The development of a nomogram to determine the frequency of elevated risk for non-medical opioid use in cancer patients.

OBJECTIVE: Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center. METHOD: 3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. "+risk" was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk. RESULTS: 731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. The C-index was 0.8. A nomogram was developed and can be accessed at https://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1. SIGNIFICANCE OF RESULTS: We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.

Coprescribing of opioids and high-risk medications in the USA: a cross-sectional study with data from national ambulatory and emergency department settings.

OBJECTIVE: Describe trends in opioid plus high-risk medication coprescribing in the USA. DESIGN: Analyses of serial, cross-sectional, nationally representative data of the National Ambulatory Medical Care Survey (NAMCS) over 2007-2016 and the National Hospital Ambulatory Medical Care Survey (NHAMCS) over 2007-2018. SETTING: US ambulatory (NAMCS) and emergency department (ED, NHAMCS) settings. PARTICIPANTS: Patient visits in which the patient was 18 years and older with an opioid prescription in the NAMCS or NHAMCS databases. PRIMARY AND SECONDARY OUTCOME MEASURES: Frequency of opioid plus high-risk medication coprescribing. RESULTS: From a combined sample of 700 499 visits over 2007-2018, there were 105 720 visits (15.1%) where opioids were prescribed. n=31 825 were from NAMCS and n=73 895 were from NHAMCS. The mean prevalence of coprescription of opioids and high-risk medications for the combined NAMCS and NHAMCS sample was 18.4% in 2007, peaked at 33.2% in 2014 and declined to 23.8% in 2016. Compared with adults receiving opioid prescriptions alone, those coprescribed opioids and high-risk medications were older, more likely female, white and using private or Medicare insurance (p<0.0001). CONCLUSIONS: Coprescribing is more common in ambulatory than ED settings and has been declining, yet one in four patient visits where opioids were prescribed resulted in coprescribed, high-risk medications in 2016. Efforts and research to help lower the rates of high-risk prescribing are needed.

Frequency of and Factors Associated With Nonmedical Opioid Use Behavior Among Patients With Cancer Receiving Opioids for Cancer Pain.

IMPORTANCE: One of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU. OBJECTIVE: To determine the overall frequency of and the independent predictors for NMOU behavior. DESIGN, SETTING, AND PARTICIPANTS: In this prognostic study, 3615 patients with cancer were referred to the supportive care center at MD Anderson Cancer Center from March 18, 2016, to June 6, 2018. Patients were eligible for inclusion if they had cancer and were taking opioids for cancer pain for at least 1 week. Patients were excluded if they had no follow-up within 3 months of initial consultation, did not complete the appropriate questionnaire, or did not have scheduled opioid treatments. After exclusion, a total of 1554 consecutive patients were assessed for NMOU behavior using established diagnostic criteria. All patients were assessed using the Edmonton Symptom Assessment Scale, the Screener and Opioid Assessment for Patients with Pain (SOAPP), and the Cut Down, Annoyed, Guilty, Eye Opener-Adapted to Include Drugs (CAGE-AID) survey. Data were analyzed from January 6 to September 25, 2020. RESULTS: A total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior. CONCLUSIONS AND RELEVANCE: This prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.

Prokinetics and ghrelin for the management of cancer cachexia syndrome.

Cancer cachexia (CC) is one of the most distressing syndromes for both patients and their families. CC can have an impact on patient reported quality of life and overall survival. It is often associated with symptoms such as fatigue, depressed mood, early satiety, and anorexia. Prokinetic agents have been found to improve chronic nausea and early satiety associated with CC. Among the prokinetic agents, metoclopramide is one of the best studied medications. The role of the other prokinetic agents, such as domperidone, erythromycin, haloperidol, levosulpiride, tegaserod, cisapride, mosapride, renzapride, and prucalopride is unclear for use in cachectic cancer patients due to their side effect profile and limited efficacy studies in cancer patients. There has been an increased interest in the use of ghrelin-receptor agonists for the treatment of CC. Anamorelin HCl is a highly selective, novel ghrelin receptor agonist. A meta-analysis was conducted of the recent randomized trials using anamorelin (daily dose of 50 and 100 mg daily). Results show that both total body weight and lean body mass were significantly increased from baseline in the anamorelin group. Anamorelin did not improve overall survival or hand grip strength, and there were no significant differences between groups for frequency or severity of any adverse events. In this review, the authors discuss the available evidence for the use of prokinetics such as metoclopramide and ghrelin receptor agonists for the treatment of CC.

Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress.

Oxygen radicals are induced under various pathologic conditions associated with neovascularization. Oxygen radicals modulate angiogenesis in cultured human microvascular endothelial cells by an unknown mechanism. Treatment of human microvascular endothelial cells for 15 min with 0.1 to 0.5 mM hydrogen peroxide (H2O2) or 100 U of tumor necrosis factor alpha per ml induced tubular morphogenesis in type I collagen gels. Gel shift assays with nuclear extracts demonstrated that H2O2 increases the binding activities of two transcription factors, NF-kappaB and AP-1, but not of Spl. Tumor necrosis factor alpha increased the binding activities of all three factors. A supershift assay with specific antibodies against JunB, JunD, and c-Jun (Jun family) showed that the antibody against c-Jun supershifted the AP-1 complex after H2O2 treatment. Coadministration of the antisense sequence of NF-kappaB inhibited H2O2-dependent tubular morphogenesis, and the antisense c-Jun oligonucleotide caused partial inhibition. The angiogenic factor responsible for H2O2-induced tubular morphogenesis was examined. Cellular mRNA levels of vascular endothelial growth factor and interleukin-8 (IL-8), but not those of transforming growth factor alpha, were increased after treatment with 0.5 mM H2O2. Coadministration of anti-IL-8 antibody inhibited tubular morphogenesis enhanced by H2O2, and IL-8 itself also enhanced the formation of tube-like structures. Treatment with antisense NF-kappaB oligonucleotide completely blocked H2O2-dependent IL-8 production by endothelial cells. The tubular morphogenesis of vascular endothelial cells after treatment with oxidative stimuli and its possible association with NF-kappaB and IL-8, is examined.

Role of intraoperative enteroscopy for surgical decision making with Crohn's disease.

BACKGROUND: This study aimed to assess the role of intraoperative enteroscopy (IOE) in determining surgical treatment. METHODS: The IOE procedure was performed for 30 patients with Crohn's disease. The degree of stricture and the presence of active ulcer were examined. Preoperative diagnoses and intraoperative findings obtained by inspection and palpation were noted and compared with the IOE findings. RESULTS: Of the 78 intestinal strictures observed by IOE (42%), 33 were not found by preoperative examination. Of the 45 strictures confirmed by IOE to be severe (<15 mm in diameter), 8 were judged to be mild (15-25 mm in diameter) or were not even identified by intraoperative inspection and palpation. Active ulcer was found at 12 of 33 mild strictures, and all 12 strictures were surgically corrected. Of 11 severe strictures detected by IOE at previous surgical sites, 9 were found preoperatively, and 4 were judged to be mild on the basis of inspection and palpation. Stricture was found at the ileocecal valve by IOE in seven patients, but was not diagnosed preoperatively in two of these patients. CONCLUSION: Intraoperative enteroscopy provides useful information regarding the status of the lumen in patients with Crohn's disease.

The effect of cholesterol on the accumulation of intracellular calcium.

Cholesterol/egg phosphatidylcholine (PC) liposomes (1:1 or 4:1, M/M), in which the absolute amount of PC was adjusted to be the same, were incubated with cultured bovine arterial smooth muscle cells for up to 8 h at 37 degrees C. The effect of increased cellular cholesterol on the accumulation of intracellular calcium in these cells was studied. The results indicate that the intracellular calcium content, measured by Fura-2/AM, was increased 2.3-fold by incubation with 4:1, cholesterol/PC liposomes. Kinetic analysis using 45Ca2+ indicated that the increased calcium influx was due to increase of pool size, not from a change of rate constant. (Ca2+ + Mg2+)-ATPase activity was decreased by 4:1, cholesterol/PC liposomes. The molar ratio of cholesterol/phospholipids in the cell membranes was directly proportional to that in liposomes. No change in phospholipid composition was noted. We suggest that the accumulation of intracellular calcium was a composite result due to the altering effect of inserted cholesterol on surface area, and to direct interactions between cholesterol and the proteins of the Ca2+ channel and (Ca2+ + Mg2+)-ATPase.

Appearance of cross linked proteins in human atheroma and rat pre-fibrotic liver detected by a new monoclonal antibody.

