Tumour and pelvic lymph node metabolic activity on FDG-PET/CT to stratify patients for para-aortic surgical staging in locally advanced cervical cancer.

PURPOSE: The aim of our study was to comprehensively evaluate the most valuable metabolic parameters of cervical tumours and pelvic lymph nodes (PLN) by FDG-PET/CT to predict para-aortic lymph node (PALN) metastasis and stratify patients for surgical staging. METHODS: The study included patients with locally advanced cervical cancer, negative PALN uptake on preoperative FDG-PET/CT, and para-aortic lymphadenectomy. Two senior nuclear medicine physicians expert in gynaecologic oncology reviewed all PET/CT exams, and extracted tumour SUVmax, MTV, and TLG, as well as PLN. Prognostic parameters of PALN involvement were identified using ROC curves and logistic regression analysis. RESULTS: One hundred and twenty-five consecutive locally advanced cervical cancer patients were included. The FDG-PET/CT false-negative rate was, respectively, 27.7% (13/47) and 5.1% (4/78) in patients with and without FDG-PET/CT PLN uptake. The AUC of cervical tumour size, SUVmax, MTV, and TLG was, respectively, 0.75 (0.62-0.87), 0.59 (0.44-0.76), 0.75 (0.60-0.90), and 0.71 (0.56-0.86). The AUC of PLN size, SUVmax, SUVmean, PLN SUVmax/Tumour SUVmax ratio, MTV, and TLG was, respectively, 0.57 (0.37-0.78), 0.82 (0.68-0.95), 0.77 (0.61-0.94), 0.85 (0.72-0.98), 0.69 (0.51-0.87), and 0.74 (0.57-0.91). The metabolic parameter showing the best trade-off between sensitivity and specificity to predict PALN involvement was the ratio between PLN and tumour SUVmax. CONCLUSION: The risk of PALN metastasis in FDG-PET/CT negative PLN patients is very low, so para-aortic lymphadenectomy does not seem justified. In patients with preoperative PLN uptake on FDG-PET/CT, surgical staging led to treatment modification in more than 25% of cases and should therefore be performed. Patients with more than one positive PLN and high PLN metabolic activity are at high risk of para-aortic extension and recurrence. Further prospective evaluation is required to consider intensified treatment modalities without prior PALN dissection.

Controversies and consensus in the innovation access for cancer therapy in the European countries: on the subject of metastatic prostate cancer.

Innovative cancer therapies and advances in drug development have created new hopes for patients and health providers. The purpose of this article was to evaluate the discrepancies in the assessment of the magnitude of benefit of four new drugs (abiraterone acetate, enzalutamide, cabazitaxel, radium-223 dichloride) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The comparison was done among three European countries (UK, Germany and France) and Canada, according to the statement of each country and to the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale. Whereas those drugs are authorized by the European Medical Agency, one can observed that clear discrepancies in the magnitude of benefit assessment exist between selected countries, as well as between national pricing evaluation agencies and ESMO. However, price setting and reimbursement decisions remain national responsibility with differences in assessment of the medical value of new treatment across countries, leading to a heterogeneous accessibility to cancer treatments. In conclusion, several procedures have to be implemented to overcome the patchwork of administrative assessments. Among them, the assessment of medical value should be based on independent statements of learned societies, and the harmonization of access to cancer therapy in Europe has to be driven by a common European reimbursement and pricing policy.

The retrospective binning method improves the consistency of phase binning in respiratory-gated PET/CT.

