Relationship between lymphoscintigraphy and clinical findings in lower limb lymphedema (LO): toward a comprehensive staging.

Although radionuclide lymphoscintigraphy (RNL) is widely used diagnostically for patients with lymphedema (LE), it has not been utilized for LE staging, which is still based upon clinical findings. The aim of this work is to establish whether the results of both conventional RNL and fusion imaging obtained from hybrid detectors may be used for a comprehensive clinicoimaging staging in LE. Radiolabeled nanocolloids (0.2 ml) were subcutaneously injected in 4,328 patients (23-78 years) with clinical lower limb LE and without venous disease. Patients were classified according to the ISL classification and had a minimal follow-up of 2 years. Images were taken 60 minutes after the injection as a whole body scanning and fusion images of functional SPET and anatomical CT. Clinical and RNL results were not in accordance, and a specific RNL staging was established. The association of clinical and functional staging yields a new method to grade LE patients, and this staging correlated with treatment efficacy. RNL is an important tool in lymphology, and its association with the clinical evaluation offers a new grading system which may be able to delineate patients with good prognosis, patients at risk for a complex decongestive physiotherapy (CDP) failure, and patients who may benefit from other therapeutic protocols.

Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

Drug-induced cardiotoxicity studied by longitudinal B-type natriuretic peptide assays and radionuclide ventriculography.

BACKGROUND: To study the longitudinal variations of plasma B-type natriuretic peptide (BNP) with reference to left ventricular ejection fraction (LVEF) during and after chemotherapy with cardiotoxic drugs. PATIENTS AND METHODS: We prospectively measured plasma BNP using an immunoradiometric assay in 12 anthracycline-treated breast cancer patients monitored for a mean time of 880+/-293 days (pilot group). Prior to each cycle and throughout the following year, LVEF and cardiac output were measured by radionuclide ventriculography. Anthracycline pharmacokinetics was studied during the first cycle. Relationships between serial observations were analysed with the general linear mixed effects model. Identical methods were subsequently applied to a test group of 67 anthracycline or trastuzumab-treated patients. RESULTS: Five out of 70 (6.33%) patients developed anthracycline-induced heart failure. BNP concentrations were found to be positively correlated to anthracycline cumulative dose and negatively to LVEF values. Variables entering the mixed models were cumulative anthracycline dose, time and cardiac output. CONCLUSION: An infra-clinical cardiotoxicity of anthracyclines as defined by BNP elevation is frequent but reversible. Patients who developed heart failure showed a continuous BNP increase and concentrations over 100 ng/ml.

Detection of occult disease in breast cancer using fluorodeoxyglucose camera-based positron emission tomography.

An isolated increase of blood tumor marker CA 15.3 in breast cancer is considered a sensitive indicator for occult metastatic disease but by itself is not sufficient for initiating therapeutic intervention. We investigated the potential of camera-based positron emission tomography (PET) imaging using [18F]-fluorodeoxyglucose (FDG) to detect clinically occult recurrences in 132 female patients (age, 35-69 years) treated for breast cancer, all presenting with an isolated increase in blood tumor marker CA 15.3 without any other evidence of metastatic disease. FDG results were correlated to pathology results or to a sequentially guided conventional imaging method. One hundred nineteen patients were eligible for correlations. Positive FDG scans were obtained for 106 patients, including 89 with a single lesion and 17 with 2 or more lesion. There were 92 true-positive and 14 false-positive cases, 10 of which became true positive within 1 year. Among the 13 negative cases, 7 were false negative and 6 were true negative. Camera-based PET using FDG has successfully identified clinically occult disease with an overall sensitivity of 93.6% and a positive predictive value of 96.2%. The smallest detected size was 6 mm for a lymph node metastasis (tumor to nontumor ratio, 4:2). FDG camera-based PET localized tumors in 85.7% of cases suspected for clinically occult metastatic disease on the basis of a significant increase in blood tumor marker. A positive FDG scan associated with an elevated CA 15.3 level is most consistent with metastatic relapse of breast cancer.

Evaluation by lymphoscintigraphy of the effect of a micronized flavonoid fraction (Daflon 500 mg) in the treatment of upper limb lymphedema.

Upper limb lymphedema after conventional treatment of breast cancer occurs in about 20% of all treated cases, even after conservative therapy. Women with mild to severe upper limb lymphedema expect a decongestive therapy, which usually associates physiotherapy and medical treatment. Upper limb lymphoscintigraphy using rhenium colloids labelled with technetium 99m can be used as a lymphatic functional test in order to evaluate the efficacy of a therapy. We report here the results of a pilot, open study carried out on 10 female patients, age ranging from 44 to 64 years, previously treated for a breast cancer. The average time delay for the occurrence [correction of occurence] of lymphedema was 17 +/- 7 months. All patients received 500 mg twice daily of a micronized flavonoid fraction (Daflon 500 mg) for 6 months. At the end of the study, all patients had a clinical improvement of symptoms and limb volume and the mean decrease in volume of the swollen limb reached 6.80%. Functional parameters (half-life, clearance and lymphatic speed of the colloid) assessed with scintigraphy were significantly improved. These preliminary results suggest that this therapy is effective for the treatment of lymphedemas.

Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer).

To assess the activity of a purified, micronized, flavonoidic fraction (Dios; Daflon 500 mg*) on upper limb lymphedema occurring after breast cancer therapy, a monocenter, randomized, double-blind, parallel group vs placebo (Plac) trial was carried out. One hundred and four women with lymphedema were included; 94 completed the study (46 Dios, 48 Plac). A subset of 24 patients with more severe lymphedema (10 Dios, 14 Plac) was subjected to a separate analysis. Treatment consisting of Dios or Plac was given two tablets daily over a six-month period. A radionuclide lymphoscintigraphy using technetium-99m was performed at inclusion and at the end of the treatment. The upper limb volume was measured every two months. In the overall population the evolution of parameters was not different between Dios and Plac. In the 24 patients with a more severe lymphedema, the lymphoscintigraphic parameters (m +/- sd) were as follows: lymphatic migration speed was significantly improved by Dios in comparison with Plac (delta Speed cm/minute: 0.84 +/- 0.6 vs 0.14 +/- 0.26, P = 0.005). The half-life of the colloidal compound was significantly improved over time in the Dios group (delta half-life = 10.3 +/- 13.07 minute, P = 0.034) but not in the Plac group (delta half-life = 0.53 +/- 15.51 minute, P = 0.086). The change over time of colloidal clearance was close to significance in the Dios group (delta clearance microL/minute: 2.18 +/- 3.10, P = 0.054) but not in the Plac group (0.11 +/- 2.26, P = 0.86). No significant difference was found for evolution of lymphedema volume, despite a tendency in favor of Dios. This can be related to wide distribution of volume values and small numbers of patients. In conclusion, these results suggest a beneficial therapeutic activity of Dios at the usual dose of two tablets/day in patients affected with more severe lymphedema. The clear improvement of the lymphatic speed illustrates its known lymphokinetic activity. Further studies with a higher dosage could confirm the beneficial activity of this drug in secondary lymphedema.

Efficacy of BN165 (Ginkor Fort) in breast cancer related upper limb lymphedema: a preliminary study.

The purpose of this study was to determine whether BN165 (Ginkor Fort), which has been reported to alleviate symptoms of venous insufficiency, has a beneficial effect on lymphatic function or lymphedema symptoms. Using a 3-arm, double-blind, placebo-controlled design in 48 patients with upper extremity lymphedema secondary to breast cancer treatment, improvement in symptoms and signs as well as lymphoscintigraphic kinetic parameters (radiocolloid half-life and lymphatic migration speed) was assessed in response to treatment. A statistically significant effect on limb heaviness was noted. Lymphatic migration speed also demonstrated a significant increase at a dose of 2 active capsules per day but not at the 3 capsules per day dose, but lymphatic migration speed also improved in the placebo group. These findings in mechanical lymphatic insufficiency in breast cancer-related lymphedemas can be compared to the previously published clinical amelioration by BN165 of the subjective symptoms (heavy limbs) of dynamic lymphatic insufficiency in patients with venous insufficiency. Further studies are needed to define the possible role of BN165 in treating patients with lymphedema.

[Tests and imaging of the lymphatic system]. / Explorations et imagerie du système lymphatique.

Methods for lymphatic imaging are numerous and can be roughly classified as anatomic or functional studies. Direct or indirect lymphographies provide useful informations in case of lymphostasis. Contrast lymphangiography is the only anatomical method giving precise informations either on lymphatic ducts or lymph nodes. Nevertheless this invasive method is no more indicated in cases of limb edemas. Indirect lymphographies study the spontaneous lymphatic drainage of inert particles injected into the dermis. The blue dye test is the most simple and the oldest indirect lymphography used in the positive diagnosis of a lymphostasis. It has been replaced with the indirect radionuclide lymphography which give more reliable informations. Fluorescence microlymphoangiography is an atraumatic method which permits the visualization of skin lymphatics. Indirect lymphangiography with contrast medium give reliable informations on the status of the initial lymphatics and is the best imaging method to differentiate between lipedema and lymphedema. Indirect radionuclide lymphoscintigraphy is a safe, non invasive and physiological method for the assessment of the limb lymphatic system used for morphological studies and objective measurement of the peripheral lymphatic function necessary to assess the lymphatic variation under therapy (decongestive physiotherapy, surgery, drugs).

18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging in the staging and prognosis of inflammatory breast cancer.