A new monoclonal antibody against malondialdehyde (MDA)-treated low density lipoprotein (LDL) was raised using homogenate of human atheroma as immunogen. This antibody, DLH2, was obtained by selecting the clones which did not react to native LDL but did react to copper-induced oxidized LDL (OxLDL). DLH2 showed a greater reactivity to MDA-LDL than to OxLDL. When LDL was treated with various aldehyde containing reagents, treatment of LDL with glutaraldehyde or MDA greatly increased the reactivity to the antibody, while LDL treated with 2,4-hexadienal or 4-hydroxynonenal was not reactive. Among many proteins tested, high density lipoprotein, bovine serum albumin and hemoglobin showed significant reactivity to DLH2 after they were treated with MDA or glutaraldehyde. When low density and high density lipoproteins treated with MDA were subjected to immunoblot analysis, newly formed products larger than the original apolipoproteins were detected with the antibody, suggesting that this antibody recognizes aggregated proteins with divalent short chain cross linkers. The antigenic materials were shown by immunohistochemical analysis to be present in foamy macrophages in human atheromatous lesions. DLH2 antigen did not colocalize either with apolipoprotein B. Furthermore, we found a massive accumulation of the antigenic material in Kupffer cells in the liver of rats treated with alcohol and carbonyl iron, a model of hepatic fibrosis due to oxidative stress. These results suggest the presence of cross linked proteins in damaged tissues.

Mechanism of action of probucol on cholesteryl ester transfer protein (CETP) mRNA in a Chinese hamster ovary cell line that had been stably transfected with a human CETP gene.

Probucol, a widely used lipid-lowering agent, is associated with a significant reduction of plasma high density lipoprotein (HDL)-cholesterol levels. To examine the mechanism of probucol HDL-lowering and probucol's effects on cholesteryl ester transfer protein (CETP) and cholesterol metabolism in cells, we used a Chinese hamster ovary (CHO) cell line that had been stably transfected with a human CETP gene (hCETP-CHO). After this cell line was incubated with various concentrations of probucol (5, 10 and 50 microM) for 24 h, mean intracellular probucol concentrations reached 0.47, 0.67, and 1.52 microg/mg cell protein, respectively. Northern blot analysis showed that cellular CETP mRNA was increased by probucol in a dose-dependent manner (137%, 162%, and 221% of the control, respectively). The specific CET activity in the culture medium, measured as the percentage of [3H]cholesterol oleate transferred from discoidal bilayer particles (which mimic HDL) to LDL, also increased in a dose-dependent manner. Intracellular total cholesterol levels were decreased to 87.5%, 74.9%, and 52.5% of the control, respectively. Probucol had no effects on HMG-CoA reductase activity or cholesterol synthesis from [14C]acetate in hCETP-CHO. However, 14C-incorporated cholesterol secretion into the culture medium from hCETP-CHO was increased to 181%, 256% and 354% of the control by 5, 10 and 50 microM probucol, respectively. We concluded that (1) treatment with probucol increased the CETP mRNA level and specific CET activity in the hCETP-CHO cell line, and (2) probucol promoted cholesterol efflux from hCETP-CHO, which resulted in a decrease in intracellular cholesterol levels.

Hyperinsulinemic hypoalphalipoproteinemia as a new indicator for coronary heart disease.

OBJECTIVES: The purpose of this study was to investigate the association among insulin resistance, high density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD), and to test the hypothesis that HDL-C may ameliorate the adverse effects of insulin. BACKGROUND: Serum low HDL-C (hypoalphalipoproteinemia) and hyperinsulinemia are independent predictors for CHD, but a strong negative correlation exists between them, as in patients with syndrome X. METHODS: Fifty-four pairs of cases (M/F: 49/5), defined as patients with angiographically proved CHD, and control subjects (M/F: 49/5) matched with cases with regard to gender and age were included. Insulin resistance was assessed by the homeostasis model assessment (HOMA). RESULTS: Cases had increased HOMA insulin resistance and lower serum levels of HDL-C than controls. A receiver operating characteristic (ROC) curve analysis indicated that HDL-C and insulin resistance were significant discriminators of CHD (area under ROC curve: 0.72 and 0.69, respectively). The interaction between HDL-C and the association of insulin resistance with CHD was significant: subjects with hyperinsulinemia and high HDL-C had no increased risk of CHD. Multivariate conditional logistic regression analysis showed that hyperinsulinemic hypoalphalipoproteinemia was a stronger indicator for CHD than either HDL-C or insulin resistance alone (-2 log likelihood: 19.0 vs. 12.6 or 15.7). CONCLUSIONS: Hyperinsulinemic hypoalphalipoproteinemia was a more potent indicator for CHD than either insulin resistance or low serum HDL-C levels alone, and the adverse effects of hyperinsulinemia seem to be ameliorated by high HDL-C levels.

