Fallibility of tattooing colonic neoplasia ahead of laparoscopic resection: a retrospective cohort study.

INTRODUCTION: Precise geographical localisation of colonic neoplasia is a prerequisite for proper laparoscopic oncological resection. Preoperative endoscopic peri-tumoural tattoo practice is routinely recommended but seldom scrutinised. METHODS: A retrospective review of recent consecutive patients with preoperative endoscopic lesional tattoo who underwent laparoscopic colonic resection as identified from our prospectively maintained cancer database with supplementary clinical chart and radiological, histological, endoscopic and theatre database/logbook interrogation. RESULTS: Some 210 patients with 'tattooed' colonic neoplasia were identified, of whom 169 underwent laparoscopic surgery (mean age 68 years, median BMI 27.8kg/m2, male-to-female ratio 95:74). The majority of tumours were malignant (149; 88%), symptomatic (133; 79%) and proximal to the splenic flexure (92; 54%). Inaccurate colonoscopist localisation judgement occurred in 12% of cases, 60% of which were corrected by preoperative staging computed tomography scan. A useful lesional tattoo was absent in 11/169 cases (6.5%) being specifically stated as present in 104 operation notes (61%) and absent in 10 (5.9%). Tumours missing overt peritumoral tattoos intraoperatively were more likely to be smaller, earlier stage and injected longer preoperatively (p=0.006), although half had histological ink staining. Eight lesions missing tattoos were radiologically occult. Four (44%) of these patients had on-table colonoscopy, and five (55%) needed laparotomy (conversion rate 55% vs 23% overall, p<0.005) with one needing a second operation to resect the initially missed target lesion. Mean (range) operative duration and postoperative length of stay of those missing tattoos compared with those with tattoos was 200 (78-300) versus 188 (50-597) min and 15.5 (4-22) versus 12(4-70) days (p>0.05). CONCLUSIONS: Tattoo in advance of attempting laparoscopic resection is vital for precision cancer surgery especially for radiologically unseen tumours to avoid adverse clinical consequence.

A theoretical investigation into post-operative, intracavitary beta therapy of high-grade glioblastomas using yttrium-90.

Beta therapy with yttrium-90 (90Y) has recently been introduced as a post-operative intra-cavitary treatment for malignant glioblastoma, a generally radioresistant tumour for which cure rates with conventional radiotherapy are usually very disappointing. This short theoretical study investigates the conditions under which 90Y treatment might be most effective and assesses the likely amounts of activity which must be infused in order to successfully cope with the low radiosensitivities which characterize such tumours. The radiobiological and physical analysis is investigated using the linear quadratic (LQ) model and a range of possible scenarios for the distribution and density of the tumour cells surrounding the surgically formed cavities are considered. The results suggest that, in the absence of diffusion of 90Y from the cavity, the activity typically required for 50% tumour cure is well over 40 mCi (1480 MBq), this being considerably more than the clinically determined activities which may be tolerated. Suggestions are provided for improving the versatility of the model.

The social context of smoking: the next frontier in tobacco control?

A better understanding of the social context of smoking may help to enhance tobacco control research and practice.

Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

UNLABELLED: Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population. METHODS: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). RESULTS: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body. CONCLUSION: 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.

Contribution to red marrow absorbed dose from total body activity: a correction to the MIRD method.

UNLABELLED: The contribution to red marrow absorbed dose from beta-emitting radionuclides distributed uniformly in the total body can be overestimated using either MIRD 11 or MIRDOSE3. The S value assigned to the red marrow target region from activity distributed in the remainder of the body is of particular concern. The assumption that the specific absorbed fraction for total body irradiating red marrow and other skeletal tissues is the inverse of the total-body mass can result in an inappropriate remainder-of-body contribution to marrow dose. We evaluated differences in the calculation of marrow dose using MIRD 11 and MIRDOSE3 formulations and developed methods to correct the results from either to remove inappropriate contributions. When bone takes up significantly less activity than is predicted from an apportionment of remainder-tissue activity based on mass, the standard remainder-of-body correction may substantially overestimate the electron component of the S value from remainder tissues to red marrow using either MIRD 11 or MIRDOSE3. If bone takes up activity, this contribution is negligible using MIRD 11 S values but remains with MIRDOSE3 S values. This overestimate can be significant, particularly when the residence time of activity in the remainder of the body is much higher than in the red marrow and a different correction is needed. As the ratio of the remainder of body to marrow residence time is lowered, the overestimate becomes less significant. CONCLUSION: In this article, we show the magnitude of this overestimate (which is most important for nuclides with large "nonpenetrating" emission components and for pharmaceuticals that have a large ratio of remainder of body to marrow residence times), show the appropriate corrections to be made in each case, and propose a new method for calculating marrow dose contributions that will avoid this complication in future applications. Because all models give approximate doses for real patients, with uncertainties within those involved in these corrections, we do not suggest that changes be made to existing marrow dose estimates. We suggest only that future calculations be as accurate as possible.

