Elevated HER2 extracellular domain level in primary breast cancer with HER2 overexpression predicts early failure of adjuvant trastuzumab.

AIM: To investigate in a prospective study the prognostic value of serum HER2 extracellular domain (ECD) level in patients with primary breast cancer overexpressing HER2 treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: All the patients treated for primary breast cancer with chemotherapy and adjuvant trastuzumab from April 1, 2005 to December 31, 2006 at the Centre de Lutte Contre le Cancer de Haute Normandie were enrolled in this prospective study. HER2 ECD was measured in frozen serum by a commercial kit with a cut-off value of 15 ng/ml. RESULTS: Sixty-five patients were enrolled. Seven patients (11%) had an elevated serum HER2 ECD level (mean=25.1 ng/ml, range 15.1-38.9 ng/ml). During follow-up, 13 patients (20%) developed metastases and seven patients (11%) died. Death was related to breast cancer metastases in six patients (9%). Out of the seven patient with elevated serum HER2 ECD level, five (71%) developed metastases and three (43%) died of metastases during follow-up. Multivariate analysis showed that elevated serum HER2 ECD level was the unique factor for both disease-free survival (p<0.0006) and overall survival (p=0.008) in this series. CONCLUSION: Elevated serum HER2 ECD level is a strong prognostic factor in primary breast cancer overexpressing HER2 treated with adjuvant therapy of trastuzumab. In addition, our results suggest that it could predict failure of adjuvant therapy of trastuzumab.

Does recombinant human thyrotropin-stimulated positron emission tomography with [18F]fluoro-2-deoxy-D-glucose improve detection of recurrence of well-differentiated thyroid carcinoma in patients with low serum thyroglobulin?

BACKGROUND: Thyrotropin (TSH) stimulates thyrocyte metabolism, glucose transport, and glycolysis. The interest in using recombinant human TSH (rhTSH) stimulation of fluoro-2-deoxy-D-glucose (FDG) with positron emission tomography (PET) has been shown, but mainly for patients with high serum thyroglobulin (Tg) concentration. We evaluated the use of rhTSH-stimulated PET-FDG in patients with low serum Tg concentration. METHODS: Sixty-one PET/computed tomography (CT)-FDG (Biograph Sensation 16; Siemens Medical Solutions, Knoxville, TN) were performed in 44 patients (28 women and 16 men; 51 +/- 16 years) with positive Tg levels, negative or no contributive iodine-131 whole-body scintigraphy results, and no contributive morphological imaging results (ultrasound, magnetic resonance imaging, and CT). Thirty-eight patients had papillary carcinoma and six had follicular thyroid carcinoma. All patients had previously undergone total thyroidectomy and postoperative iodine ablation of thyroid bed remnant tissue. The rhTSH-stimulated PET/CT-FDG (5 MBq/kg) was performed after two 0.9 mg intramuscular doses of rhTSH (Thyrogen; Genzyme) which were administered 48 and 24 hours before imaging, while patients continued levothyroxine (LT(4)). Blood sampling was performed immediately before FDG injection for measurement of serum TSH and Tg concentrations (TSH(1) and Tg(1)) and after 48 hours (TSH(2) and Tg(2)). PET/CT-FDG findings were compared with the Tg: (i) at the initial iodine treatment during T(4) withdrawal (Tg(ini)), (ii) under T(4) (Tg(T4)) within 3 months before the PET/CT-FDG, (iii) with Tg(1), and (iv) with Tg(2). PET/CT-FDG findings were correlated with the findings of histology, iodine-131 whole-body scintigraphy, morphological imaging, or clinical follow-up. RESULTS: The mean Tg(ini) was 785 +/- 2707 microg/L for a TSH of 73 +/- 64 mU/L. The mean Tg(T4) was 7 +/- 15 microg/L (T(4) = 195 +/- 59 microg/day; mean TSH of 0.24 +/- 0.57 mU/L). Among the 44 patients, PET/CT-FDG findings were positive in 20 and negative in 24. Among the 61 PET/CT-FDG, 25 PET/CT-FDG were positive (41%). Among the 25 positive PET, the Tg(T4) values were less than 10 microg/L for 19, including 9 true-positive patients (20% of the 44 patients). There was no difference of PET/CT-FDG results (positive vs. negative) as related to the serum Tg concentrations (p = 0.99 for Tg(ini), p = 0.95 for Tg(T4), p = 0.07 for Tg(1), and p = 0.42 for Tg(2)). No relation was observed with PET/CT-FDG results and initial tumor size (p = 0.52) or node metastasis (p = 0.14). CONCLUSION: In the diagnosis of recurrent disease in patients with differentiated thyroid carcinoma and low Tg level, the sensitivity of rhTSH-stimulated PET/CT-FDG seems to be low and no correlation was observed between PET/CT-FDG findings and Tg level. However, positive PET-FDG results have been found in 9/44 (20%) patients with serum Tg levels lower than 10 microg/L. Therefore, this series shows that a cutoff value of 10 microg/L for the Tg under T(4) is probably not the best criteria to select patient candidates for PET/CT-FDG examination to detect the recurrence of differentiated thyroid carcinoma.