The effect of 25-hydroxycholesterol on accumulation of intracellular calcium.

Liposomes prepared with 25-hydroxycholesterol and egg phosphatidylcholine (PC) were incubated with bovine arterial smooth muscle cells for 8 h at 37 degrees C. Cells incubated in the absence of liposomes or with liposomes containing cholesterol and PC were used as controls. The results indicated that calcium accumulated in the smooth muscle cells incubated in the presence of 25-hydroxycholesterol containing liposomes in an amount proportional to the time of incubation. The calcium accumulation, as indicated by kinetic analysis, resulted from an increased compartment size. (Ca(2+)+Mg2+)-ATPase exhibited decreased activity after pretreatment with 25-hydroxycholesterol containing liposomes and the increased intracellular calcium content was directly proportional to the decreased (Ca(2+) + Mg2+)-ATPase activity. When lipids in the cell membrane were examined, a failure to change the cholesterol/phospholipids ratio in the membrane was noted. The 25-hydroxycholesterol content in the membrane determined by HPLC did not increase. An increase in sphingomyelin and a decrease in phosphatidylethanolamine and acidic phospholipids in the membrane was noted. We suggest that the accumulation of intracellular calcium comes from both an increase of calcium influx and a decrease of (Ca(2+) + Mg2+)-ATPase activity, which may be the consequence of changes in membrane phospholipid composition.

Stimulation of cell-surface urokinase-type plasminogen activator activity and cell migration in vascular endothelial cells by a novel hexapeptide analogue of neurotensin.

To investigate if neurotensin (NT) could induce activation of urokinase-type plasminogen activator (uPA) in vascular endothelial cells, we utilized the acetyl-NT (8-13) analogue, TJN-950, in which the C-terminal leucine is reduced to leucinol. TJN-950 inhibited the binding of 125I-NT to membranes of newborn rat brains and of COS-7 cells transfected with rat NT receptor cDNA, but at 10(4) higher doses than NT (8-13). However, TJN-950 was as effective as NT in inducing the fibrinolytic activity in bovine vascular aortic and human umbilical vein endothelial cells, and enhanced the migration of vascular endothelial cells. Moreover, administration of TJN-950 induced neovascularization in the rat cornea in vivo. TJN-950 had no effect on expression of uPA, plasminogen activator inhibitor-1 or uPA receptor mRNA. The binding of 125I-TJN-950 to cell membranes was blocked by unlabeled uPA and TJN-950, but not the amino-terminal or 12-32 fragment of uPA. TJN-950 may enhance uPA activity in vascular endothelial cells by interacting with the uPA receptor, resulting in induction of angiogenesis.

Low density lipoproteins bind more to type I and III collagens by negative charge-dependent mechanisms than to type IV and V collagens.

The accumulation of low density lipoprotein (LDL) in the arterial intima is an important characteristic of atherosclerosis. We investigated the mechanisms by which LDL binds to different types of collagen. The binding activities of 125I-labeled human native LDL (nLDL) and copper-oxidized LDL (oxLDL) with different collagen gels prepared in type I collagen-based mixtures with types I, III, IV and V (I+I, I+III, I+IV and I+V, respectively) were examined. A concentration of 20 micrograms LDL protein/150 micrograms collagen/well was used. The diffusion of both nLDL and oxLDL into the collagen gels reached an equilibrium after 48 h. All of the collagen gels showed the same rates of diffusion with both LDLs. The binding activities of oxLDL were significantly greater than those of nLDL (P < 0.001%), while the binding activities for both LDLs followed the order I+I and I+III > I+V > I+IV. However, the increased binding rate of oxLDL compared to nLDL was 1.66 for I+IV, 1.50 for I+V, 1.33 for I+I and 1.19 for I+III. When a 10-fold higher dose of NaCl (1 M) was added to the oxLDL medium, the binding rate of oxLDL was reduced (rate of reduction: 52% (I+I), 48% (I+III), 35% (I+IV), 13% (I+V)). These results suggest that oxLDL binds more to type I and III collagens by negative charge-dependent mechanisms than to type IV and V collagens. Therefore, types I and III collagens may play an important role in trapping LDL, especially oxLDL. Therefore, oxidatively modified LDL may contribute to atherogenesis due to its longer retention in the arterial wall.