Rats with hypothalamic obesity are insensitive to central leptin injections.

Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness.

Radiation dosimetry of a 99mTc-labeled IgM murine antibody to CD15 antigens on human granulocytes.

UNLABELLED: 99mTc-labeled anti-stage specific embryonic antigen-1 (anti-SSEA-1) is an injectable IgM antibody derived from mice. It binds to CD15 antigens on some granulocytic subpopulations of human white blood cells in vivo after systemic administration. The purpose of this study was to measure biodistribution of 99mTc-labeled anti-SSEA-1 and perform radiation dosimetry in 10 healthy human volunteers. METHODS: Transmission scans and whole-body images were acquired sequentially on a dual-head camera for 32 h after the intravenous administration of about 370 MBq (10.0 mCi) of the radiopharmaceutical. Renal excretion fractions were measured from 10 to 14 discrete urine specimens voided over 27.9 +/- 2.0 h. Multiexponential functions were fit iteratively to the time-activity curves for 17 regions of interest using a nonlinear least squares regression algorithm. The curves were integrated numerically to yield source organ residence times. Gender-specific radiation doses were then estimated individually for each subject, using the MIRD technique, before any results were averaged. RESULTS: Quantification showed that the kidneys excreted 39.5% +/- 6.5% of the administered dose during the first 24 h after administration. Image analysis showed that 10%-14% of the radioactivity went to the spleen, while more than 40% went to the liver. Residence times were longest in the liver (3.37 h), followed by the bone marrow (1.09 h), kidneys (0.84 h) and the spleen (0.65 h). The dose-limiting organ in both men and women was the spleen, which received an average of 0.062 mGy/MBq (0.23 rad/mCi, range 0.08-0.30 rad/mCi), followed by the kidneys (0.051 mGy/MBq), liver (0.048 mGy/MBq) and urinary bladder (0.032 mGy/MBq). The effective dose equivalent was 0.018 mSv/MBq (0.068 rem/mCi). CONCLUSION: The findings suggest that the radiation dosimetry profile for this new infection imaging agent is highly favorable.

The need for better methods to determine release criteria for patients administered radioactive material.

In current NRC regulations, three options exist that may be used to determine release criteria for patients administered radioactive materials. Absorbed dose estimates may be based on administered activity, measured dose rate, or on patient-specific calculations. All of these methods proposed by the NRC can lead to overestimation of the dose equivalent to others due to their oversimplified nature. The primary oversimplifications are the use of a point source methodology and using the measured surface entrance dose rate to determine whole body dose. In order to show the inaccuracy of these oversimplifications for 131I, results using Monte Carlo radiation transport analysis with simplified anthropomorphic mathematical phantoms were determined. These results were then compared to actual patient measurements and the results of point source analysis. The measurement data were taken from 49 131I radioimmunotherapy patients. The point source calculations were performed using well established methodologies and using the same assumptions as in the NRC regulations for patient release criteria. Monte Carlo results were obtained by implementing two simplified 70 kg anthropomorphic phantoms and performing radiation transport simulation. The activity in the "patient" phantom was assumed to be localized in the abdominal region to correspond to the activity localization seen in the radioimmunotherapy patients who were measured. Dose equivalents per unit cumulated activities were determined for 131I using the various methods. The relationship between measured dose equivalent per unit cumulated activity and whole body dose equivalent per unit cumulated activity was also investigated using Monte Carlo analysis. The point source method as implemented by the NRC yields an estimated dose equivalent per unit cumulated activity of 1.6 x 10(-8) mSv MBq(-1) s(-1) at 1 m (2.2 x 10(-4) rem mCi(-1) h(-1) at 1 m), and the Monte Carlo based method yielded a whole body dose equivalent per unit cumulated activity in the target phantom of 6.8 x 10(-9) mSv MBq(-1) s(-1)(9.0 x 10(-5) rem mCi(-1) h(-1)) for abdominal localization of activity in the source phantom. The measurements of the radioimmunotherapy patients yielded an average result of 1.0 x 10(-8) mSv MBq(-1) s(-1) (13 x 10(-4) rem mCi(-1) h(-1)). When corrected for the difference between measured surface dose equivalent and whole body dose equivalent as determined by Monte Carlo analysis, these measurements represent a whole body dose equivalent per unit cumulated activity of about 6.2 x 10(-9) mSv MBq(-1) s(-1) (8.1 x 10(-5) rem mCi(-1) h(-1)). Based on these results, the current NRC dose-based methodology for the release of patients administered radioactive materials significantly overestimates the dose equivalent to others from 131I therapy patients.

