Evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for adjuvant radiotherapy in breast cancer.

BACKGROUND: The European Society of Medical Oncology (ESMO) has suggested using the ESMO-Magnitude of Clinical Benefit Scale (MCBS) to grade the magnitude of clinical benefit of cancer therapies. This approach has not been applied to radiation therapy (RT) yet. We applied the ESMO-MCBS to experiences describing the use of RT to assess (1) the 'scoreability' of the data, (2) evaluate the reasonableness of the grades for clinical benefit and (3) identify potential shortcomings in the current version of the ESMO-MCBS in its applicability to RT. MATERIALS AND METHODS: We applied the ESMO-MCBS v1.1 to a selection of studies in radiotherapy that had been identified as references in the development of American Society for Radiation Oncology (ASTRO) evidence-based guidelines on whole breast radiation. Of the 112 cited references, we identified a subset of 16 studies that are amenable to grading using the ESMO-MCBS. RESULTS: Of the 16 studies reviewed, 3/16 were scoreable with the ESMO tool. Six of 16 studies could not be scored because of shortcomings in the ESMO-MCBS v1.1: (1) in 'non-inferiority studies', there is no credit for improved patient convenience, reduced patient burden or improved cosmesis; (2) in 'superiority studies' evaluating local control as a primary endpoint, there is no credit for the clinical benefit such as reduced need for further interventions. In 7/16 studies, methodological deficiencies in the conduct and reporting were identified. CONCLUSIONS: This study represents a first step in determining the utility of the ESMO-MCBS in the evaluation of clinical benefit in radiotherapy. Important shortcomings were identified that would need to be addressed in developing a version of the ESMO-MCBS that can be robustly applied to radiotherapy treatments. Optimization of the ESMO-MCBS instrument will proceed to enable assessment of value in radiotherapy.

Long-Term Safety of Transplanting Human Bone Marrow Stromal Cells into the Extravascular Spaces of the Choroid of Rabbits.

Incurable neuroretinal degeneration diseases cause severe vision loss and blindness in millions of patients worldwide. In previous studies, we demonstrated that transplanting human bone marrow stromal cells (hBMSCs) in the extravascular spaces of the choroid (EVSC) of the Royal College of Surgeon rats ameliorated retinal degeneration for up to 5 months. Assessing the safety of hBMSC treatment and graft survival in a large animal is a crucial step before initiating clinical trials. Here, we transplanted hBMSCs into the EVSC compartment of New Zealand White rabbits. No immunosuppressants were used. Transplanted cells were spread across the EVSC covering over 80 percent of the subretinal surface. No cells were detected in the sclera. Cells were retained in the EVSC compartment 10 weeks following transplantation. Spectral domain optical coherence tomography (SD-OCT) and histopathology analysis demonstrated no choroidal hemorrhages, retinal detachment, inflammation, or any untoward pathological reactions in any of transplanted eyes or in the control noninjected contralateral eyes. No reduction in retinal function was recorded by electroretinogram up to 10 weeks following transplantation. This study demonstrates the feasibility and safety of transplanting hBMSCs in the EVSC compartment in a large eye model of rabbits.

A minimally invasive adjustable-depth blunt injector for delivery of pharmaceuticals into the posterior pole.

PURPOSE: To investigate the feasibility and safety of a novel minimally invasive adjustable-depth blunt injector for pharmaceuticals delivery into the posterior segment. METHODS: Indocyanine green (ICG), sodium fluorescein and iron oxide nanoparticles (IONPs) were injected using the new injector into the extravascular spaces of the choroid (EVSC) compartment of rabbits and cadaver pig eyes. Spectral domain optical coherence tomography (SD-OCT), fundus imaging and histology analysis were performed for assessment of injection safety and efficacy. RESULTS: Indocyanine green, fluorescein and IONPs were detected across the EVSC in rabbit eyes, covering over 80 per cent of the posterior eye surface. Injected IONPs were retained in the EVSC for at least 2 weeks following injection. No retinal detachment, choroidal haemorrhage or inflammation was detected in any of the injected eyes. In cadaver pig eyes, ICG was detected across the EVSC. CONCLUSIONS: This novel minimally invasive delivery system may be used to safely deliver large volumes of pharmaceuticals into a new treatment reservoir compartment - the EVSC which can serve as a depot, in close proximity to the retina, covering most of the surface of the back of the eye without insertion of surgical instruments under the central retina. This system is predicted to enhance the therapeutic effect of treatments for posterior eye disorders.