Comparison of fifteen immunoassays for the measurement of serum MUC-1/CA 15-3 in breast cancer patients.

BACKGROUND: Quality control results for serum MUC-1/CA 15-3 assays have always shown large discrepancies. METHODS: This multicentre study of 15 methods (labelled M1-M15) measured coded sera from 35 patients with breast cancer without recurrence (group 1), 46 patients at 1st metastasis (group 2), and 39 patients with advanced metastases (group 3). Results were compared using parametric statistics, ANOVA, principal component analysis, and receiver operating characteristic (ROC) curves. RESULTS: Mean MUC-1/CA 15-3 concentrations varied widely (75.1-303.0 U/mL, 24.8%) among methods. The false positive (FP) rate for group 1 was 8/521 (1.5%); for group 2 and group 3 false negative (FN) results were 21/680 (3.1%) and 11/583 (1.9%), respectively. Using the ROC cut-offs, we found no FPs for group 1 and no FNs for group 3. However, group 2 showed 16 FNs. All p-values for Pearson's correlation were <0.0001 between methods, except for M11. When comparing methods using different antibodies, discordance rates reached a maximum of 15.2%. Principal component analysis revealed a grouping of methods using: CanAg monoclonal antibodies (mAbs) (M2, M7 and M12); Centocor/Fujirebio mAbs (M3-M6, M8-M10, M14-M15) and Biomira mAbs (M1 and M13); and Centocor/Fujirebio mAbs (M11). CONCLUSIONS: Results were more consistent among methods using the same antibody type. Principal component analysis showed that antibody type was the strongest determinant of immunoassay results.

Usefulness of the serum carcinoembryonic antigen kinetic for chemotherapy monitoring in patients with unresectable metastasis of colorectal cancer.

PURPOSE: The aim of the study was to evaluate the relationship between serum carcinoembryonic antigen (CEA) kinetic and response to chemotherapy in patients with unresectable metastasis of colorectal cancer. PATIENTS AND METHODS: The kinetic was calculated using the slope of an exponential-regressive curve connecting the semi-logarithmic values of CEA. Receiver operating characteristic (ROC) curves were drawn to select the CEA slope thresholds to define patients with progressive or responsive disease with the highest sensitivity, specificity, and diagnosis accuracy odds ratio (DOR). The correlation between the CEA slopes and progression-free survival (PFS) was evaluated by the Cox model and Kaplan-Meier methods. RESULTS: A total of 122 patients were included. Progression defined by CEA slope greater than +0.05 resulted in sensitivity of 85.7%, specificity of 85.1%, and DOR of 34. The area under the ROC (AUROC) curve was 0.885 (95% CI, 0.815 to 0.936; P = .0001). Response defined by CEA slope less than -0.2 resulted in sensitivity of 74.7%, specificity of 82.5%, and DOR of 16. The AUROC curve was 0.847 (95% CI, 0.770 to 0.906; P = .0001). The difference between AUROC curves calculated with six or four CEA values was not significant. PFS was correlated with CEA slopes (hazard ratio, 4.6; 95% CI, 2.48 to 8.57). The median PFS was 10 months for patients with CEA slope values less than -0.2 months versus 6 months for patients with CEA slope values greater than -0.2 (P < .0001). CONCLUSION: These results suggest that the CEA kinetic is an accurate, simple, and noninvasive method to identify the disease progression in patients with unresectable metastasis of colorectal cancer.

