Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

BACKGROUND: Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2 years after the completion of neoadjuvant treatment. STUDY DESIGN: Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8 weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2 cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2 years in the enrolled patients. CONCLUSION: This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

[Rare association of a mixed tumor of the skin with a carcinoma of low grade malignancy. Clinical case]. / Rara associazione di un tumore misto della cute con un carcinoma a basso grado di malignità. Caso clinico.

Chondroid syringoma, previously called mixed tumor of the skin is a fairly uncommon type of sweat gland tumor, most often diagnosed in the sixth and seventh decade of life. It presents as a well encapsulated dermal or subcutaneous module and it is most frequently found in the skin of the head and neck. The neoplasm is asymptomatic and is featured by a slow rate of growth. At histopathological examination, the tumor consists of an epithelial component, with glandular or ductal differentiation, either eccrine or apocrine, and a stromal component with myxoid or chondroid elements. Surgical removal is the treatment of choice and recurrence may occur. Malignant chondroid syringoma has been reported rarely, most frequently arising in previously benign lesions. They behave as lethal tumors and often metastasize to the regional lymph nodes and lung. We report a most unusual case of a mixed tumor of the skin localized in the sacral area associated with a peripheral low grade malignant component of the adenocystic type. Association of these two types of sweat gland tumors has never been previously described, to our knowledge.

Diets enriched in unsaturated fatty acids enhance apolipoprotein A-I catabolism but do not affect either its production or hepatic mRNA abundance in cynomolgus monkeys.

To determine the mechanisms whereby dietary fatty acids influence high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I concentrations, ten cynomolgus monkeys were fed each of three experimental diets enriched in saturated (SAT), monounsaturated (MONO), or polyunsaturated (POLY) fatty acids in a crossover design consisting of three 13-week periods, with each animal serving as its own control. Each diet contained 30% of energy as fat with 0.22 mg cholesterol/kcal and differed solely by the isocaloric substitution of fatty acids as 18% of total energy calories. The replacement of dietary saturated fatty acids with either monounsaturated or polyunsaturated fatty acids, respectively, resulted in significant reductions of plasma total cholesterol (-17%; -30%), HDL cholesterol (-32%; -41%), and apo A-I (-37%; -44%) concentrations, while no significant differences were noted in plasma lipid or apo A-I concentrations when the MONO and POLY phases were compared. Although the MONO and POLY diets were similar in their effects on plasma lipids and apolipoproteins, the HDL of monkeys fed the POLY diet, as compared with either the SAT or the MONO diets, contained more cholesteryl ester and phospholipid but less total protein, resulting in a significantly lower total lipid to protein constituent ratio. Metabolic experiments revealed that the significantly lower plasma apo A-I concentrations observed during both the MONO and POLY phases relative to SAT were directly attributable to enhanced HDL apo A-I catabolism. Conversely, neither HDL apo A-I production rates nor hepatic apo A-I mRNA concentrations were significantly affected by dietary fatty acid perturbation in this study. Taken together, these data indicate that fractional catabolic rate is the predominant mechanism by which dietary fatty acids differentially modulate circulating concentrations of HDL apo A-I in this species when all other dietary variables are held constant.

Unidirectional transfer in vivo of high-density lipoprotein cholesteryl esters to lower-density lipoproteins in the pig, an animal species without plasma cholesteryl ester transfer activity.

The metabolism of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesteryl esters (CE) was studied in the pig, an animal species without plasma cholesteryl ester transfer activity (CETA). In the first series of experiments, LDL and HDL from normocholesterolemic pigs were radiolabeled with cholesteryl (1-14C)oleate and intravenously administered to two groups of four normocholesterolemic pigs. Radioactive tracer in LDL remained associated with the LDL fraction, and there was no transfer of LDL-CE to HDL. The transport rate (which represents the production and disposal rate) of LDL-CE in normocholesterolemic pigs was 39 mumol CE/h/L. However, radiolabeled HDL-CE were transferred to LDL (25%), and 36% of the LDL-CE mass was derived from the HDL. The transport rate of HDL-CE was 54 mumol CE/h/L, and the flux of HDL-CE to LDL was 14 mumol CE/h/L. There was no accumulation of radiolabeled HDL-CE in very-low-density lipoprotein (VLDL), which suggests that there was no transfer to VLDL. However, this does not rule out the possibility that either the very low levels of VLDL-CE (< 0.09 mmol/L) or the rapid turnover rate of the VLDL pool might have prevented the accumulation of substantial amounts of tracer in VLDL. Therefore, in a second set of experiments, the kinetics of HDL-CE were studied in high-fat-and high-cholesterol-fed pigs with elevated VLDL-CE concentrations (1.92 mmol/L). Hypercholesterolemia was associated with increased transport rates of LDL-CE (165 mumol/h/L) and HDL-CE (78 mumol/h/L) and with an increased flux of HDL-CE to LDL (78 mumol/h/L).(ABSTRACT TRUNCATED AT 250 WORDS)

A diet enriched in monounsaturated fats decreases low density lipoprotein concentrations in cynomolgus monkeys by a different mechanism than does a diet enriched in polyunsaturated fats.

