Ornithine decarboxylase activity in the rat and human colon

We have investigated the effect of age, a high-fat diet, sodium deoxycholate, and the ornithine analogue alpha-difluoromethylornithine on ornithine decarboxylase (ODC) activity in the rat colon. The relative levels of ODC activity were also determined in normal mucosa and tumor tissue from rat and human colon. The colonic ODC activity induced by intrarectal instillation of sodium deoxycholate in male Sprague-Dawley rats was highest in young animals, and it decreased with increasing age. A high level of dietary fat caused both an increased in basal colonic ODC activity and enhanced ODC induction by deoxycholate. alpha-Difluoromethylornithine given in drinking water inhibited, in a dose-dependent fashion, deoxycholate-induced ODC activity. The frequency of azoxymethane-induced intestinal tumors was also significantly reduced by alpha-difluoromethylornithine. Since colonic ODC activity is increased in carcinogenesis by known promoting agents and decreased by tumor inhibitors, this short-term assay may provide a useful system for identifying colon tumor promoters and inhibitors. The ODC activity in colon tumors of Sprague-Dawley rats was found to be significantly higher than in normal-appearing mucosa in the same animals. Similarly, ODC activity in human colon cancer was found to be higher than that of the normal-appearing mucosa in the same specimen. These results strengthen the utilization of the rat model for studies, the results of which may apply to the human situation.     

Colonic polyamine content and ornithine decarboxylase activity as markers for adenomas

Polyamine content (putrescine, spermidine, and spermine) or ornithine decarboxylase (ODC) activity was measured in normal-appearing colonic mucosa from patients undergoing colonoscopy. Comparisons were made between those with and those without adenomatous polyps. Colonic mucosal polyamine content was measured in 44 persons. Mean putrescine content was 1.25 +/- 0.26 (SE) nmol/mg protein in 22 patients with adenomatous polyps compared with 0.53 +/- 0.12 nmol/mg protein in patients without polyps (P less than 0.02). Tissue content of spermidine and spermine did not differ between these two groups. Ornithine decarboxylase activity was measured in tissue from 45 patients. Mean ODC activity was 2.84 +/- 0.73 pmol/hr/mg protein in 23 persons with adenomatous polyps compared with 1.15 +/- 0.18 pmol/hr/mg protein in persons without polyps (P less than 0.05). Mucosal putrescine and ODC activity are elevated in patients with adenomatous polyps compared with patients without polyps. These biochemical markers may prove helpful in improving surveillance methods for colorectal cancer and premalignant adenomatous polyps.     

Ornithine decarboxylase enzyme activity in human and hamster pancreatic tumor cell lines

We measured ornithine decarboxylase (ODC) enzyme activity, protein and DNA levels in 4 pancreatic cancer cell lines, 2 derived from human tumors (COLO-357 and PANC-1) and 2 derived from hamster tumors (WDPaCa and PDPaCa). We measured the parameters in confluent stage conditions and in log-growth phase. We report that the enzyme levels in all cell lines are elevated with respect to normal pancreatic tissue. Half-life studies of ODC in the PDPaCa cell line indicate a 3-fold increase in half-life.     

Ornithine decarboxylase and polyamine levels in columnar upper gastrointestinal mucosae in patients with Barrett's esophagus

Ornithine decarboxylase (ODC) activity was elevated in the premalignant metaplastic columnar epithelium (mean activity, 0.13 unit/mg protein, N = 18 individual samples from 18 patients), compared to either adjacent gastric (mean activity, 0.02 unit/mg protein, N = 9) or small intestinal (mean activity, 0.02 unit/mg protein, N = 9) epithelium in patients with Barrett's esophagus. Enzyme activity ranged from 0 (less than detectable) to more than 0.5 unit/mg protein in the metaplastic tissue. However, neither putrescine, spermidine, spermine (as individual parameters), nor total polyamine contents were related to ODC activity in the individual patient biopsies. Spermidine/spermine ratios ranged from 0.38 to 2.18 and were also not related to enzyme activity in any apparent manner. Nevertheless, cell strains derived from the metaplastic tissue were growth inhibited by alpha-difluoromethylornithine, an enzyme-activated, suicide inhibitor of ODC. In two different cell strains derived from Barrett's epithelium, growth was affected with drug concentrations as low as 0.05 mM. While the mechanism responsible for the elevation in enzyme activity is unknown, the regulation of polyamine metabolism appears to be altered in this premalignant tissue. The growth inhibition of Barrett's epithelium-derived cell lines by ODC inhibitors suggests a potential role for these compounds in the treatment of this disease.     

