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The combination of doxorubicin and cisplatin showed response rate varying between 0-33% [14. Although, there was not a single complete response, there were three partial responses lasting for 9, 10 and 18 months. There was no complete response either in terms of tumour size reduction or decrease in the levels of tumour markers. Two patients had partial biochemical response and reduction in tumour size; one had partial biochemical response with stable tumour size, while three had progressive disease. The response was partial regression of tumours in three patients (at 11, 9 and 3 months) and stabilization of the disease in 11 patients. Yet another combination of doxorubicin (45-70 mg/m2), imidazole carboxamide (600-800 mg/m2), vincristine (2 mg) and cyclophosphamide (600-750 mg/m2) has been tried. There was progressive improvement in three patients and one patient had progressive disease [14. Hence although there is no hope of a complete response, it appears that single or combination drug regimes can in a small number of subjects induce a partial response or stabilize disease for some months. There is not enough data to indicate whether the partial response is transient or long lasting. Conclusion the response to chemotherapy in patients with advanced differentiated thyroid carcinoma is not encouraging. Doxorubicin, cisplatin, and etoposide alone or in combination are the drugs currently considered effective. However, side effects may be severe and chemotherapy cannot as yet be routinely recommended. Chemotherapy in combination with external radiotherapy should be tried in cases of anaplastic thyroid cancer and chemotherapy remains the only alternative, though not very effective, in cases of aggressive and widespread medullary thyroid cancer. Chemotherapy in metastatic non-anaplastic thyroid cancer: Experience at the Institut Gustave-Roussy, Tumouri 76 (1990) 480-483. The success of this management structure is highly dependent on the bulk of thyroid tissue left behind after thyroidectomy and the effectiveness of ablation. Its disadvantages include relatively low specificity and sensitivity, its tendency to induce stunning and the need for intensive patient preparation including withdrawal of thyroxine for at least 3-4 weeks and adopting a strict iodine-free diet that may not appeal to all patients. When uptake by residual or recurrent tumour is documented, it can be assumed that the tumour is amenable to treatment with a subsequent therapy dose of 131I (Fig. However, the issue of stunning has thrown doubt on the effectiveness of an immediate therapy dose following a diagnostic scan. Others have shown variable sensitivities but the most optimistic is probably not higher than 80%. Effect of surgery and131I repeat therapy doses on a locally invasive follicular carcinoma of the thyroid in a 16 year old girl. Low specificity Acquisition errors, artifacts, physiologic distribution and non-thyroidal pathologic uptake of 131 I constitute the majority of false positive results. It is prudent to keep a comprehensive and updated list of these conditions to aid in the interpretation of scans [15. Correlation with ultrasound, computed tomography and other imaging modalities can be helpful. There are conflicting reports of how often and with what dose of 131I this can take place. The likelihood of stunning has somewhat altered long established imaging protocols and, in some institutions, has abolished preablation diagnostic scans. Other measures include postponement of therapy for weeks/months following a diagnostic scan or the use of 123I (Fig. They have been employed in anticancer treatment and showed positive effects in haematopoietic and various epithelial tumours. Experimental data with follicular thyroid tumour cells showed strong evidence of induction of differentiated cell function and antiproliferative effects [15. An overall response, evaluated by changes in Tg production, 131I uptake and tumour regression, was noted in 38%. Note the higher uptake and wider distribution of metastasis on the post therapy scan. However, pre-treatment imaging is valuable in these circumstances to document the site(s) of residual or recurrent disease for future follow up and to assist in the management.

