. CONCLUSIONS: The finding of this study with a limited number of patients supports previous reports suggesting that BSCC is a highly aggressive tumor that presents in older population with male predominance. The frequency of associated regional as well as distant metastases suggests that aggressive treatment is indicated and that systemic chemotherapy should be contemplated.

Laser surgery for the treatment of glottic carcinomas.

PURPOSE: The standard treatment for patients with early glottic carcinoma in Israel has been radiotherapy. In recent years, encouraging results with laryngo-microscopic carbon dioxide laser surgery as a treatment for early glottic carcinoma has changed our treatment strategy. We conducted a retrospective study to investigate the results of carbon dioxide laser excisional technique for early glottic carcinoma (T1, T2). MATERIALS AND METHODS: Twenty-six had squamous cell carcinoma (SCC), (21 patients with T1 and 5 patients with T2 lesions), 3 had carcinoma in situ, (CIS) and 3 had verrucous carcinoma (VC). RESULTS: All patients were free of disease after salvage treatment at the most recent follow-up. CONCLUSIONS: Careful patient selection with endoscopic staging and strict follow-up are essential to secure good results in the treatment of carbon dioxide laser for early laryngeal carcinoma.