To determine the mechanisms whereby dietary fat saturation influences LDL cholesterol and apolipoprotein B concentrations, 10 cynomolgus monkeys were fed each of three experimental diets enriched in saturated, monounsaturated or polyunsaturated fatty acids in a crossover design consisting of three 13-wk periods. Each diet contained 30% of energy as fat with 0.05 mg cholesterol/kJ and differed solely by the isocaloric substitution of fatty acids as 60% of total fat energy. The replacement of dietary saturated fatty acids with either mono- or polyunsaturated fatty acids resulted in significant reductions of plasma total cholesterol (-17% and -30%, respectively), HDL cholesterol (-32% and -41%, respectively), apoA-1 (-37% and -44%, respectively), and apolipoprotein B (-28% and -36%, respectively) concentrations. Additionally, when dietary polyunsaturated fatty acids were substituted for saturated fatty acids, a 27% reduction in VLDL + LDL cholesterol was significant. Metabolic experiments suggested that the significantly reduced concentrations of apolipoprotein B observed during the monounsaturated and polyunsaturated fatty acid phases relative to the saturated fatty acid phase could not be entirely explained by changes in LDL apolipoprotein B clearance but rather were likely due to decreased LDL apolipoprotein B production rates. However, enhanced LDL apolipoprotein B catabolism accounted for the even greater reductions in VLDL + LDL cholesterol and apolipoprotein B concentrations observed during the polyunsaturated fatty acid phase vs. the monounsaturated fatty acid phase. Our data suggest that monounsaturated and polyunsaturated fatty acids lower apolipoprotein B concentrations by distinct mechanisms, with polyunsaturated fatty acids affecting LDL apolipoprotein B catabolism as well as production.

Effects of doxazosin, an alpha 1-adrenergic inhibitor, on plasma lipid and lipoprotein levels, low density lipoprotein metabolism and cholesterol absorption in cynomolgus monkeys.

The mechanism(s) by which doxazosin, an alpha 1 inhibitor, regulates plasma low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) levels were investigated in 'normocholesterolemic' (average total cholesterol (TC) of 218 mg/dl) and 'hypercholesterolemic' (average TC of 350 mg/dl) cynomolgus monkeys. Twelve weeks of doxazosin treatment (1 mg/kg per day) significantly reduced plasma TC and LDL-C levels in both groups while high density lipoprotein cholesterol and apolipoprotein A-I concentrations rose. Despite these changes in plasma lipids, LDL and HDL lipid composition was not affected by doxazosin. The reduction in LDL-C and apo B in the doxazosin-treated 'hypercholesterolemic' group was associated with a significant increase in both receptor-dependent and -independent LDL apo B fractional catabolic rates. Similar associations were noted in the 'normocholesterolemic' group. LDL apo B production or transport rate was not affected by doxazosin. Cholesterol absorption was also significantly reduced by doxazosin which may also contribute to lowering plasma LDL-C levels. These studies suggest that doxazosin treatment can produce beneficial changes in the plasma lipid profile over a wide rage of plasma cholesterol levels by up-regulating LDL fractional clearance.

Effect of corn and coconut oil-containing diets with and without cholesterol on high density lipoprotein apoprotein A-I metabolism and hepatic apoprotein A-I mRNA levels in cebus monkeys.

The mechanism(s) by which diets containing corn or coconut oil (31% of energy as fat) totally free of cholesterol or with 0.1% added cholesterol by weight (0.3 mg/kcal) affect plasma high density lipoprotein cholesterol (HDL-C), apoprotein (apo) A-I levels, apo A-I kinetics, and hepatic apo A-I mRNA concentrations were investigated in 26 cebus monkeys. Coconut oil-fed monkeys had elevated levels of plasma total cholesterol (217%), very low density lipoprotein plus low density lipoprotein cholesterol (331%), HDL-C (159%), and apo A-I (117%) compared with corn oil-fed animals. Although the addition of cholesterol to the corn oil diet significantly increased these parameters, no such effects were seen when cholesterol was added to the coconut-oil diet. Both the type of fat and cholesterol in the diet significantly affected HDL apo A-I metabolism by decreasing apo A-I fractional catabolic rate and increasing apo A-I production rate in the coconut oil-fed groups. The decrease in apo A-I fractional catabolic rate in the coconut oil-fed animals was also associated with an increase in the HDL core lipid to surface ratio. Liver apo A-I mRNA abundance was elevated in the coconut oil-fed groups; however, dietary cholesterol had no affect on these levels. The lack of parallel effects of dietary fat and cholesterol on apo A-I production rate and liver apo A-I mRNA levels suggests that the increase in the apo A-I production rate observed in the coconut oil-fed groups resulted from the fat-induced rise in liver apo A-I mRNA abundance, whereas the cholesterol-induced rise in the apo A-I production rate resulted from a mechanism other than changes in liver apo A-I mRNA levels.

Effect of hyperthermia on isolated perfused rat liver.

Four groups of isolated rat livers underwent perfusion at 37 degrees C for 1 h, at 37, 40, 43 or 45 degrees C, respectively, during the 2nd hour and then at 37 degrees C again for the 3rd hour. Vascular resistance slightly decreased during hyperthermia and then significantly increased after restarting normothermic perfusion. At 40 degrees C bile production, oxygen consumption, glucose and lactate release did not significantly differ from those found in the 37 degrees C group. At 43 and 45 degrees C all these parameters were significantly impaired when compared to the 37 and 40 degrees C groups and did not recover after normothermic perfusion was restored. GOT and GPT release increased in proportion to the temperature. Microscopic examination revealed normal histologic features in 37 and 40 degrees C specimens while alterations such as vacuolization and focal necrosis were found in the 43 and 45 degrees C groups. These data indicate that the highest temperature that is well tolerated by isolated rat livers for 1 h is located between 40 and 43 degrees C.