Properties of ornithine decarboxylase in human colorectal adenocarcinomas

Ornithine decarboxylase (ODC) activity was measured in colon adenocarcinomas and adjacent normal-appearing colon mucosa from a total of 40 patients undergoing surgical resections. The enzyme activity was measured in the presence and absence of GTP, since recent work has demonstrated a GTP-activatable form of ODC in some murine and human tumors. In general, ODC specific activity was higher in adenocarcinomas than in adjacent normal-appearing mucosa. Of greater interest, however, was the finding that 13 of 40 tumors and 3 of 40 mucosae contained a GTP-activatable form of ODC. These are minimal estimates of the proportion of tissues positive for this enzyme form, since a multiple sampling protocol indicated that expression of a GTP-activatable ODC was not uniform throughout a given tumor. Chromatographic analyses of tumor extracts revealed the presence in some tumors of multiple size forms of ODC, only some of which were activated by GTP. Enzyme kinetic data indicated that the multiple forms of ODC can have different affinities for L-ornithine and that GTP can "normalize" the aberrant kinetic properties of these forms. While there was no statistically significant correlation of the presence of a GTP-activatable ODC with stage of disease, analysis of our data revealed a positive association of a GTP-activatable ODC with tumor site; a much higher percentage of tumors of the cecum contained this ODC isoform than tumors of other colonic segments (64% versus less than or equal to 25% for other sites). These results demonstrate (a) the presence of a functionally distinct form of ODC in some human colon adenocarcinomas and (b) a distinct regional distribution of this ODC form within the colon. We suggest this alteration in a key enzyme in the growth-associated pathway of polyamine biosynthesis may play a role in colon tumor progression.     

Ornithine decarboxylase activity in chemically induced mouse skin papillomas

The activity levels of L-ornithine carboxy-lyase (ODC) (E.C.4.1.1.17 [EC] ) and S-adenosyl-L-methionine carboxy-lyase (SAMD) (E.C.4.1.1.50 [EC] ) were determined in individual papillomas induced inmouse skin by a two-stage technique, and in normal mouse epidermis.Cycloheximide treatment abolished both enzyme activities. Innormal epidermis the ODC activity was barely detectable, whereasthe tumors exhibited high levels of ODC. Levels of SAM-D activityabove those of normal epidermis were detected in some papillomas,but in contrast to ODC the SAM-D activity levels were not consistentlyincreased in skin tumors. By pooling a great number of papillomas,the variations in ODC and SAM-D activities between differentpapillomas could be minimized so that reliable measurementsof the biological half-lives of ODC and SAM-D in the tumorswere obtained using cycloheximide treatment. The half-life ofSAM-D in squamous papillomas was 45 min, almost identical tothe 41 min half-life of the 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced level of this enzyme in normal mouse epidermis.In contrast, the ODC activity of the mouse skin papillomas declinedat a rate similar to that in TPA-treated epidermis for onlythe first 15–20 min after cycloheximide injection. Thereafter,at time points when protein synthesis was 90% inhibited, theODC activity reverted to high levels. These results show thatthe high level of ODC activity in squamous papillomas is stabilized.This observation is compatible with the hypothesis that thecontrol mechanism of the ODC activity level in these tumorsis severely deranged. This change in polyamine turnover patternmay be related to altered differentiation of the epidermal cells,which constitute the main bulk of cells in these tumors.     

Ornithine decarboxylase activity, prolactin blood levels, and estradiol and progesterone receptors in human breast cancer

Ornithine decarboxylase (ODC) activity in human breast cancer tissues was correlated with prolactinemia (Prl), estradiol and progesterone cytosol receptors (ER and PR), and histopathologic pattern. Ninety-two cases of breast cancer, six benign mammary disease, and three normal breast tissues were studied for ER, PR, and ODC. Prolactinemia was assessed in 59 cancer patients, 14 of whom showed hyper-Prl along with significantly higher ODC than in patients with normal-Prl [(20.01 +/- 6.33) 10(-2) vs (5.20 +/- 0.90) 10(-2) pmol CO2/micrograms protein/h; P less than 0.0125]. A direct correlation was found between Prl and ODC in postmenopausal women (n = 40). Prl was assayed in seven of 13 ER-PR breast cancer patients; a highly significant, direct correlation was found between Prl and ODC in this group (r = 0.934, P less than 0.0025). ODC did not correlate with ER or PR. Carcinomas with higher ODC (n = 17) had higher cellularity, lower histologic differentiation, and higher nuclear anaplasia than those in which ODC was not detectable (n = 13). In normal breast and five of six benign mammary disease tissues, ODC was not detectable. These findings suggest that ODC could be a reliable marker for prognosis.     

