Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: the French randomised trial ACCORD12/0405 PRODIGE 2.

Circumferential resection margin (CRM) appears as a new powerful prognostic factor of survival after surgery for rectal cancer. We aimed to evaluate predictive factors of positive CRM following preoperative radiochemotherapy in a French trial. Patients with rectal cancer were randomised in long course preoperative radiotherapy 45 Gy plus capecitabine versus 50 Gy plus capecitabine and oxaliplatin. Mesorectal excision was performed 6 weeks after treatment. Impact of clinical, pathological and surgical variables on positive CRM (≤1 mm) were analysed by multivariate analysis. Of 565 randomised patients, CRM was recorded in 390 cases and was positive in 8% (30/390). Patients with 50 Gy plus capecitabine and oxaliplatin had a 6% rate of positive CRM while those treated by 45 Gy plus capecitabine had a 10% rate (p=0.128). Three independent predictive factors of positive CRM were identified: abdominoperineal resection (APR) (odds ratio OR=3.24; p=0.004), vascular tumour invasion (OR=2.78; p=0.026) and poor histological response (modified Dworak 0-2) (OR=9.01; p=0.003). Significant predictive factors of positive CRM are related to type of surgery, especially APR, and poor histological prognostic factors. Intensification of neoadjuvant radiochemotherapy does not seem to have a major role in this study.

Clinical impact of cervical lymph node involvement and central neck dissection in patients with papillary thyroid carcinoma: a retrospective analysis of 368 cases.

The impact of cervical lymph node metastases and the optimal surgical management of the neck in patients with papillary thyroid carcinoma (PTC) remain controversial. The objectives of this retrospective study were to determine, in patients with PTC, the predictive factors and the impact on tumor recurrence rate of cervical lymph node involvement, and to evaluate the oncologic results and the morbidity of central neck dissection (CND). We reviewed the records of patients who had undergone surgical treatment for PTC at our institution between 1990 and 2000. A total of 368 patients (86 men and 282 women) were included in this study. Young age (p = 0.02), tumor size (p = 0.001) and extrathyroidal tumor extension (p = 0.003) were significant predictive factors of cervical lymph node metastatic involvement (multivariate analysis). Initial metastatic cervical lymph node involvement was identified as an independent risk factor of tumor recurrence (multivariate analysis, p = 0.01). Metastatic lymph node(s) were found in prophylactic CND specimens in 31% of the patients. CND increased the risk of postoperative hypocalcemia (p = 0.008) and of permanent hypoparathyroidism (p = 0.002). In conclusion, cervical lymph node metastatic involvement at the time of initial surgery is an independent risk factor of tumor recurrence. CND provided an up-staging of more than 30% of patients with a clinically N0 neck, but was associated with significant morbidity regarding parathyroid function.

Second conservative treatment for ipsilateral breast cancer recurrence using high-dose rate interstitial brachytherapy: preliminary clinical results and evaluation of patient satisfaction.

PURPOSE: To assess early clinical results and evaluate patient satisfaction in case of second conservative treatment (2nd CT) combining lumpectomy plus high-dose rate (HDR) interstitial brachytherapy for patients (pts) presenting with ipsilateral breast cancer recurrence (IBCR). METHODS AND MATERIALS: From June 2005 to July 2009, 42 pts presenting with an IBCR underwent a second lumpectomy with intraoperative implantation of plastic tubes in the tumor bed. After performing the dose distribution analysis on the postimplant CT scan, a total dose of 34 Gy in 10 fractions over 5 consecutive days was delivered. Toxicity evaluation was based on the Common Terminology Criteria for Adverse Events v3.0 criteria. Applying a visual analogic scale (VAS) analysis, patient satisfaction regarding cosmetic result and 2nd CT possibility was performed after the end of brachytherapy. RESULTS: Median followup was 21 months (range, 6-50 months) and median age at the time of local recurrence was 65 years (range, 30-85 years). Median delay between primary and recurrence was 11 years (range, 1-35 years). Median recurrence tumor size was 12 mm (range, 2-30 mm). Median number of plastic tubes and planes were nine (range, 5-12) and two (range, 1-3), respectively. Median clinical target volume was 68 cc (range, 31.2-146 cc). Second local control rate was 97%. Twenty-two pts (60%) developed complications. Cutaneous and subcutaneous fibrosis was the most frequent side effect. Median VAS satisfaction score regarding cosmetic result was 7 of 10 (range, 4-9), whereas median VAS satisfaction score for 2nd CT was 10 of 10 (range, 8-10). CONCLUSION: A 2nd CT for IBCR using high-dose rate brachytherapy seems feasible with encouraging results in terms of second local control with an acceptable toxicity. Patient satisfaction regarding the possibility of second breast preservation should be considered.

[Update of the GEFPICS' recommendations for HER2 status determination in breast cancers in France]. / Mise à jour des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers du sein en France.