Neutrophil but not eosinophil inflammation is related to the severity of a first acute epidemic bronchiolitis in young infants.

Acute bronchiolitis is the main cause of emergency visits and hospitalizations in infants. Recent data suggest that neutrophil- and eosinophil-mediated inflammations were part of bronchiolitis pathophysiology. Apart from the defined risk factors, few was known on the underlying pathophysiology, which might point out the differences observed in the severity of the disease. The aim of this study was to assess whether the clinical severity of acute epidemic bronchiolitis in young infants might be related to a specific underlying inflammatory process. Total and differential cell counts, IL-8, eotaxin, eosinophil cationic protein (ECP) and albumin levels were assessed at the time of admission in bronchial secretions from 37 infants (median age 17 wk) with acute bronchiolitis. Outcome severity variables were: hypoxemia, Silverman score, tachypnea, feeding alteration, and duration of hospitalization. Neutrophils predominated, and eosinophils were present in 54% of the infants. IL-8 levels strongly correlated with ECP and albumin levels. Albumin levels were correlated with ECP and eotaxin levels. IL-8 levels were higher in infants with hypoxemia and inversely related with SaO(2) levels. IL-8 and albumin levels significantly rose with respiratory rate, and Silverman score. IL-8, albumin and ECP levels were significantly higher in infants hospitalized >/=7 days. Furthermore, IL-8 levels were correlated with the duration of hospitalization. Neither cell counts nor eotaxin levels were related to the severity criteria studied. This study suggests that IL-8-associated airway inflammation significantly contributed to the severity of acute epidemic bronchiolitis.

Evaluation of a standardized short-time calcium suppression test in healthy subjects: interest for the diagnosis of primary hyperparathyroidism.

OBJECTIVE: The diagnosis of primary hyperparathyroidism (PHP) can be difficult in patients with normal plasma calcium or parathyroid hormone (PTH) levels. We perfected a standardized short-time i.v. calcium loading test in healthy controls (HC) and compared the results with those of patients with PHP. METHODS: Sixteen HC received 0.33 mmol/kg calcium gluconate intravenously for 3 h. Plasma calcium and serum PTH levels (assayed with immunoluminescent sandwich methods) were measured before, at the end of the infusion and 3 h later. Results were compared with those of 16 PHP patients. RESULTS: In HC, basal total plasma calcium (mean +/- s.e.m.) was 2.33 +/- 0.02 mmol/l. At the end of calcium loading, calcemia reached 3.21 +/- 0.05 mmol/l and decreased to 2.94 +/- 0.08 mmol/l 3 h later. In PHP patients, basal plasma calcium was 2.54 +/- 0.03 mmol/l and reached similar values as in HC during the testing. Basal serum PTH levels were 32.5 +/- 3.3 ng/l in HC and 86.9 +/- 6.3 ng/l in PHP. At the end of calcium loading, they dropped to 8.8 +/- 0.6 ng/l (HC) and to 31.4 +/- 4.2 ng/l (PHP). Three hours later, they were 11.6 +/- 0.8 and 39.8 +/- 4.0 ng/l respectively. There was a cut-off in serum PTH values between the two groups at the end of calcium loading and 3 h later. CONCLUSION: The standardized short-time PTH suppression test appears reliable to differentiate healthy subjects from PHP whose serum PTH levels remain >14 and >23 ng/ml respectively at the end of loading and 3 h later. This well-tolerated and easily performed test could be used for the diagnosis of PHP in patients suspected for the disease despite the normality of some basal biological markers.

Current usefulness of free/total PSA ratio in the diagnosis of prostate cancer at an early stage.