Nonenzymatic glycation and extractability of collagen in human atherosclerotic plaques.

The relationship between the extractability of collagen by enzymatic digestion and the degree of nonenzymatic glycation of collagen was examined in the aorta and skin from 38 subjects without diabetes mellitus (mean age: 62.3 +/- 20.2 years). Samples were obtained from the aortic media (M), lesion-free intima (I), atherosclerotic intima (A) and dermis of the skin (S). Collagen was extracted first by incubation with 1/50 (enzyme/substrate weight ratio) pepsin at 4 degrees C for 24 h (P-fraction) and then by incubation with 1/10 (enzyme/substrate weight ratio) pepsin at room temperature for 24 h (EP-fraction). The pepsin-insoluble precipitates were digested by incubation with 270 units of bacterial collagenase at 37 degrees C for 24 h (PIS-fraction). Collagen contents, ketoamines and collagen-linked fluorescence (CLF) were measured in each fraction. The amount of ketoamines and the level of CLF correlated inversely with the susceptibility of collagen to pepsin digestion in various tissues, including M, I, A and S. These values were highest in both the P- and EP-fractions of M, which contained the least amount of collagen extracted by pepsin digestion. In contrast, they were lowest in S, where the concentration of collagen extracted by pepsin digestion was greatest among all of the tissue samples. Atherosclerotic intima (A) and aortic media (M) showed an age-related increase in the total amount of collagen digested with pepsin and collagenase, which depended mainly on an increase in the content of pepsin-insoluble collagen. Although the total amount of collagen did not increase with advancing age in I or S, collagen in I and S became progressingly resistant to pepsin digestion. These results suggest that the age-related decrease in the susceptibility of collagen to pepsin digestion may be due to nonenzymatic glycation in atherosclerotic lesions as well as normal tissues, including the aortic media, lesion-free intima and skin. The level of CLF significantly increased with age in the P-fraction and/or EP fraction of M, I and S. However, there was no relationship between the level of CLF and the subject's age in A. Thus, the accumulation of advanced glycation endproducts (AGEs) on collagen fibers may be partially responsible for the increase in collagen matrix in atherosclerotic lesions of subjects without diabetes mellitus.

Oxidized low density lipoprotein stimulates collagen production in cultured arterial smooth muscle cells.

We examined the interactive effect of oxidized low density lipoprotein (LDL) and ascorbic acid on collagen production in cultured smooth muscle cells (SMCs). Porcine aortic SMCs were incubated with 50-200 micrograms/ml of human LDL with/without 5 microM Cu2+ for 24 h. Collagen production was assayed by successive salt precipitation at acidic and neutral pH after pepsin digestion of 3H-proline-labeled collagenous protein. Oxidation of LDL was evaluated by electrophoresis and by the level of thiobarbituric acid reactive substances (TBARS). Ascorbic acid reduced the oxidation of LDL + Cu2+ (53% reduction). In the presence of ascorbic acid, no differences were noted in collagen production between LDL and LDL + Cu2+. Without ascorbic acid, collagen production with LDL + Cu2+ was increased dose-dependently up to 6-fold with 150 micrograms/ml LDL, while no such effects were observed at any doses of native LDL. The addition of butylated hydroxytoluene to LDL + Cu2+ strongly suppressed oxidation (88% reduction), and significantly reduced collagen production close to that seen with native LDL. These results indicate that oxidized LDL stimulates collagen production in SMCs, while native LDL does not. Therefore, oxidized LDL may play a direct role in stimulating collagen production in SMCs, which could lead to collagenosis in atherosclerosis.

Thyroid carcinoma distinctively expresses intracellular fibronectin in vivo.

Fibronectin is a multifunctional protein that plays a role in tumor invasion. We immunohistochemically examined the in vivo expression of fibronectin in thyroid carcinoma in comparison with other carcinomas, such as hepatocellular carcinoma, transitional cell carcinoma and gastric adenocarcinoma. Intracellular localization of fibronectin was found in almost all cases of thyroid carcinoma. In contrast, hepatocellular carcinoma showed a lower expression rate and the other carcinomas were all negative. These results indicate that the intracellular expression of fibronectin is not a common phenomenon in carcinoma, but rather is distinctive for thyroid carcinoma.