The latter have been shown to be commonly associated with lymph node metastases and local recurrences. Therefore, it is recommended that hemithyroidectomy is adequate for unifocal tumours, whereas, multifocal tumours should be treated by total thyroidectomy [8. Diffuse sclerosing variant of papillary thyroid carcinoma is commonly encountered in children and adolescents. It involves the whole thyroid diffusely and also shows sclerosis, squamous metaplasia, tumour-associated lymphocytic infiltrate, abundant psammoma bodies, and marked lymphatic invasion. All patients affected by these tumour show nodal disease and up to 25% also have lung metastases. Because of its clinical presentation some authors classify this tumour as an aggressive form of papillary thyroid carcinoma, whereas, other believe that it behaves like the usual papillary thyroid carcinoma [8. Hurthle cell carcinoma is a variant of follicular carcinoma, which is predominantly or solely composed of oncocytic cells (at least 75%). These, tumours are frequently associated with extrathyroidal extension and with both distant and nodal metastases. Several studies have shown that Hurthle cell carcinoma is a more aggressive tumour and follows a less favourable clinical course than follicular carcinoma [8. In encapsulated carcinoma, up to 14% of papillary carcinoma can be encapsulated [8. These tumours consist of either pure papillary, follicular, or a mixture of both growth patterns. Usually the tumour capsule is thick, can show dystrophic calcifications and there is no evidence of capsular and/or vascular invasion [8. It is generally believed that these tumours follow an indolent clinical course [8. These tumours can be associated 66 with lymph node metastases, however, local recurrence and metastatic spread is uncommon [8. The diagnosis of follicular carcinoma is dependent on the presence of capsular and/or vascular invasion [8. Some authors believe that the follicular carcinoma diagnosis should only be made in the presence of vascular invasion only [8. The angio-invasive tumours lead to haematogenous metastasis to bone and lungs, causing death in 50% of patients at 10-year follow-up. In general, compared to widely invasive follicular carcinoma that diffusely infiltrates the affected lobe or entire thyroid, the 10-year survival rates for encapsulated tumours range from 70% to 100% and for widely invasive type are 25% to 45% [8. Autoimmune thyroid disease Approximately one-third of cases of papillary cancer can arise in the background of lymphocytic thyroiditis or show a tumour associated lymphocytic infiltrate. Some studies have suggested that these associations can lead to favourable outcome. After treatment disappearance of these antibodies suggests a successful initial treatment, whereas, their persistence is indicative of persistent or recurrent disease [8. These are often multifocal, show invasion and have nodal, and distant metastases [8. However, multivariate analysis has failed to substantiate its role as an independent prognostic indicator [8. Some studies have shown that death and tumour recurrences are more common in patients with aneuploid Hurthle cell carcinomas [8. Its prevalence ranges from 3-35% in spontaneous papillary thyroid carcinoma depending upon geographic location, however, it is expressed in up to 70% of radiation induced papillary cancers [8. Inactivating 69 point mutations of the p53 gene are more commonly seen in poorly differentiated and anaplastic carcinomas [8. Prognostic schemes Several scoring systems have been devised on the basis of various prognostic factors. These systems present an algorithm to divide the patients into low- and high-risk groups for management purposes. Because the majority of thyroid cancers are indolent in clinical behaviour, these schemes are dissimilar from those predicting outcome in other human cancers. None of the current systems specifically includes histological tumour subtype, which may influence prognosis. Factors studied in 500 patients were age at diagnosis, sex, histopathology, extent of primary tumour, lymph node status and systemic metastases. The contribution of the study was the development of a summary prognostic index, which could be used to predict survival of individual patients.

The relative sensitivity and specificity of those enzymes for diagnosing liver disease vary, and a diagnosis can require several tests. The estimated serum activity of that enzyme is a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract obstruction. Increases are noted after many chemical and drug exposures that are not followed by evidence of liver injury. Cirrhosis is an irreversible chronic injury of the liver with extensive scarring and a resulting loss of function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis can lead to portal hypertension with associated gastroesophageal varices, an enlarged spleen, abdominal swelling attributable to ascites, and, ultimately, hepatic encephalopathy that can progress to coma. It is generally impossible to distinguish the various causes of cirrhosis through the clinical signs and symptoms or pathologic characteristics. The most common cause of cirrhosis in North America and many parts of western Europe and South America is excessive alcohol consumption. Other causes are chronic viral infection (hepatitis B or hepatitis C), the poorly understood condition primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related conditions. Some studies that have been reviewed focused on liver enzymes, while others reported on specific liver diseases. Studies of Vietnam veterans have generally examined different laboratory endpoints and clinical conditions, making comparisons and overall conclusions difficult. However, mortality studies of the Ranch Hand cohort have not found an increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005). Studies of digestive and liver disease among other Vietnam veterans cohorts have not found associations with presumed herbicide exposure. The relationship between possible herbicide exposure and liver and gastric-ulcer disease was described in a sample of Korean Vietnam-era veterans in three publications by Yi et al. Based on health insurance claims data, the adjusted prevalence of peptic-ulcer disease was found to be 3% higher in those with high exposure than in those with low exposure after adjusting for several behavioral, demographic, and service-related factors. For liver cirrhosis, there was likewise a small elevation in the prevalence and a significant log-linear relationship between an exposure opportunity score and the odds of having cirrhosis. In the mortality study in the same cohort of Korean Vietnam veterans, there was no association between putative log-transformed exposure and mortality from peptic ulcers (Yi et al. However, highly exposed veterans were 17% more likely to die from cirrhosis than those with low exposure. Deaths from alcoholic liver disease were also statistically significantly elevated in the more highly exposed veterans. Most of the analyses of occupational or environmental cohorts have had insufficient numbers of cases to support confident conclusions. The exception was 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, which was associated with only a slight elevation (< 1%) (Yorita Christensen et al. A study of the International Agency for Research on Cancer cohort of phenoxy-herbicide and chlorophenol production workers and sprayers (Vena et al. The mortality results through 2001 for the Seveso cohort in Italy (Consonni et al. Thus, the reports have been inconsistent, and interpreting individual studies is difficult because of a lack of information on alcohol consumption and other risk factors. In the studies that showed the strongest association between potential exposure and gastrointestinal disease (specifically cirrhosis), there was strong evidence that excess alcohol consumption was the cause of the cirrhosis. Additional information available to the committees responsible for subsequent updates has not changed that conclusion. Update of the Epidemiologic Literature One new study of gastrointestinal diseases among Vietnam veterans and two occupational studies of workers in herbicide producing plants have been identified since Update 2014. Those conditions were: esophageal disorders, gastroduodenal ulcer, gastritis, appendicitis, abdominal hernia, intestinal obstruction, diverticulosis, anal/rectal disorders, biliary disorders, alcoholic liver disease, other liver disease, pancreatic disease, abdominal pain, and gastrointestinal hemorrhage. No other increased or decreased risks of gastrointestinal and hepatobiliary outcomes were found. Moreover, the analysis did not control for smoking or ethnicity or other potentially important risk factors.