[A novel system for minimally invasive transplantation of bone marrow derived stem cells as a thin layer in the subretina and extravascular spaces of the choroid--for treatment of retinal degeneration].

BACKGROUND: Incurable retinal degenerations affect millions worldwide. Stem cell transplantation rescued visual functions in animal models of retinal degeneration. In those studies, cells were transplanted in subretinal "blebs". A limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection sites. PURPOSE: To develop a minimally-invasive surgical system for stem cell transplantation in the subretina and extravascular spaces of the choroid. METHODS: A novel syringe with flexible needle and adjustable pin was developed. Human bone marrow mesenchymal stem cells [hBM-MSCs) were transplanted in the eyes of RCS rats and NZW rabbits through a longitudinal triangular scleral incision. No immunosuppressants were used. Retinal function was determined by electroretinogram analysis and retinal structure was determined by histological analysis and optical coherence tomography (OCT). RESULTS: Transplanted cells were identified as a thin layer across the subretina and extravascular spaces of the choroid. In RCS rats, cell transplantation delayed photoreceptor degeneration across the entire retina and significantly enhanced retinal functions. No changes in retinal functions were recorded in rabbits following transplantation. No retinal detachment or choroidal hemorrhages were observed. CONCLUSIONS: The novel syringe facilitates cell transplantation across the subretina and extravascular spaces of the choroid using a minimally-invasive procedure. Human BM-MSC transplantation using this system ameliorates retinal degeneration in the animal model. DISCUSSION: This new transplantation system may increase the therapeutic effect of other cell-based therapies and therapeutic agents. This study is expected to lead directly to phase I clinical trials for autologous hBM-MSCs transplantation in patients with retinal degeneration.

Attenuation of cue-induced smoking urges and brain reward activity in smokers treated successfully with bupropion.

Twenty-two regular smokers (15+ cigarettes per day) were treated with bupropion and group therapy for 2 months. Subjects underwent positron emission tomography (PET) studies using measures of brain global and regional glucose metabolism (regional cerebral metabolic rates of glucose [rCMRglc]) with [18F]-Fluorodeoxyglucose (FDG) twice, after watching a videotape showing smoking scenes and after watching a control movie in counter-balanced order. A questionnaire of smoking urges (QSU) was filled in before and after watching both the movies. Changes in brain metabolic rates of FDG were analysed using Statistical Parametric Maps (SPM 2) in 11 smokers who abstained from smoking in comparison with 11 smokers who continued to smoke during the second month of treatment. Still-smokers had higher craving scores after watching the videotape showing smoking scenes compared with non-smokers. Second, watching the videotape showing smoking scenes compared with the control videotape in still-smokers resulted in increased metabolic rates in the striatum, thalamus and midbrain. Third, the ratings of the urge to smoke cigarettes while watching the videotape showing smoking scenes in still-smokers were associated with brain metabolic activity in the ventral striatum, anterior cingulate, orbitofrontal cortex, middle temporal lobe, hippocampus, insula, midbrain and thalamus. In conclusion, successfully treated smokers showed attenuated craving and reduced activity in the mesolimbic reward circuit.

A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

Integrated 18F-fluorodeoxyglucose positron emission tomography and computerized tomography in endodermal sinus tumor.

Application of an in-line positron emission tomography and computerized tomography (PET-CT) in endodermal sinus tumor (EST) is described in this study. CASE 1: A young female with massive ascites postovarian mass resection had elevated alpha-fetoprotein (AFP) serum levels. Following a positive PET-CT study with increased (18)F-fluorodeoxyglucose (FDG) uptake, a CT-guided core biopsy of a peritoneal mass was performed. EST was diagnosed histologically. The patient was disease free after chemotherapy. Follow-up PET-CT was negative in keeping with no viable tumor tissue. CASE 2: A large pelvic mass diagnosed histologically as primarily EST was removed in a teenage patient with elevated AFP levels. PET-CT showed diffuse abdominal spread of FDG uptake, suggesting extensive peritoneal seeding. The patient was disease free after chemotherapy. Follow-up PET-CT was negative. EST is an FDG-avid tumor. PET-CT delineated the prechemotherapy tumor extent adequately ruled out the presence of residual tumor after a successful treatment.

PET-CT findings in surgically transposed ovaries.