Occupational physical activity and risk of adenocarcinomas of the esophagus and stomach

Physical activity may have a role in many cancers, but little is known about its effect on esophageal and gastric adenocarcinoma risk. We investigated occupational physical activity and esophageal and gastric adenocarcinoma risk in a population-based, case-control study including 212 esophageal, 264 gastric cardia and 389 distal gastric cancer cases, and 1,330 controls in Los Angeles County. Lifetime occupational histories were obtained during in-person interviews, and total lifetime occupational activity (Total Activity Index) was calculated using US Census job codes classified as sedentary, or moderately or highly physically active. Average Annual Activity Index was a per-year Total Activity Index counterpart. Unconditional logistic regression was used to calculate odds ratios, 95% confidence intervals and trend tests adjusting for gender, race, age, birthplace, education, smoking, body mass index (BMI) and number of years worked. Esophageal adenocarcinoma risk tended to decrease with increasing Total Activity Index (OR = 0.67, 95% CI = 0.38,1.19 for highest versus lowest quartile), but neither gastric cardia nor distal gastric cancer was associated with the Total Activity Index. This inverse association held for esophageal adenocarcinoma (OR = 0.61, 95% CI = 0.38,0.99 for highest vs. lowest quartile) and modest associations were observed for gastric cardia (OR = 0.76, 95% CI = 0.49,1.18) and distal gastric cancer (OR = 0.77, 95% CI = 0.52,1.14) when based on Average Annual Activity Index before age 65 years. Analyses stratified by gender, race, age, BMI, education and years worked provided similar results. We found a modest protective effect of Total Activity Index on esophageal adenocarcinoma. Future studies with more complete information on occupational and recreational physical activity are needed to confirm and further investigate the suggested protective effect of physical activity on these tumor types.     

Development of adenocarcinomas in the stomach

To elucidate the histogenesis of gastric adenocarcinomas, the author looked for smaller carcinomas, and studied their histologic features and the histologic characteristics of the neighboring gastric mucosa. In 325 resected stomachs, 27 microcarcinomas, including initial lesions, were detected. Most of them were typical adenocarcinomas, whose histologic features were different from those of dysplasias. The gastric mucosa around the microcarcinomas was mostly intestinalized. However, the smaller the carcinomas, the less complete was the form of intestinal metaplasia, and the metaplasia was under progression in many gastric tubules. The smallest carcinomas consisted of a few, newly formed glandular complexes, confined to the neck region of the tubules, whereas the upper and the lower part of the tubules were still lined by normal gastric cells. The smallest dysplasia was an in situ lesion, also confined to the neck region of the tubules. These findings indicate that a starting point of adenocarcinomas and dysplasias is in the proliferative cell zone at the neck region. Intestinal metaplasia, dysplasia, and adenocarcinoma arise coincidentally. This implies that no precursor is present for each of them. It appears that most adenocarcinomas arise in gastric tubules when an abnormal differentiation is induced in stem cells after intestinal metaplasia. They are not a consequence of dysplasia, but share a common origin with it.     

Ornithine decarboxylase activity, cell proliferation, and tumor promotion in mouse epidermis in vivo.

The effect of different phorbol esters and of mechanical treatment on the activity of ornithine decarboxylase in mouse epidermis in vivo was investigated. The strong promoter 12-O-tetradecanoylphorbol-13-acetate as well as the weak promoters phorbol dibenzoate and the 12-O-tetradecanoylphorbol-13-acetate analog 12-O-tetradeca-2-cis, 4-trans-6,8-tetraenoylphorobol-13-acetate strongly increased the activity of the enzyme and the intraepidermal level of putrescine, with a maximum at 5 hr after application, when applied in doses which evoke comparable proliferative and irritant responses in skin. The hyperplasiogenic but nonirritant and almost nonpromoting 4-O-methyl ether of 12-O-tetradecanoylphorbol-13-acetate did not show such effects. Mechanical removal of the uppermost horny layer led to a considerable increase of ornithine decarboxylase activity after 4 to 8 hr, while skin massage showed only a minute effect under conditions in which both treatments exhibit about the same mitogenic efficiency. Neither manipulation promotes tumor development. After skin massage, the induction of ornithine decarboxylase was influenced neither by treatments which alter the cyclic adenosine 3',5'-monophosphate level in epidermis (inhibition of phosphodiesterase, beta-adrenergic stimulation, and injection of dibutyryl cyclic adenosine 3',5'-monophosphate) nor by injection of epidermal G1 chalone. The results indicate that no clear-cut correlation exists between epithelial cell proliferation, development of hyperplasia, and tumor promotion on the one hand and an activation of epidermal ornithine decarboxylase on the other.     