BACKGROUND: : To prospectively assess fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging and prognosis value in patients with suspected inflammatory breast cancer (IBC). METHODS: : Sixty-two women (mean age 50.7 +/- 11.4 years) presenting with unilateral inflammatory breast tumors (59 invasive carcinomas; 3 mastitis) underwent a PET/CT scan before biopsy. RESULTS: : PET/CT scan was positive for the primary malignant tumor in 100% and false positive in 2 of 3 benign mastitis. In 59 IBC patients, FDG nodal foci were detected in axillary (90%; n = 53) and extra-axillary areas (56%; n = 33) ipsilateral to the cancer. Compared with clinical examination, the axillary lymph node status by PET/CT was upstaged and downstaged in 35 and 5 patients, respectively. In 7 of 9 N0 patients, the axillary lymph node positivity on PET/CT was correct, as revealed by pathological postsurgery assessment (not available in the 2 remaining patients). The nodal foci were compared with preoperative fine needle aspiration and/or pathological postchemotherapy findings available in 44 patients and corresponded to 38 true positive, 4 false-negative, and 2 false-positive cases. In 18 of 59 IBC patients (31%), distant lesions were found. On the basis of a univariate analysis of the first enrolled patients (n = 42), among 28 patients who showed intense tumoral uptake (standard uptake value(max)>5), the 11 patients with distant lesions had a worse prognosis than the 17 patients without distant lesions (P = .04). CONCLUSIONS: : FDG-PET/CT imaging provides additional invaluable information regarding nodal status or distant metastases in IBC patients and should be considered in the initial staging. It seems also that some prognostic information can be derived from FDG uptake characteristics. Cancer 2009. (c) 2009 American Cancer Society.

Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.

Trophoblast research over the past decades has underlined the striking similarities between the proliferative, migratory and invasive properties of placental cells and those of cancer cells. This review recapitulates the numerous key molecules, proto-oncogenes, growth factors, receptors, enzymes, hormones, peptides and tumour-associated antigens (TAAs) expressed by both trophoblastic and cancer cells in an attempt to evaluate the genes and proteins forming molecular circuits and regulating the similar behaviours of these cells. Among the autocrine and paracrine loops that might be involved in the strong proliferative capacity of trophoblastic and cancer cells, epidermal growth factor (EGF)/EGF receptor (EGFR), hepatocyte growth factor (HGF)/HGF receptor (HGFR) (Met) and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) loops may play a predominant role. Similar mechanisms of migration and invasion displayed by trophoblastic and malignant cells comprise alterations in the adhesion molecule phenotype, including the increased expression of alpha1beta1 and alphavbeta3 integrin receptors, whereas another critical molecular event is the down-regulation of the cell adhesion molecule E-cadherin. Among proteases that may play an active role in the invasive capacities of these cells, accumulating evidence suggests that matrix metalloproteinase-9 (MMP-9) expression/activation is a prerequisite. Finally, an overview of molecular circuitries shared by trophoblast and cancer cells reveals that the activation of the phosphatidylinositol 3'-kinase (PI3K)/AKT axis has recently emerged as a central feature of signalling pathways used by these cells to achieve their proliferative, migratory and invasive processes.

Possibilities and restriction of isotopic lymphography for the assessment of therapeutic effects in lymphedema.

Whatever the results are, we must keep in mind that the method used must be safe, simple, reproductive, quite physiological. The RNL with distal registration during 40 min give more precise and reliable informations particularly in transient or permanent lymphatic dysfunctions. This should be the protocol used for the assessment of the lymphatic function and the treatment efficacy. The RNL with nodal uptake registration is totally related to the lymphatic transport from the extremities and the exercise applied. When performed by well trained physicians concerned with the lymphatic physiology and informed of all factors interfering with the results, the quantitative functional lymphoscintigraphy is really giving objective and reproductive parameters to evaluate a treatment efficacy (decongestive physiotherapy, surgery, drugs) in lymphedemas useful to assess new lymphotonic treatments.

[1959-1999: from serum markers to 18-FDG in oncology. The experience of the René-Huguenin Center]. / 1959-1999: des marqueurs sériques au 18-FDG en oncologie. L'expérience du centre René-Huguenin.

Blood tumour markers are widely used in the follow up of patients treated for a malignant tumour. In many cases where the tumour associated marker is increasing the clinical and radiological evaluations remain normal. PET and CDET-scan with 18-FDG have been demonstrated as powerful tools in oncology and their use in such situations may give a new appraisal on the development of the disease. Seventy patients with an isolated increasing of a tumour associated marker (CEA or CA19.9, CA15.3, CA125) were tested. Accuracy and sensitivity of the method were 82.8 and 96.5%, specificity 25%, and positive and negative predictive values 50% and 87%. Focusing on breast carcinomas and CA15.3 as well as ovarian cancers and CA125, the sensitivity and the predictive value are reaching 100%. Patients exhibiting a tumor target associated to an increasing in blood tumour marker may be treated earlier with dedicated protocols.