Luca Calabrese

Joint Practice Guidelines for Radionuclide Lymphoscintigraphy for Sentinel Node Localization in Oral/Oropharyngeal Squamous Cell Carcinoma

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

Laser Surgery for Early Glottic Cancer Impact of Margin Status on Local Control and Organ Preservation

OBJECTIVE To assess the impact of margin status on disease-free survival, overall survival, and organ preservation in early glottic cancer treated by endoscopic laser surgery. DESIGN Prospective nonrandomized study. SETTING Tertiary referral center. PATIENTS A total of 274 patients with untreated (possibly biopsied) cTis, cT1a/b, cT2, cN0 glottic cancer; adequate exposure of the glottic region; no contraindications to general anesthesia; and the ability to give informed consent. INTERVENTIONS European Laryngological Society laser cordectomy. Patients with negative margins (>1 mm) were followed, patients with close margins (< or =1 mm) or 1 positive margin (tumor on margin) had another operation, and patients with more than 1 positive margin had postoperative radiotherapy. Median follow-up was 58 months. MAIN OUTCOME MEASURES Eight-year disease-free survival, 5-year overall survival, and organ preservation rate. RESULTS Margins were negative in 180 patients, close in 40, and positive in 54. A second laser resection was performed in 36 of 94 patients with close or positive margins. Radiotherapy was administered to 36 patients. Patients with close or positive margins who did not undergo further treatment had a greater recurrence risk (hazard ratio, 2.53; 95% confidence interval, 0.97-6.59, P = .06) than did those with negative margins, mainly owing to relapses in 5 of the 8 protocol breakers with positive margins not treated further. Eight-year relapse-free survival was 88.2%, 5-year overall survival was 90.9%, and the larynx was preserved in 97.1%. CONCLUSIONS Laser removal of early glottic cancer is oncologically adequate with margins greater than 1 mm from the tumor edge. Positive margins require further treatment; close margins may require further treatment depending on tumor characteristics.

Primary follicular and marginal-zone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group

BACKGROUND Primary breast lymphoma (PBL) of low-grade histology is a rare disease. This multicentric retrospective study was carried out to determine clinical features, prognosis and relapse. PATIENTS AND METHODS Patients with histologically proven, previously untreated follicular or marginal-zone PBL (MZL PBL) diagnosed from 1980 to 2003 were included in the study. Major end points were progression-free survival (PFS), overall survival (OS) and potential prognostic factors. RESULTS We collected data on 60 cases of PBL [36 follicular and 24 marginal-zone lymphoma (MZL)]. Stage was I(E) or II(E) in 57 patients and IVE in three patients due to bilateral breast involvement. Surgery, chemotherapy and radiotherapy (RT), alone or in combination, were used as first-line treatments in 67%, 42% and 52% of patients, respectively. Overall response rate was 98%, with a 93% complete response rate. Five-year PFS were 56% for MZL and 49% for follicular PBL (P = 0.62). Relapses were mostly in distant sites (18 of 23 cases); no patients relapsed within RT fields. CONCLUSIONS Our data showed an indolent behaviour of MZL PBL, comparable to other primary extranodal MZL. Conversely, patients with follicular PBL had inferior PFS and OS when compared with limited-stage nodal follicular non-Hodgkins lymphomas, suggesting an adverse prognostic role of primary breast localisation in this histological subgroup.

Surfing prognostic factors in head and neck cancer at the millennium.

The ability to reliably predict cancer outcome could tailor therapy to the aggressiveness of the tumour to achieve the best results in terms of loco-regional control, overall survival and quality of life. Retrospective and prospective clinical trials involving large series of patients have validated some predictive clinical and pathological factors, whereas the utility of many other prognostic factors has not been established. This has led to some confusion in clinical practice. In order to clarify the significance, role and cost of these prognostic factors we carried out a Medline search of all papers published between 1993 and 1998 concerning the reliability and cost of markers with prognostic significance, in head and neck squamous cell carcinoma, and assessed the results according to a number of criteria relating to reliability and cost. Regarding reliability we classified prognostic factors into: (1) those with a proven significance based on the fact that they were unanimously reported as having an independent statistical correlation with outcome and prognosis; and (2) those for which results were not unanimous, and which significance is still controversial. Cost analysis showed a substantial difference between validated tests which are of low cost and experimental tests which are expensive. Based on these data regarding both the reliability and cost of each prognostic factor, we propose guidelines for their use in clinical practice in the year 2000.

Lymphatic mapping to tailor selective lymphadenectomy in cN0 tongue carcinoma: beyond the sentinel node concept.