Ornithine decarboxylase activity in L929 cells following exposure to 60 Hz magnetic fields.

To determine whether there is a biological basis for epidemiological studies which suggest an association between exposure to magnetic fields and cancer, we have attempted to replicate earlier findings on cellular enzymes related to cell proliferation. Here we report on an effort to replicate the doubling of ornithine decarboxylase (ODC) activity in L929 murine fibroblasts following exposure to 60 Hz magnetic fields reported by Litovitz et al. Efforts were made to reproduce the methods and exposure conditions used by the original investigators. Positive controls showed that our assay system responded to other known stimuli of ODC activity. We extended the previously reported investigations by testing a number of exposure conditions and other associated variables. Initial results suggested that cells exposed in the original investigators' laboratory demonstrated an enhanced enzyme activity, whereas cells exposed in our laboratory did not. Experiments in our laboratory using the most important elements of the original investigators' exposure system did not demonstrate any enhancement of ODC activity. Finally, a series of magnetic field exposure and sham exposure experiments conducted in the original investigators' laboratory failed to demonstrate an effect of magnetic fields on ODC activity.     

Telomerase activity in human intestine

In human somatic cells without the activity of telomerase, the ends of chromosomes consisting of the telomeric repeats TTAGGG progressively erode with each cell division. In germline and immortal cells telomerase activity maintains telomere length and thus compensates for the 'end-replication problem'. Progressive telomere shortening and reactivation of telomerase activity have been considered to be one of the key mechanisms in cellular senescence and immortalization. It has been shown that while most somatic cells do not have detectable telomerase activity, almost all cancers do have telomerase activity. Thus, detection of telomerase activity may have utility in the early diagnosis of cancer and may be a new target for therapeutic intervention. However, there is recent evidence that some cells of renewal tissues, such as hematopoietic cells and basal cells of the epidermis, have detectable telomerase activity. In the present study, we report detectable telomerase activity in normal human intestinal mucosa. This activity is localized to the lower third of each crypt and may be derived from intestinal stem cells. Since intestinal telomeric repeats are shorter in adults when compared to children, the telomerase activity in the intestine is insufficient to maintain telomere length but may be sufficient to provide extended proliferative capacity for such renewal tissues.     

Ornithine decarboxylase attenuates leukemic chemotherapy drugs-induced cell apoptosis and arrest in human promyelocytic HL-60 cells

Ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway, plays an important role in cell cycle, tumor promotion and anti-apoptosis. In our previous studies, overexpression of ODC prevented apoptosis induced by tumor necrosis factor-alpha and methotrexate. We further investigated the apoptotic mechanisms of the cancer chemotherapeutic drugs, including etoposide (VP-16), paclitaxel (TAX) and cisplatin (CDDP), and the influences of ODC on apoptosis and cell cycle. Our results showed that the investigated drugs induced caspase-dependent apoptosis, the generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (Deltapsi m) in HL-60 cells, all of which were reversed by putrescine, glutathione or N-acetyl-l-cysteine. Overexpression of ODC prevented the cancer chemotherapeutic drugs-induced apoptosis, ROS generation and the disruption of Deltapsi m. After drug administrations, the decline of Bcl-2, cytochrome c release and caspases' activation were inhibited by ODC overexpression. In cell cycle, ODC overexpressed cells seemed to overcome the G1 arrest and G2/M arrest, caused by VP-16 and TAX, respectively, and kept on the cell cycle rolling. Overexpression of ODC increased the expression of Cyclin A, D, E and Cdk4 and the enzyme activity of Cdk1 and Cdk2 after the treatment of VP-16 and TAX, respectively. In conclusions, the cancer chemotherapeutic drugs-induced apoptosis is through ROS-related, mitochondria-mediated and caspase-dependent pathways. With higher ODC activity, cells are resistant to the cancer chemotherapeutic drugs-induced apoptosis and keep on the cell cycle rolling with the significant interference in G1/S arrest caused by VP-16 and G2/M arrest by TAX.     