This study assesses the accuracy of prospective phase-gated PET/CT data binning and presents a retrospective data binning method that improves image quality and consistency. Respiratory signals from 17 patients who underwent 4D PET/CT were analysed to evaluate the reproducibility of temporal triggers used for the standard phase-based gating method. Breathing signals were reprocessed to implement retrospective PET data binning. The mean and standard deviation of time lags between automatic triggers provided by the Real-time Position Management (RPM, Varian) gating device and inhalation peaks derived from respiratory curves were computed for each patient. The total number of respiratory cycles available for 4D PET/CT according to the binning mode (prospective versus retrospective) was compared. The maximum standardized uptake value (SUV(max)), biological tumour volume (BTV) and tumour trajectory measures were determined from the PET/CT images of five patients. Compared to retrospective binning (RB), prospective gating approach led to (i) a significant loss in breathing cycles (15%) and (ii) the inconsistency of data binning due to temporal dispersion of triggers (average 396 ms). Consequently, tumour characterization could be impacted. In retrospective mode, SUV(max) was up to 27% higher, where no significant difference appeared in BTV. In addition, prospective mode gave an inconsistent spatial location of the tumour throughout the bins. Improved consistency with breathing patterns and greater motion amplitude of the tumour centroid were observed with retrospective mode. The detection of the tumour motion and trajectory was improved also for small temporal dispersion of triggers. This study shows that the binning mode could have a significant impact on 4D PET images. The consistency of triggers with breathing signals should be checked before clinical use of gated PET/CT images, and our RB method improves 4D PET/CT image quantification.

Routine FDG PET-CT in patients with a high-risk localized melanoma has a high predictive positive value for nodal disease and high negative predictive value for the presence of distant metastases.

BACKGROUND: FDG PET-CT is the superior imaging modality for the detection of visceral metastases (M+) in patients with melanoma. Conflicting evidence exists regarding its role for the initial staging of patients with high risk localized melanoma (large Breslow Thickness (BT) and/or ulceration). OBJECTIVE: To assess the role of routine staging with FDG PET-CT in melanoma patients with localized high risk melanoma. METHODS: Forty-eight consecutive patients with 1 < BT < 4 mm with ulceration and with BT ≥ 4 mm were staged with PET-CT. PET-CT procedures were performed on a GE Discovery ST® scanner. PET-CT findings for regional nodal status and presence of distant metastatic disease were collected. The gold standard for nodal assessment was pathological examination. The gold standard for M+ was conventional imaging and clinical follow-up, confirmed by biopsy whenever feasible. RESULTS: No patient had a positive PET-CT for M+. Six patients (13%) had a non-conclusive PET-CT; none of them presented with M+ within 6 months. Forty-three patients (90%) had a negative PET-CT, amongst them only one patient (2.5%) presented with M+ within a year. Six patients had FDG-avid lymph nodes in the drainage territory of the primary melanoma, either SLNB or lymph node dissection confirmed metastatic nodal involvement. The predictive positive value of PET for regional node involvement was 100%. COMMENTS: FDG PET-CT does not seem to be effective at detecting M+ at baseline staging in patients with high risk localized melanoma. However, it has a high negative predictive value for the presence of M+ at 6 months and a high positive predictive value for nodal involvement.

Fluorodeoxyglucose positron emission tomography fails to detect distant metastases at initial staging of melanoma patients with metastatic involvement of sentinel lymph node.

BACKGROUND: Positron emission tomography (PET) using fluorodeoxyglucose (FDG) has proven to be more sensitive and accurate than other imaging modalities for the detection of distant metastases in patients with melanoma. Sentinel lymph node (SLN) status is the most important prognostic factor in melanoma patients with no evidence of distant metastasis. OBJECTIVES: To assess the rate of distant metastases in patients with a positive SLN biopsy (SLNB). METHODS: Forty-six consecutive patients with a positive SLNB underwent PET or PET-computed tomography within 6 weeks of the SLNB procedure. The patients did not present any clinical sign of nodal involvement or of distant metastasis. PET findings were classified as positive, negative or nonconclusive. RESULTS: No patient had a positive PET scan for distant metastasis. Six patients (13%) had a nonconclusive PET scan; none of them presented distant metastasis within 12 months. Forty patients (87%) had a negative PET scan; among them five (12%) presented with distant metastasis within 12 months. CONCLUSIONS: Fluorodeoxyglucose positron emission tomography failed to detect distant metastases at initial staging in patients with a positive SLNB, even in patients who presented with distant metastases within 12 months after the FDG PET scan. These results could be explained by the low prevalence of macroscopic metastatic disease at this stage and by the important delay between the onset of the spread of microscopic metastatic disease and the identification by PET scan of macroscopic metastatic disease.