The aim of this study is to present the PET/CT findings of surgically transposed ovaries. PET/CT studies and associated abdominal imaging studies of seven women, aged 28-43 years, with 11 transposed ovaries were retrospectively reviewed. Attention was directed to the location and the 18F-Fluorodeoxyglucose (FDG) avidity of the transposed ovaries. On the CT part of the PET/CT, location of the transposed ovaries was in the ipsilateral iliac fossa or paracolic gutter abutting the anterior aspect of the ipsilateral colon (n = 6), posterolateral to the cecum (n = 4) and in the anterior abdominal cavity (n = 1). Ovaries were of soft-tissue density (n = 10 with a hypodense region in two) and one was cystic. In three patients, the transposed ovary was associated with increased FDG uptake with standard uptake values ranging from 2.4 to 4.8. Two of the latter patients had more than one PET/CT study. FDG uptake altered between studies, probably related to the performance of the study on different phases of the cycle. Menstrual history in one of the patients confirmed that the study was performed at the ovulatory-phase of the cycle. To conclude, a transposed ovary may appear on a PET-CT study as a mass with occasionally increased FDG uptake that may be related to its preserved functionality. Physicians interpreting PET/CT should be aware of surgically transposed ovaries in young female patients to avoid misdiagnosing it as tumour.

Mesenteric panniculitis in oncologic patients: PET-CT findings.

The aim of this study is to assess the role of PET/CT in differentiating between mesenteric panniculitis (MP) and co-existing MP and mesenteric tumoural involvement. A total of 33 PET/CT examinations, of 19 oncologic patients (16 men and three women with ages ranging from 48 years to 83 years) with findings of MP on the CT part of the study were retrospectively reviewed. The FDG uptake in mesenteric nodules was recorded. The final diagnosis of malignant mesenteric involvement was based on clinical and imaging follow-up. Based on the FDG uptake in mesenteric nodules, patients were categorized as group A: increased mesenteric uptake (n=8) and group B: no mesenteric uptake (n=11). In seven of the eight patients in group A, a co-existing MP and mesenteric tumour involvement was found: one patient had a recurrent cervical carcinoma and the other six patients had lymphoma. In four of these six patients, the positive PET findings disappeared on follow-up PET/CT with complete remission while the CT findings of the MP remained unchanged. In the other two, the PET findings progressed along with clinical deterioration. In the last patient of group A, with rectal carcinoma without evidence of recurrence, the mesenteric FDG uptake was a false positive uptake. In all 11 patients with CT findings of MP and negative PET, no malignant involvement of the mesentery was diagnosed. To conclude, a negative PET has a high diagnostic accuracy in excluding tumoural mesenteric involvement while increased uptake suggests the co-existing of mesenteric deposits, particularly in patients with lymphoma.

Is CT scan still necessary for staging in Hodgkin and non-Hodgkin lymphoma patients in the PET/CT era?

BACKGROUND: The clinical impact of fused PET/CT data on staging and patient management of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) was assessed. PATIENTS AND METHODS: A total of 103 consecutive patients with newly diagnosed NHL (n = 68) and HD (n = 35) were assessed retrospectively. Three comparisons were carried out in an attempt to assess the added value of each modality. RESULTS: For NHL patients, there were significant differences between staging by CT versus PET/CT (P = 0.0001). Disease was upstaged by PET/CT in 31% (mostly in stages I and II) and downstaged in only 1% of patients. In 25% of the patients, the treatment approach was changed according to CT versus PET/CT findings. For HD patients, disease was upstaged by PET/CT in 32% and downstaged by PET/CT in 15% (P = NS). As for NHL, upstaging by PET/CT versus CT was evident mostly for stages I and II. The treatment strategy was altered as determined by CT versus PET/CT in 45% of the patients. CONCLUSIONS: The addition of PET/CT to CT changed the management decisions in approximately a quarter of NHL and a third of HD patients, mostly in early disease stages. Thus, PET/CT performed as the initial staging procedure may well obviate the need for additional diagnostic CT in the majority of patients.

Lymphoscintigraphic sentinel node identification in patients with breast cancer: the role of SPECT-CT.