Many neuropathies also affect autonomic fibers and thus can result in changes in blood pressure and heart rate and in symptoms related to the control of digestion. The immediate effects of toxicants may involve all regions of the nervous system, whereas delayed effects are likely to be related to focal deficits. In this update, the chapter reviews data pertinent to persistent neurologic disorders of all types. Case identification of neurologic disorders is also an important consideration and is often difficult because there are few disorders for which there are specific diagnostic tests. Because the nervous sys tem is not readily accessible for biopsy, pathologic confirmation is usually not feasible. However, identifiable neurologic disorders always result in objective abnormalities that are reflected in anatomic or functional tests or discovered via clinical examination. The scientific evidence supporting the biologic plausibility of each category of disorders is also reviewed here. For citations new to this update that revisit previously studied populations, the relevant details on the experimental design can be found in Chapter 5. This section summarizes in a general way some of the information reviewed in the current update and, for completeness, includes pertinent information from prior updates. In addition, earlier studies in hepatocytes indicated that 2,4D affects aspects of mitochondrial energetics and mitochondrial calcium flux (Palmeira et al. Neuronal cultures treated with 2,4D exhibited decreased neurite extension associated with intracellular changes, including a decrease in microtubules, the inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and the inhibi tion of ganglioside synthesis (Rosso et al. Those mechanisms are im portant for maintaining the connections between nerve cells, which are necessary for neuronal function and are involved in axon regeneration and recovery from peripheral neuropathy. As discussed in Chapter 4, extrapolating observations of cells in culture or in animal models to humans is complicated by differences in sensitivity and susceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects occurring consistently across species; and by differences in the route, dose, duration, and timing of chemical exposures. Therefore, such results were not considered by the committee when weighing the evidence for specific conclusions. Results were presented for eight categories of mental and neurologic disorders and a ninth category for "other nervous disorders. Overall, the results of this study for hospital admissions due to all causes combined showed a small increase in rates for Vietnam veterans compared with the population of New Zealand. Historic concentrations for each dioxin congener were calculated from the median concentrations of serum samples and the known halflives associated with each congener. Difficulties in case identification and diagnosis, misclassification of exposures because of a lack of quantitative measures, subject ascertainment and selection bias, and uncontrolled confounding from many comorbid conditions are common weaknesses in the studies reviewed. No urinary marker of 2,4-D was associated with any deficit in any of the domains of neurobehavior that were tested. The cohort consisted of 237 individu als, half of whom were workers, and the other half were family members of the workers, employees of surrounding companies, and area residents. Subjects were excluded primarily for lack of German fluency, leading to 187 individuals with complete data on the neuropsy chological battery. However, fewer than 10% of the participants had detectable levels (limit of detection = 0. Exposure was dichotomized into high and low, with the 95th percentile for each congener serving as the cutpoint. For each class (low, high, and dioxinlike), an individual was placed in the category of high if his or her level of at least one congener in that class was elevated. Adjusting the model for highly correlated variables can introduce a large bias in a nonpredictable direc tion. Thus, it is difficult to interpret the findings of this study, although it should be noted that the crosssectional nature is not a weakness, given that the halflives of these compounds are generally a decade or longer. The women were evaluated for their physical function in 1996 (n = 154) and with neurocognitive tests in 2008 (n = 459). The physical function tests were a 10foot walking test of functional mobility, a coin-flipping test of manual dexterity, a grip strength test, and a reach down test of lower body mobility.