Trastuzumab induced in vivo tissue remodelling associated in vitro with inhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinoma model.

BACKGROUND: The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy. Unlike breast cancer, the prognostic role of the human epidermal growth factor receptor-2 (HER-2) in ovarian carcinoma remains controversial. METHODS: The aim of this preclinical study was to further characterise the biological, molecular and cellular effects of trastuzumab (Herceptin) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo. RESULTS: In vitro assessments have shown that trastuzumab treatment inhibited total and phosphorylated HER-2. This was associated with inhibition of the phosphorylated form of phosphatase and tensin homologue (PTEN), mitogen-activated protein kinase and AKT, and the total level of p27(kip). Inhibition of PTEN is associated with phosphorylated MEK1/2 upregulation, suggesting a specific inhibition of the protein phosphatase function of PTEN. Moreover, trastuzumab induced the upregulation of RhoB. These molecular modifications promote inhibition of cell migration and potentially restoration of tumour cell contact inhibition. RhoB induction in NIH-OVCAR-3 control cell lines mimics the molecular and cellular trastuzumab long-time exposition effects. RhoB inhibition in NIH-OVCAR-3 long-time exposed to trastuzumab cell line reverses the cellular and molecular effects observed in this model. In vivo examinations have shown that these changes are also associated with the restoration of structural, morphological and normal functions of the peritoneum of an ovarian carcinoma mouse model. CONCLUSION: These results provide an indication of the mechanisms underlying the anti-tumour activity of trastuzumab that strongly implicate RhoB in an ovarian carcinoma model that does not show HER-2 amplification or overexpression. These findings highlight that trastuzumab effects involve a possible cross-talk between RhoB and PTEN in the early stages of tumour re-growth in a model of micrometastatic ovarian cancer.

Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism.

BACKGROUND: The long-term efficacy of somatostatin analogues on insulinomas has not been studied. DESIGN: A prospective study to evaluate the response of octreotide in 21 patients with hypoglycaemia related to endogenous hyperinsulinism who were not treated by surgery. RESULTS: Reasons for not undergoing surgery were: refusal (n = 3), old age with multiple diseases (n = 5), unlocalized insulinomas (n = 2), malignant unresectable insulinomas (n = 5), multiple insulinomas (n = 3) and diffuse beta-cell disease (n = 3). Hypoglycaemia was responsive to octreotide in 14 of the 21 patients. A short 100-microg octreotide test correctly predicted the efficacy of treatment in six patients with benign insulinomas. Octreoscan scintigraphy was positive in 6 of the 16 patients of whom three were responsive and three unresponsive to octreotide. Octreoscan scintigraphy was negative in 10 of the 16 patients, eight of whom were responsive to octreotide. Subcutaneous octreotide treatment was prolonged for > 6 months (7-144 months, 67 +/- 47 months) in 11 responsive patients. No tachyphylaxis was observed. However, the octreotide dose had to be increased in two patients after 3 and 18 months, respectively. Only one patient suffered from symptomatic biliary lithiasis after 3 years of treatment. CONCLUSION: Long-term octreotide treatment can be used to control hypoglycaemia in patients with endogenous hyperinsulinism who are not eligible for surgery; octreotide efficacy on hypoglycaemia could be predicted by a short 100 microg-octreotide test in patients with benign insulinomas, but was not correctly predicted by Octreoscan scintigraphy.

Defective efficacy of retinoic acid treatment in patients with metastatic thyroid carcinoma.