PurposeCervical lymph node status is the most important pathological determinant of prognosis and decision making in head and neck squamous cell carcinoma (SCC). The aim of this study was to demonstrate that lymphoscintigraphy (LS) can supply a complete map of the lymphatic drainage before surgery, allowing planning of the type of intervention and serving to guide lymphadenectomy.MethodsThe study population comprised 14 patients with T2–4 SCCs of the tongue and clinically negative lymph nodes in the neck (cN0) who were scheduled to undergo tumour resection and selective level I–IV neck dissection extended to level V. LS was performed in all patients following the injection of 99mTc-colloidal sulphide in three aliquots around the primary lesion. Dynamic, static and tomographic images of the head and neck were acquired. The operative specimens were subjected to lymphoscintigraphic evaluation. Preoperative and postoperative imaging results were compared with the pathological findings. All nodes were examined using haematoxylin-eosin staining.ResultsPreoperative LS was successful in all patients. Preferential pathways of lymphatic drainage were identified: level II of the neck was the most common lymphatic drainage pattern, followed by levels IV and III. Contralateral drainage occurred in 11 patients and in two of them metastatic nodes were found on the contralateral side. Metastases were observed only in radioactive lymph nodes.ConclusionLS is able to supply a complete map of the lymphatic drainage before surgery, making it possible to tailor selective neck dissection to each individual patient based on the results of preoperative mapping, thereby sparing healthy lymphatic tissue and reducing surgery-related morbidity.

Relationship between histologic thickness of tongue carcinoma and thickness estimated from preoperative MRI

Several studies have shown that the thickness of tongue carcinoma is related to prognosis and to the likelihood of cervical node metastases. We investigated whether preoperative estimates of tumor thickness and volume, as determined from magnetic resonance imaging (MRI), correlated with histologic thickness and might therefore predict the presence of neck metastases. We assessed relationships between histologic tumor thickness and MRI tumor thickness and volume in a retrospective series of 33 patients with squamous cell carcinoma of the tongue. Thicknesses were determined by direct measurement and by considering corrections for ulceration or tumor vegetation (reconstructed thickness). Relationships between MRI thickness and the presence or absence of homolateral and contralateral nodal metastases were also investigated. We found that MRI thicknesses correlated strongly and directly with histologic tumor thicknesses, although mean MRI thicknesses were significantly greater than histologic thicknesses. MRI thicknesses were significantly greater in patients with contralateral neck involvement than in those with no neck involvement. We conclude that MRI provides an accurate and reproducible means of estimating the thickness of tongue carcinomas, paving the way for further studies on more extensive series of patients to determine whether preoperatively determined MRI thickness can reliably predict homolateral and bilateral neck involvement.

In vitro and in vivo hematopoietic potential of human stem cells residing in muscle tissue.

OBJECTIVE We studied the in vitro and in vivo hematopoietic potential of human stem cells residing in muscle tissue collected from adults with head and neck cancer. MATERIALS AND METHODS Adherent muscle cells were cultured in F12 medium with 10% fetal bovine serum and transplanted into immunodeficient mice. RESULTS On day 12 we obtained a median of 500,000 adherent cells per gram muscle sample. Thy-1, endoglin, HER2/neu, and P1H12 were expressed in the majority of cells. CD34, VEGFR2, c-kit, VCAM-1, and CXCR4 were expressed in 0.5-1.5%, 1-5%, 1-15%, 9-15%, and 30% of cells, respectively. Immunodeficient mice transplanted with fresh muscle cells or less than 500,000 cultured cells showed little or no human engraftment. In mice transplanted with more than 500,000 cultured cells, up to 14% human CD45(+) hematopoietic cells (including myeloid and lymphoid subsets) were detected by flow cytometry. Engraftment was confirmed by polymerase chain reaction, Southern blotting, and DNA sequencing. Liver, muscle, and spleen evaluated for human DNA were positive in the majority of mice showing hematopoietic engraftment in the bone marrow. In vivo hematopoietic engraftment potential was maintained in cultured CD45(-) muscle cells transduced with the green fluorescence protein gene. CONCLUSIONS Human stem cells residing in muscle tissue can generate multilineage hematopoiesis in immunodeficient mice. Surprisingly, this hematopoietic potential increased in cultured versus fresh cells from muscle tissue.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method of determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histological nodal staging and avoids over-treating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This article was designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. These guidelines were prepared by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial Committee.

Endoscopic CO2 laser surgery for early glottic cancer in patients who are candidates for radiotherapy: Results of a prospective nonrandomized study

Treatment of early glottic malignancies is controversial, particularly if postoperative endoscopy shows minimal/no residual disease.

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down‐regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5‐aza‐2′deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and haematopoietic malignancy (64% in Burkitts lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic‐based therapy.