PURPOSE: Lymph node status is a major factor in determining the stage, appropriate therapy and outcome in patients with breast cancer. It is therefore of clinical importance to accurately identify all sentinel nodes (SNs) for each individual tumour before surgery. The purpose of this study was to assess the role of SPECT-CT lymphoscintigraphy in SN identification in patients with breast cancer. METHODS: Lymphoscintigraphy comprising planar and SPECT-CT acquisition was performed in 157 consecutive patients with breast cancer (mean age 54.7+/-10.6, range 27-81 years) with a palpable mass (n=100), with a non-palpable mass (n=52) or post lumpectomy (n=5). Planar and SPECT-CT images were interpreted separately and the two imaging techniques were compared with respect to their ability to identify hot nodes. RESULTS: Planar imaging alone was negative for identification of hot nodes in 15% of the patients. SPECT-CT alone was negative in 10% and both techniques were negative in 9% of the patients. Forty-six of the total of 361 (13%) hot nodes identified by lymphoscintigraphy were detected only on SPECT-CT, including 21 nodes obscured by the scattered radiation from the injection site, nine adjacent nodes misinterpreted on planar images as a single node and 16 nodes which were missed on planar images and detected on SPECT data. SPECT-CT detected additional sites of drainage unexpected on planar images, including axillary (n=23 patients), internal mammary (n=5 patients), interpectoral (n=3 patients) and intramammary (n=2 patients) lymph node sites. Fourteen of the 329 (4%) hot lesions seen on planar images were false positive non-nodal sites of uptake that were accurately assessed by SPECT-CT and further validated by surgery. In a single patient, SPECT-CT was negative while planar images identified the SN. CONCLUSION: SPECT-CT may improve the preoperative localisation of draining nodes in patients with breast cancer. It may detect hot nodes missed by planar imaging, exclude non-nodal false positive sites of uptake and accurately localise axillary and extra-axillary nodes.

Intraperitoneal heated chemotherapy affects healing of experimental colonic anastomosis: an animal study.

BACKGROUND: The peritoneal spread of cancer is a well-known entity carrying a dismal prognosis. A new therapeutic approach is the combination of cytoreduction with heated intraperitoneal chemotherapy (HIPC). The risk of an intra-abdominal anastomosis in the presence of such chemotherapy is recognized clinically but the experimental data on the subject are lacking. The aim of this study is to examine the influence of chemotherapy and hyperthermia on the healing of colonic anastomosis. MATERIALS AND METHODS: Colonic anastomosis were performed in four groups of male Wistar rats: (1) control (operation only), (2) HIPC with saline, (3) with mitomycin C (MMC), and (4) with cisplatinum. HIPC was performed using a closed circulation system at 40 degrees C over 20 min. Anastomotic strength was tested on day 4, 7, 10, and 21. RESULTS: The bursting pressure of anastomoses in rats treated by HIPC was significantly lower than in controls. On day 4, it was 54.8 mm Hg, 38 mm Hg, 18 mm Hg, and 14.8 mm Hg in groups 1-4, respectively, while on day 7 it was 170 mm Hg, 188 mm Hg, 83 mm Hg, and 19 mm Hg, respectively (P < 0.01). The difference decreased on day 10 and almost vanished on day 21. HIPC with cisplatinum had the worst effect on anastomotic healing during the early postoperative period. CONCLUSIONS: Cytoreduction and HIPC are gaining popularity. However, the use of heated chemotherapy has a detrimental effect on the strength of colonic anastomosis, especially during the early postoperative period (until day 10). This may cause anastomotic failure and postoperative morbidity. Therefore, careful selection and avoidance of unnecessary anastomoses are mandatory.

The new technology of combined transmission and emission tomography in evaluation of endocrine neoplasms.

UNLABELLED: The clinical value of a novel technology of combined transmission and emission tomography (TET) was assessed in patients with endocrine tumors. METHODS: TET technology, which combines simultaneous acquisition of SPECT and CT images, using the same imaging device, allows correct fusion of images of both modalities. TET was performed on 27 patients with known or suspected endocrine tumors. The radiopharmaceuticals used for the emission part of the study were chosen according to the tumor type: (111)In-octreotide for patients with neuroendocrine tumors (n = 10), (99m)Tc-sestamibi for patients with primary hyperparathyroidism (n = 8), (131)I for patients with thyroid cancer (n = 4), and (123)I-metaiodobenzylguanidine and (75)Se-cholesterol for patients with adrenal masses (n = 3 and n = 2, respectively). The additional information provided by TET compared with scintigraphy was assessed for both image interpretation and clinical utility. RESULTS: TET did not provide any additional data in 16 patients (59%), including 5 patients with normal scintigraphy. In 11 patients (41%) with abnormal SPECT findings, TET improved image interpretation by providing a better anatomic localization of SPECT-detected lesions. It showed unsuspected bone involvement in 4 patients, it identified the organs involved and the relationship of the lesions to neighboring structures in 5 patients, and it differentiated physiologic uptake from tumor uptake in 2 patients. TET provided additional information of clinical value in 9 patients (33%). It assisted in better planning of surgery in 2 patients with neuroendocrine tumors and in 2 patients with ectopic parathyroid adenomas. It changed the treatment approach in 2 patients with neuroendocrine tumors and 1 patient with thyroid carcinoma, and it altered prognosis in 2 patients with thyroid malignancy. CONCLUSION: TET enhances the already unique role of nuclear medicine procedures in the assessment and management of patients with endocrine neoplasms.