Radioiodine (I-131) therapy is of proven efficacy for differentiated thyroid carcinoma. However, its efficacy relies on specific uptake mechanisms, which may be lost during the evolution of the disease. Attempts to increase the iodine uptake of such tumors have been made using retinoic acid because it exerts redifferentiating effects on thyrocytes. This study aims to assess the capability of the retinoic acid (RA) treatment to reinforce iodine 131-irradiation efficacy for metastatic and progressive multi-irradiated thyroid cancer. In this clinical prospective study, 11 patients (mean age +/- 1 SD = 61 +/- 12 years, sex ratio M/F = 5/6) with a progressive disease despite iterative surgery and iodine irradiations were treated with 13-cis-retinoic acid (1.5 mg/kg day) over 8 weeks prior to I-131 irradiation. The redifferentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring during RA treatment and qualitative analysis of iodine uptake on the post-therapeutic whole body scan. The clinical usefulness of RA treatment was assessed by clinical follow-up, Tg monitoring, and tumor size. No serious event that could possibly be related to the treatment was reported. The mean follow up time was 24.2 +/- 12 months (range 3-46 months). Iodine uptake was only slightly improved in two patients. Nevertheless, the clinical benefits of RA seem to be very poor. Five patients died of a metastatic disease. Five others presented new clinical evidences of a progressive disease. In conclusion, this prospective study demonstrates the absence of efficacy of I-131 irradiation combined with RA for the treatment of patients with aggressive, rapidly growing metastatic thyroid cancer. Thus, patients with highly aggressive disease, rapidly growing in a short period from 2 to 6 months, should not be considered for RA therapy.

Iodine-131 pharmacokinetics in patients on hemodialysis for end stage renal disease: clinical implications.

AIM: Curative treatment of thyroid cancer is a major issue for patients with end stage renal disease (ESRD) undergoing dialysis because they might not be included in a renal transplant protocol once they have overcome this disease. Since 131I is mostly eliminated by the kidneys, there is concern regarding the toxicity, efficacy and feasibility of 131I-therapy of anuric dialyzed patients. METHODS: This paper reports on 131I uptake and elimination from remnant thyroid tissue (T), salivary glands (SG), stomach (S) and blood, after administration of 3.7 GBq of 131I for 2 patients on twice weekly dialysis for ESRD. RESULTS: Compared to normal renal function patients, radio-iodine recirculation is observed, and SG and blood irradiation is about 6 times higher, but the dose delivered to the thyroid is not significantly enhanced. Dialysis removes more 131I from SG, S and blood than from T. Anticipated dialysis will reduce irradiation by 38% for the blood, 45% for SG and 34% for T. CONCLUSIONS: Therefore, a higher 131I amount could then be used, providing that accurate personalized dosimetry is previously performed using 131I pharmacokinetic models. Concerning radiation protection issues, no significant dialysis equipment contamination is noted, and nurses and medical staff exposure remains below 0.2 mSv.

[The impact of 18F-fluorodeoxyglucose positron emission tomography on the 3D conformal radiotherapy planning in patients with non-small cell lung cancer]. / Intérêt de la tomographie par émission de positons au [18F]-fluoro-2-désoxyglucose dans la détermination des volumes cibles de radiothérapie. Application à l'irradiation conformationnelle des cancers bronchiques non à petites cellules.

Traditional radiation treatment planning relies on density imaging such as Computed Tomography for anatomic information of various structures of interest including target and normal tissues. However, the difficulties to distinguish malignant from normal tissue on CT slides often leads to inaccurate outlining of the GTV and/or to geographic misses. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has shown an increase in both sensitivity and specificity over CT in locoregional staging of patients with non-small cell lung cancer (NSCLC). The co registration of FDG-PET images to the data of the CT planning offers the radiation oncologist the possibility to include functional information into the target outlining. For the treatment of patients with NSCLC, it has been shown that the use of FDG-PET images: 1) modified the shape and volume of radiation fields in 22-62% of cases, mainly due to a better nodal staging and distinction of atelectasis from tumor and; 2) significatively reduced the interobserver and intraobserver variability. This paper reviews the results reported in the literature. Challenges and proposed solutions are discussed.