In Europe, patients who may benefit from an HER2 targeted drug are currently selected by immunohistochemistry (IHC). In situ hybridization (ISH) techniques should be used for complementary assessment of ambiguous 2+ IHC cases and for the calibration of the IHC technique. Eligibility to an HER2 target treatment is defined by an HER2 positive status being IHC test 3+ or 2+ amplified. Reliable detection of HER2 status is essential to the appropriate usage of HER2 targeted drugs because its specificity is limited to tumors overexpressing HER2. It is essential that the IHC evaluation of the HER2 status of a mammary carcinoma is optimized and reliable. This GEFPICS' guidelines look over the different steps of the IHC technique, the controls and, the rules for interpretation. Once acquired, this knowledge must be perpetuated by the observation of rules of good technical practice (internal and external controls, quality assurance programs).

[Data quality of cancer registration by Adicap codes, used by French pathologists from Paca, 2005-2006]. / Evaluation de la qualité du recueil des codes Adicap de tumeurs invasives et in situ par le Crisap de Paca Est, 2005-2006.

AIM: To assess the reliability of systematic and exhaustive cancer Adicap code registration by French pathology laboratories within the Crisap of Paca East network. METHODS: The Adicap code includes tumour site, histology and pathology technique. A quality control programme was applied to malignant and in situ tumours with an Adicap code to assess data quality, correct errors and supply missing data, based on IARC recommendations. RESULTS: In 2005 and 2006, 45,980 pathology examinations were entered in the Crisap of Paca East database. There was at least one Adicap code per examination, patients, surgeons and pathologists were identified and date of diagnosis was completed, as recommended by the HAS-Afaqap 2005 French pathologist professional quality control. Discrepancies between histopathology tissue and tumour site were found in 0.32% of cases (n=147), between age and histopathology in 0.04% of cases (n=19), and between genital tumour and sex in 0.01% of cases (n=3). In 2006, within 9535 subjects, dates of birth and postcodes of residence were missing, respectively, in 0.39% (n=37) and 22.46% (n=2142) of cases. CONCLUSION: Data quality for the Adicap code database may be considered satisfactory. Extended to Paca in 2007, Crisap Paca database can now be exploited for Paca regional cancer control strategy.

Immunoanalysis indicates that the sodium iodide symporter is not overexpressed in intracellular compartments in thyroid and breast cancers.

OBJECTIVE: The active transport of iodide into thyroid cells is mediated by the Na(+)/I(-) symporter (NIS) located in the basolateral membrane. Strong intracellular staining with anti-NIS antibodies has been reported in thyroid and breast cancers. Our initial objective was to screen tumour samples for intracellular NIS staining and then to study the mechanisms underlying the altered subcellular localization of the transporters. METHODS: Immunostaining using three different anti-NIS antibodies was performed on paraffin-embedded tissue sections from 93 thyroid or breast cancers. Western blot experiments were carried out to determine the amount of NIS protein in 20 samples. RESULTS: Using three different anti-NIS antibodies, we observed intracellular staining in a majority of thyroid tumour samples. Control immunohistochemistry and western blot experiments indicated that this intracellular staining was due to non-specific binding of the antibodies. In breast tumours, very weak intracellular staining was observed in some samples. Western blot experiments suggest that this labelling is also non-specific. CONCLUSIONS: Our results strongly indicate that the NIS protein level is low in thyroid and breast cancers and that the intracellular staining obtained with anti-NIS antibodies corresponds to a non-specific signal. Accordingly, to increase the efficiency of radiotherapy for thyroid cancers and to enable the use of radioiodine in the diagnosis and therapy of breast tumours, improving NIS targeting to the plasma membrane will not be sufficient. Instead, increasing the expression level of NIS should remain the major goal of this field.

Pathologic complete response to trastuzumab-based neoadjuvant therapy is related to the level of HER-2 amplification.

PURPOSE: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. EXPERIMENTAL DESIGN: Breast biopsies from 93 HER-2-positive patients treated with trastuzumab-based neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. RESULTS: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low- and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P < 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P < 0.005). In the subgroup of low- plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen, T or N stage, tumor grade, or hormonal receptors. CONCLUSIONS: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.

Value of MRI in the surgical planning of invasive lobular breast carcinoma: a prospective and a retrospective study of 57 cases: comparison with physical examination, conventional imaging, and histology.

PURPOSE: The objective of this study was to determine the value of magnetic resonance imaging (MRI) for the surgical planning of invasive lobular carcinoma (ILC)-a diagnostic challenge for radiologists. MATERIALS AND METHODS: Fifty-seven patients with histologically proven ILC were studied between 1998 and 2006. All patients underwent physical examination, mammography, ultrasound, and MRI. All anomalies detected were graded using the Breast Imaging Reporting and Data System (BI-RADS) classification, and careful research was made for the presence of multifocal/multicentric disease. RESULTS: On MRI, 72% of images were visualized as masses and 18% corresponded to non-mass-like enhancements. The size correlations, compared with histological findings, were .88 (MRI; P<.001), .57 (ultrasound), .53 (physical examination), and .40 (mammography). The kappa correlations for multifocality were .87 (MRI), .22 (ultrasound), and .22 (mammography). MRI had a sensitivity of 100% and a specificity of 87%. Forty-nine percent of therapeutic strategy cases were modified. CONCLUSION: MRI is unquestionably valuable for the management of ILC. It provides the most accurate estimate of tumor size and is highly sensitive for multifocal disease. Its main drawback is its lack of specificity, which requires preoperative histological verification. MRI often justifies the modification of the initial therapeutic strategy, generally ruling out conservative procedures.

HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome.

Hypoxia stabilizes HIF-1alpha (Hypoxia Inducible Factor-1alpha), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF-1alpha and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O2-dependent instability of the protein, we first validated HIF-1alpha staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF-1alpha and CA IX was evaluated in 132 invasive breast carcinomas with a 10-year follow-up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF-1alpha or CA IX. Statistically significant association was found between HIF-1alpha or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF-1alpha and CA IX correlates with a poor prognosis in breast cancer. We show that HIF-1alpha is an independent prognostic factor for distant metastasis-free survival and disease-free survival in multivariate analysis. Furthermore, overexpression of HIF-1alpha or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF-1alpha, and its association with HIF-1alpha does not modify the survival curve neither response to therapy, compared to HIF-1alpha alone.

Long-term results of hypofractionated radiotherapy and hormonal therapy without surgery for breast cancer in elderly patients.

BACKGROUND AND PURPOSE: To evaluate early and late reactions, local control, disease-free survival, cause-specific survival, and overall survival of elderly breast cancer patients treated with definitive once-a-week hypofractionated radiotherapy together with hormonal therapy. PATIENTS AND METHODS: Between 1987 and 1999, 115 patients with a median age of 83 presenting with 124 non-metastatic breast carcinoma were treated with definitive once weekly hypofractionated radiotherapy associated with hormonal therapy. The main reasons for adopting this schedule were patient refusal of surgery, very old age, locally advanced case, and/or comorbid disease. Radiation was delivered as once-a-week, 6.5 Gy for a total breast dose of 32.5 Gy in five fractions, followed with 1-3 fractions of 6.5 Gy to the tumour site. The median follow-up was 41 months. RESULTS: Neoadjuvant hormonal therapy led to 56% reduction of the tumour volume. Late reactions occurred in 46 patients; they were mild to moderate in 87% of these patients. The Kaplan-Meier rate was 52% of patients, with 6% experiencing grade 3 reactions. The 5-year local progression-free rate was 78%. The corresponding cause-specific survival was 71%, and was influenced by T classification, nodal status, oestrogen receptors and the total dose. The first three factors retained an independent prognostic impact on multivariate analysis. The 5-year overall survival was 38%. It was affected by the T classification, lymph node involvement and the performance status (PS). Using a multivariate analysis, only T classification and PS were identified as independent factors regarding overall survival. CONCLUSIONS: Definitive hypofractionated radiotherapy allows a good local control, with acceptable toxicity. This schedule associated with hormonal therapy is a good alternative to surgery in non-operable old patients and in case of patient refusal to surgery and to standard fractionation.

[Parathyroid carcinoma]. / Le carcinome parathyroïdien.

Parathyroid carcinoma is a rare disease accounting for 1 to 5% of parathyroid neoplasms. This malignant tumour must be suspected when a severe primary hyperparathyroidism occurs with high hypercalcemia and elevated parathormon levels. At this time, a cervical mass is often palpable. Both head and neck ultrasonography and 99mTc-sestamibi scintigraphy are the best preoperative imaging tests to suspect and localize the tumour. Surgical approach with simultaneous tumorectomy and hemithyroidectomy, completed by selective neck dissection (level VI) is the treatment of choice. An elective lateral neck dissection should be performed if necessary. Tumour control should be monitored by regular measurement of calcium and parathormon levels. Local recurrence or metastasis risk is 30 to 70% and the 5 year overall survival about 50 to 80%. In case of recurrence, aggressive surgical management should be applied and adjuvant radiation therapy may be discussed.

[2003 Update of Standards, Options and Recommendations for management of patients with salivary gland malignant tumors (excluding lymphoma, sarcoma and melanoma) (summary report)]. / Standards, Options et Recommations 2003 pour la prise en charge des patients atteints de tumeurs malignes des glandes salivaires (lymphomes, sarcomes et mélanomes exclus), mise à jour (rapport abrégé).

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. OBJECTIVES: To update clinical practice guidelines for the management of patients with salivary gland malignant tumors previously validated in 1997. These recommendations cover diagnosis, classification, treatment and follow-up of patients with these tumors. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPG s according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers. RESULTS: This article is a summary version of the full document presenting the updated clinical practice guidelines with algorithms. The main questions addressed by the expert group in this update concern the place of fine needle aspiration biopsy in preoperative diagnosis, the place of cervical lymph node area surgical treatment, the place of postoperative irradiation and neutron therapy in the treatment of unresectable tumors and also the place of medical imaging, especially RMI, for the diagnosis of these tumors.