Radiation absorbed dose to the embryo/fetus from radiopharmaceuticals.

Radiation protection practice requires the knowledge of estimated absorbed radiation doses to aid in the understanding of the potential detriment of various exposures. In nuclear medicine, the radiation doses to the internal organs of the subject are commonly calculated using the MIRD methods and equations. The absorbed dose to the embryo or fetus has long been an area of concern. The recent release of the pregnant female phantom series, and its incorporation into the MIRDOSE 3 computer software, has made possible the estimation of absorbed doses from radionuclides in the body to the fetus in early pregnancy and at 3, 6, and 9 mo gestation. A survey of several major medical institutions was made to determine the radiopharmaceuticals which might be given, whether intentionally or not, to women of childbearing years. Biokinetic data for these radiopharmaceuticals were gathered from various documents and other resources, and the absorbed doses to the embryo and fetus at these different stages of gestation from radiations originating within the mother's organs were estimated. In addition, information about activity distributed within the placenta and fetus was included where quantitative data were available. These absorbed dose estimates can be used to evaluate the risk associated with the use of different radiopharmaceuticals so that a more informed evaluation of the risks and benefits of the different procedures may be made. Further research is needed into the mechanisms and quantitative aspects of the placental transfer of many radiopharmaceuticals.

Lesions associated with mineral deposition in the lymph node and lung of the dog.

This report includes details of the clinical and pathologic features of 31 dogs with a range of systemic illness and granulomatous lymphadenopathy associated with the presence of birefringent crystalline material within lymph nodes. Similar crystalline material was found in the lymph nodes of dogs with lymphoma (n = 9) and as an incidental finding within the canine lung (n = 9). The mineral content of these crystals was determined by electron microprobe analysis and interpreted in light of the composition of known geological or human-made compounds. A wide range of elements was identified including silicon, sulfur, copper, calcium, and aluminium, with lesser proportions of phosphorus, sodium, potassium, iron, magnesium, titanium, nickel, and chromium. Many of these compounds may have originated from exogenous natural and human-made sources, but some compounds (notably phosphates and sulfates) are uncommon or not found in nature and may have been formed within the tissues of the body (biomineralization). The inflammatory response induced by the presence of these minerals within lymphoid tissue may trigger altered immunoregulation, accounting for the spectrum of disease observed.

Regulation of differentiation and protein kinase C expression in 3T3 T proadipocytes: effects of TGF-beta and transformation.

We are studying the mechanisms that regulate proliferation and differentiation of normal 3T3 T proadipocytes and neoplastically transformed clones which have lost the ability to differentiate. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and transforming growth factor beta (TGF-beta) are known inhibitors of the same step of the differentiation process in 3T3 T cells. Here, we examined the expression of the phorbol ester receptor/protein kinase C (PKC) during adipocytic differentiation of 3T3 T cells and its modulation by the differentiation inhibitor TGF-beta. PKC receptor assays were performed using a tritiated analogue of TPA and it was found that PKC receptor levels decreased approximately threefold during differentiation. Northern blot analyses revealed an even greater decrease of PKC transcripts during differentiation. TGF-beta inhibited not only differentiation, but the differentiation-dependent decrease in PKC levels as well. Transformed 3T3 T cells which have lost the ability to differentiate were found to express aberrant levels of PKC. The data suggest that TGF-beta may inhibit differentiation via a PKC-dependent pathway and that disruption of normal PKC levels or its regulation may be involved in the loss of differentiation control in transformed 3T3 T cells.