Renal multigated spectral Doppler imaging before and after captopril challenge.

RATIONALE AND OBJECTIVES: A new method of measurement, simultaneous multigated spectral Doppler imaging (MSDI), was used to quantify the hemodynamic changes in kidneys after administration of captopril. METHODS: Forty kidneys in 22 hypertensive patients were included in the study. All underwent MSDI and scintigraphy before and after administration of captopril. RESULTS: With scintigraphy used as the gold standard for diagnosing renal artery stenosis (RAS), three kidneys were found to be positive for RAS. Multigated spectral Doppler imaging detected a decrease in the resistive index after administration of captopril in all patients with RAS and correctly excluded RAS in one patient who was diagnosed as having RAS on scintigraphy. The resistive index was increased after captopril administration in normally functioning kidneys and was unchanged in kidneys with impaired function. CONCLUSIONS: With further supportive evidence, MSDI may prove to be a powerful tool for the acquisition of resistive index information and may increase the value of the resistive index as a physiological hemodynamic parameter in the evaluation of normal and abnormal conditions.

Clinical applications of gamma-detection probes - radioguided surgery.

Radioguided surgery (RGS) is a surgical technique that enables the surgeon to identify tissue "marked" by a radionuclide before surgery, based on the tissue characteristics, the radioactive tracer and its carrying molecule, or the affinity of both. Thus, yet another tool has been added to the inspection and palpation traditionally used by the surgeon. Current clinical applications of radioguided surgery are: radioimmunoguided surgery (RIGS) for colon cancer, sentinel-node mapping for malignant melanoma (which has become state-of-the-art), sentinel-node mapping for breast, vulvar and penile cancer, and detection of parathyroid adenoma and bone tumour (such as osteid osteoma). Although the same gamma-detecting probe (GDP) may be used for all these applications, the carrier substance and the radionuclide differ. MoAb and peptides are used for RIGS, sulphur colloid for sentinel-node mapping, iodine-125 for RIGS, technetium-99m for sentinel node, parathyroid and bone. The mode of injection also differs, but there are some common principles of gamma-guided surgery. RIGS enables the surgeon to corroborate tumour existence, find occult metastases, and assess the margins of resection; this may result in a change on the surgical plan. Sentinel lymph-node (SLN) scintigraphy for melanoma guides the surgeon to find the involved lymph nodes for lymph-node dissection. SLN for breast cancer is being investigated with promising results. This procedure has also changed the outlook of lymph-node pathology by giving the pathologist designated tissue samples for more comprehensive examination. Gamma-guided surgery will result in more accurate and less unnecessary surgery, better pathology and, hopefully, in better patient survival.

Single-injection gamma probe-guided sentinel lymph node detection in 40 melanomatous lymphadenectomies.

The aim of the study was to evaluate single-injection gamma probe-guided sentinel lymph node (SLN) detection, applied in 40 melanomatous selective sentinel lymphadenectomies (SSLNDs). Thirty-four patients underwent preoperative lymphoscintigraphy, intraoperative SLN identification by a gamma-detecting probe and blue dye, and SLN sampling. The first 11 patients underwent formal lymphadenectomy. The following 23 patients underwent formal lymphadenectomy only when the SLN was involved with tumor. Evaluation included hematoxylin-eosin-stained slide microscopy, monoclonal antibodies to S-100 protein, and the melanoma-associated antigen HMB45. In all patients, single or multiple SLNs were identified by the gamma-detecting probe. However, only 82.5% of these specimens included blue-stained nodes. None of the non-SLN specimens were the exclusive site of metastases. Four patients had metastases in their SLN specimen without non-SLN involvement. We conclude that SSLND can be performed easily and precisely with the exclusive use of the gamma-detecting probe. A single injection is feasible, and decreases operating room contamination and patient discomfort.