Retention of intracellular fibronectin expression in primary and metastatic thyroid carcinoma: an immunohistochemical study.

We previously showed that thyroid carcinoma distinctively expresses intracellular fibronectin (FN) compared to other carcinomas. To determine the persistency of such FN accumulation in metastasis, we immunohistochemically examined the accumulation of intracellular FN in 92 cases of different carcinomas originating from the thyroid gland, lung and kidney, 44 of which showed metastasis to other organs. In all of the cases, normal epithelial cells adjacent to carcinomas did not show intracellular FN. Almost all of the cases (31/32) of thyroid carcinoma with/without metastasis to the lung and/or kidney showed intracellular FN in both the primary and metastatic lesions. Few cases (2/38) of lung carcinoma and none of the 22 cases of kidney carcinoma showed intracellular FN in the primary and metastatic lesions. In conclusion, the intracellular accumulation of FN acquired after carcinogenic transformation is not a common phenomenon in carcinomas, but rather is distinctive for thyroid carcinoma, even when it metastasizes to other organs. The immunohistochemical detection of intracellular FN may be useful for diagnosing thyroid carcinoma, even in metastatic lesions.

Strong intracellular and negative peripheral expression of fibronectin in tumor cells contribute to invasion and metastasis in papillary thyroid carcinoma.

The intracellular and stromal expression of fibronectin (FN) in invading and central parts of papillary thyroid carcinomas with/without lymph node (LN) metastasis (54 metastasizing cases, 52 non-metastasizing cases) were examined immunohistochemically. The intracellular expression of FN in tumor cells in invading parts was stronger than that in central parts in most cases (79/106 cases, 74.5%). In invading parts, negative stromal FN was frequently found at the periphery of the tumor in cases with extracapsular soft tissue invasion (26/37 cases). Tumor cells in invading parts in metastatic cases were significantly more likely to be negative for stromal FN at the periphery of the tumor than those in non-metastatic cases (P < 0.0001). The strong intracellular and negative stromal FN at the periphery of the tumor in invading parts were associated with invasion and metastasis in papillary thyroid carcinoma. These results suggest that these distinctive characteristics of FN may be useful for understanding invasion and metastasis in vivo.

Expression of matrix metalloproteinases 1 and 2 genes in a possible association with metastatic abilities of human pancreatic cancer cells.

We determined if any extracellular matrix degradative proteases were possibly associated with metastatic potentials of human pancreatic cancer cells. Liver metastatic abilities of six human pancreatic cancer cell lines were examined in nude mice, and divided into two high (2 lines) and low (4 lines) metastatic cell lines. Of six cell lines, matrix metalloproteinases-1 (MMP-1) was overexpressed in two high metastatic cell lines: and MMP-2 was overexpressed in one high metastatic cell line. Of the four low metastatic lines, two cell lines had relatively higher mRNA levels of tissue inhibitors of metalloproteinases-3 (TIMP-3). MMP activities due to MMP-1 and MMP-2 might be positively associated with liver metastasis of pancreatic cancer cells. Moreover, expression of TIMP-3 might be partly involved in the low metastatic potentials of pancreatic cancer.

Clinical choroidal thrombosis, hypertension, and diabetes mellitus: an electron microscopic study.

Changes in the choroidal artery were examined at autopsy in 16 Japanese patients with hypertension and insulin-dependent diabetes mellitus. These changes could be divided into 1) arteriosclerotic ones consisting of intimal thickening due to migration of smooth muscle cells, 2) hyaline deposits in the subendothelium, 3) extensive degeneration (moth-eaten atrophy and necrosis) of medial smooth muscle cells, and 4) changes resulting from fibrinoplatelet thrombi and their organization (recanalization and obstruction). The intimal thickening and medial damage correlated with aging, were accelerated by hypertension, and were remarkable in arterioles less than 60 micron in diameter. Diabetes mellitus apparently did not enhance these vascular changes. Thrombotic occlusion or narrowing of the choroidal artery was frequently observed in the arterioles of patients with hypertension and diabetes mellitus who had chronic azotemia or renal insufficiency. Subendothelial hyaline deposits were increased in patients with diabetes. The narrowing or obstructive changes in the choroidal artery were extensive in the intraocular blood vessels. These changes may be secondary and induce damage to other intraocular blood vessels and tissues, including the retina.