Loss of differentiation control in transformed 3T3 T proadipocytes.

Nontransformed 3T3 T mesenchymal/proadipocyte stem cells can be readily induced to differentiate, yet previous work has shown that 3T3 T cells that are spontaneously or virally transformed not only lose their normal growth control mechanisms but also lose the ability to differentiate. Loss of growth control can be due to autocrine mechanisms in some transformed cells, but the mechanisms involved in disrupting differentiation control are poorly understood. Our goal is to further define the growth and differentiation defects that arise in neoplastically transformed cells and the mechanisms underlying those defects. For example, exogenous transforming growth factor beta and tumor necrosis factor, both of which are secreted aberrantly by some tumor cells, are known inhibitors of different steps of the normal 3T3 T adipocyte differentiation process, suggesting a potential role as autocrine factors in disrupting differentiation of transformed 3T3 T cells. In the current study we transformed 3T3 T cells in vitro with chemical or UV irradiation treatment in order to determine if the acquisition of the transformed phenotype after these treatments is also associated with loss of differentiation control as it is with spontaneously or virally transformed cells. Four chemically and two UV-treated 3T3 T cell lines were isolated from type III foci and all have been found to be tumorigenic in syngeneic animals and to have lost the ability to differentiate. Relative to the parental cell line the differentiation abilities of the transformed clones ranged from 0 to less than 5%. In this regard, we also analyzed the normal and aberrant expression of three growth factors and differentiation inhibitors in transformed cells. Both transforming growth factor alpha and beta were found to be expressed in non-transformed 3T3 T cells as determined by Northern blot analyses. In addition, both were found to be down-regulated during differentiation of 3T3 T cells. Transformed/differentiation-defective 3T3 T cells expressed varied levels of transforming growth factor alpha and beta. Three of the new transformed clones expressed particularly high levels of transforming growth factor alpha. Very low levels of tumor necrosis factor expression were found in the normal cells and the transformed cells appeared to express tumor necrosis factor at similar levels. In contrast, none of the transformed cells expressed any of the differentiation-specific genes tested (lipoprotein lipase, glycerol-3-phosphate dehydrogenase, etc.). Even a transformed clone which could undergo growth arrest but not morphological differentiation expressed no differentiation-specific genes. Together, these data suggest that neoplastic transformation in general disrupts differentiation control.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuropsychological abnormalities in patients with pituitary tumours.

Neuropsychological assessment of 65 patients with pituitary tumours revealed impairment of memory and executive function. This did not appear to be related to the size or type of tumour or the effects of radiotherapy or surgery. It is possible that the problems arose from multiple unconnected factors but this observation lends support to the suggestion that pituitary or hypothalamic hormones have a role in the modulation of memory and behavioural pathways. Whatever the cause, neuropsychological impairment is common in patients with pituitary tumours and is an aspect of their disability which has received insufficient attention in the past.

TGF-beta blocks early but not late differentiation-specific gene expression and morphologic differentiation of 3T3 T proadipocytes.

Transforming growth factor-beta (TGF-beta) inhibits morphologic differentiation of BALB/c 3T3 T cells as well as other proadipocyte models. Our prior studies suggested that TGF-beta may act only during the early stages of differentiation induction. However, we did not determine whether TGF-beta was differentially effecting expression of any of the various differentiation-specific genes or if it could cause down-regulation of these genes in differentiated cells. Therefore, in the current study we tested the effects of exogenous TGF-beta (0.01-5.0 ng/ml) on morphologic differentiation and on differentiation-dependent gene expression (Northern and slot blot analyses) at various times during differentiation. When induced to differentiate, 3T3 T cells first undergo predifferentiation growth arrest and from this state molecular, biochemical, and morphological differentiation proceeds. Here it was found that when added prior to the onset of differentiation, TGF-beta was a potent inhibitor or morphologic differentiation as well as of the expression of differentiation-specific genes such as lipoprotein lipase (LPL) and glycerol-3-phosphate dehydrogenase (GPD). However, once morphologic differentiation began, TGF-beta was ineffective in blocking differentiation. In addition, exposure of fully differentiated cells to TGF-beta for up to 72 hours caused no decrease of differentiation-specific genes and even a 7-day treatment caused no morphologic dedifferentiation. Tumor necrosis factor also had no detectable effect on fully differentiated cells.