Granulocyte-macrophage colony-stimulating factor alone or with dacarbazine in metastatic melanoma: a randomized phase II trial.

The potential antitumoral effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) led us to evaluate GM-CSF alone or with dacarbazine (DTIC) in metastatic melanoma in first line randomized phase II. Treatment was arm A: GM-CSF: 5 microg kg(-1), bid, 14 consecutive days every 21 days and arm B: GM-CSF: 5 microg kg(-1), bid, day 2 to day 19 every 21 days and DTIC: 800 mg m(-2), day 1 of each cycle. 32 patients (pts) were included, 15 pts in arm A and 17 in arm B. All pts had visceral metastatic sites. 9 had only one metastatic site. The median number of cycles given was 2 in arm A and 3 in arm B. 100% and 89.4% of the planned dose of GM-CSF was given in arm A and arm B respectively. No objective response was obtained. 19 pts experienced at least WHO grade 3 toxicity. All pts had fever, 29 had a decrease in performance status and 23 had pain. Grade 3 toxicity were fever (38.7%), decrease in performance status (32.3%), pain (19.4%) and dyspnoea (12.5%). In this study, GM-CSF alone or in association with DTIC did not induce any antitumoral activity with subsequent toxicity.

[Radio-guided resection of residual metastatic lymph node from a previously resected neuroendocrine tumor]. / Exérèse radioguidée d'une adénopathie résiduelle métastatique d'une tumeur neuroendocrine antérieurement réséquée.

Neuroendocrine tumors are slowly growing and carry a high risk of recurrence. Somatostatin receptor scintigraphy is considered as the gold standard for preoperative evaluation and postoperative follow-up. The use of an intraoperative detection probe makes easier a complete resection of abdominal residual or recurrent tumor. These resections may be incomplete because of the small size of the tumor and the postoperative adhesions. Radio-guided surgery is recommended in order to reduce the need for reoperation.

A pharmacokinetic interpretation of increasing concentrations of DEHP in haemodialysed patients.

The degree of exposure to DEHP was assessed in 11 patients with chronic renal failure undergoing maintenance haemodialysis. The amount of DEHP leached from the dialyser during a 4-h dialysis session was estimated by monitoring the DEHP blood concentration using a HPLC method. When a patient undergoes a dialysis treatment, the concentration of di-2-ethylhexyl phthalate (DEHP) in venous blood is increased when the blood crosses through the dialysis apparatus. This increase may be explained either because DEHP is not extracted by the dialyser or because DEHP comes from the dialysis bath due to contact of blood against plasticized pipes. To explain the increasing concentration of DEHP during treatment of renal failure using plasticized tubing, we propose a pharmacokinetic compartmental model in order to fit raw data obtained from dialysed patients and to get the amount of DEHP which enters the body by AUC calculations. Results obtained after HPLC analysis show a high degree of interpatient variability in DEHP retained. This amount can reach a toxicity level because of repetitive dialysis treatments over prolonged periods of time. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of haemodialysis tubing.

Consequence of equal absorption, distribution and/or elimination rate constants.

When fitting experimental data to an open one- or two-compartment model, with first order kinetics, it may happen that no optimized value is obtained for model parameters. Several authors pointed out that this case is especially encountered when absorption and elimination coefficients approach each other in a one-compartment model or when absorption and exponential elimination or distribution rate constants are equal in a two-compartment model. We analyze these situations of equal coefficients here. Firstly, dealing with a one-compartment model, we get the concentration in the central compartment after a single oral dose and after successive various doses at various times (first order kinetics). Secondly, dealing with a two-compartment model, also for single or successive various doses, the concentration is expressed when absorption and exponential elimination or distribution rate constants are equal. In all cases, the areas under concentration curves and the mean residence time of the drug are calculated even when cancellation of one exponential term occurs. Furthermore, the concentration at steady-state is taken into account.