The aim of our study was to evaluate five different free/total PSA (f/t PSA) kits for the diagnosis of early stage prostate cancer. We compared the PSA density and the f/t PSA ratio to differentiate between benign prostatic hyperplasia (BPH) and prostate cancer. This prospective study included a total of 120 patients with suspected prostate cancer (PSA between 4 and 15 ng/ml) observed over a period of 30 months. All patients had a blood test as well as a prostate biopsy prior to inclusion. Serum immunoassay total-PSA (t PSA) and free-PSA (f PSA) were carried out using five different assay kits: IMX Abbott (A), Kryptor Brahms (B), Immulite DPC (D), IRMA Immunotech (I) and IRMA DiaSorin (S). The results were compared to determine sensitivity, specificity, threshold values, and to differentiate between BPH and cancer. No difference was found between assay reproducibility and variation in the assays, however, only a slight variation was observed in the mean t PSA values, whereas a significant difference was found with f/t PSA. Receiver operating curves were generated for t-PSA and f/t PSA. The area under the curves did not show any significant differences for either t PSA or f/t PSA. A low comparative variability between the five kits tested for tPSA was observed, which suggest that the f/t PSA ratio has no current usefulness in the initial diagnosis of prostate cancer, particularly in patients with larger prostates. Furthermore, no prognostic value was found for surgically positive margins in radical prostatectomy.

[Clinical practice guidelines: Standards, Options and Recommendations for first line medical treatment of patients with ovarian neoplasms (summary report)]. / Recommandations pour la pratique clinique Standards, Options et Recommandations 2003 pour le traitement médical de première ligne des patientes atteintes de tumeurs épithéliales malignes de l'ovaire, mise à jour (rapport abrégé).

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the French Federation of 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. OBJECTIVE: To update clinical practice guidelines for first line medical treatment of patients with ovarian neoplasms in collaboration with the French Society for Gynaecologica Oncology. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts. The CPGs are defined following the definitions of the Standards, Options and Recommendations project. Once the guideline has been developed, the document is submitted for review by independent reviewers. RESULTS: This article is a summary version of the full document presenting the clinical practice guidelines with algorithms. After surgery, most patients with ovarian neoplasms need adjuvant medical treatment. These guidelines concern the initial medical treatment (chemotherapy, hormone treatment and immunotherapy) and potential consolidation treatment. To complete the indications, two alternative treatment strategies are taken into account: no treatment and radiotherapy. This updated version concerns the indications and the modalities of chemotherapy. The main modifications are: 1) first-line chemotherapy for ovarian neoplasm can be taxane-platinum or carboplatine alone; 2) poly-chemotherapy is no longer a standard; 3) for early stages, except for stage IA grade I non-clear-cell tumours, adjuvant chemotherapy should be preferred to no treatment; 4) chemotherapy is standard for all stage III tumours, irrespective of the surgical result; 5) for stage IA G2-3 to IIA tumours, complete surgical staging and determination of the histological grade are standards.

[Standards, Options and Recommendations for the management of invasive cervical cancer patients (non metastastic)]. / Standards, Options and Recommandations Cancers invasifs du col utérin stades non métastatiques, version abrégée.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French cancer centers and specialists from French public university and general hospitals and private clinics. Its main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop, according to the definitions of the Standards, Options and Recommendations, clinical practice guidelines for the management of invasive cervical cancer patients. Methods : Data were identified by searching Medline and the personal reference lists of members of the expert groups, then submitted for review to independent reviewers. RESULTS: This is a synthesis of the Standards, Options and Recommendations elaborated by a working group of experts. Pretherapeutic assessment, classification, diagnosis, therapeutic modalities (surgery, radiotherapy, radiochemotherapy, chemotherapy), therapeutic strategies by disease stage and follow-up are covered. Algorithms for the management of patients are also included.

Hypocalcemia following pamidronate administration for bone metastases of solid tumor: three clinical case reports.

Bisphosphonates, such as pamidronate, are a new class of drugs, initially described for treatment of neoplasic hypercalcemia. Currently, they also may be used in the treatment of bone metastases from solid tumor, even without hypercalcemia. Hypocalcemia is a potential adverse effect of these drugs, which is considered infrequent and rarely symptomatic. We describe three cases of severe hypocalcemia following one injection of pamidronate. The three patients had bone metastases from solid tumors (breast in two cases, prostate in one), at least partially osteoblastic, and none had hypercalcemia. The induced hypocalcemia was rapid in onset, severe, and durable. The mechanism seems to be multiple and may include both the expected reduction of osteolysis and also a rapid and direct action on parathyroid glands followed by resistance to parathormone. Some elements could amplify the phenomenon, such as latent hypoparathyroidism after surgery, cervical radiotherapy, hypomagnesemia, or low 25 hydroxy vitamin D (25OH D). For patients who have such risk factors, it may be useful to check calcium several days after the first injection.