Ornithine decarboxylase over-expression stimulates mitogen-activated protein kinase and anchorage-independent growth of human breast epithelial cells

In these experiments we tested the hypothesis that constitutive activation of polyamine(PA) biosynthesis may contribute to mammary carcinogenesis. Spontaneously immortalized normal human MCF-10A breast epithelial cells were infected with the retroviral vector pLOSN containing a cDNA which codes for a truncated and more stable ornithine decarboxylase (ODC), the rate-limiting enzyme in PA synthesis. Upon chronic selective pressure with α-difluoromethyl-ornithine (DFMO) (an irreversible inhibitor of ODC), infected MCF-10A cells exhibited an approximately 250-fold increase in ODC activity, which persisted despite discontinuation of DFMO. ODC-over-expressing MCF-10A cells showed a modest decrease in S-adenosylmethionine decarboxylase and an increase in spermidine/spermine N¹-acetyltransferase. Analysis of cellular PA profile revealed a selective accumulation of putrescine without alterations in spermidine and spermine contents. Lesser degrees of increased ODC activity were obtained reproducibly by re-exposing the cells to incremental small doses of DFMO. We observed a bell-shaped dose-related positive effect of ODC activity on clonogenicity in soft agar of MCF-10A cells. Since anchorage-dependent growth was actually reduced, such positive influence on this feature of transformation was not a non-specific consequence of a growth advantage provided by ODC over-expression. In addition, we observed a close parallelism between the dose-dependent effects of ODC expression on clonogenicity and activity of the ERK-2 kinase, a central element of the MAPK cascade. Our data demonstrate an interaction between PA and the MAPK signalling pathway and suggest that the latter may be involved in ODC-induced transformation of mammary epithelial cells. Int. J. Cancer, 70:175–182, 1997. © 1997 Wiley-Liss, Inc.     

Daily excretion of melatonin in patients with cancer of the stomach and large intestine

Diurnal excretion of melatonin was studied in 37 cases of gastric and rectal cancer. In cancer patients nocturnal excretion was lower than in daytime while in healthy subjects the situation was reversed. Increased extrapineal production of melatonin as a possible cause of disorders in its excretion rhythm is discussed.     

Ornithine decarboxylase assay in human colorectal mucosa. Methodologic issues of importance to quality control.

Ornithine decarboxylase may be a useful biomarker for risk of neoplasia in colorectal tissues. Investigators have reported enzyme activities varying by as much as 10- to 20-fold using variations of the usual 14CO2 release assay. We have examined the effect of different methodologic factors on calculated ornithine decarboxylase activity. Major effects on the assay result (greater than 20% change) were produced by: (1) use of Tris vs. phosphate buffer, the former yielding 1.5- to 4-fold greater activity; (2) protein content of the reaction mixture with significant error if less than 50 micrograms; (3) use of alpha-difluoro-methylornithine-inhibited blank versus buffer-only blank. Other changes in assay conditions, including addition of sucrose, detergent, protease inhibitors, specific activity of 14C-ornithine, the nature of the trapping agent used, and incorporation of a sonication step, did not have a significant effect on ODC quantification (less than or equal to 20%). Thus, seemingly minor variations in assay conditions can greatly affect the results, which may provide a partial explanation for the variability of ODC activities reported in the literature. Strict quality control measures are mandatory in the interpretation of clinical observations utilizing this marker as an endpoint.     

Ornithine decarboxylase activity and DNA synthesis after treatment of cells in culture with 12-O-tetradecanoylphorbol-13-acetate.

The ability of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce the enzyme ornithine decarboxylase (ODC) and to stimulate DNA synthesis was studied in four different cell types in vitro. The effects of this agent on each cell type were different: (a) in hamster embryo cells, TPA induced ODC but had no effect on DNA synthesis; (b) TPA induced ODC and stimulated DNA synthesis in BALB/c 3T3 mouse cells; (c) it did not induce ODC in human fibroblasts but did stimulate DNA synthesis; and (d) it induced neither ODC nor DNA synthesis in rat embryo fibroblasts. In contrast to the effects of TPA, ODC was induced and DNA synthesis was stimulated in all cell types by fresh serum-containing medium. Treatment of the cells with a combination of fresh medium and TPA resulted in an approximate summation of the effects of treatment with each agent alone. These results emphasize the differences in the responses of various cells to TPA. They also show that in some cells, at least, the induction of ODC and stimulation of DNA synthesis following TPA treatment can be regulated independently.     

Ornithine decarboxylase lability in 2 transplantable highly deviated rat hepatomas

A strong ornithine decarboxylase (ODC)-inactivating capacity has been previously shown (M.F. Zuretti and E. Gravela (1983) Biochim. Biophys. Acta, 742, 269-277) to be bound to rat liver microsomes. Present results show that in 2 fast-growing transplantable tumors, the 3924A Morris hepatoma and the AH 130 Yoshida ascites hepatoma, microsomes are endowed with a greatly enhanced ODC-inactivating capacity, and, concurrently, ODC displays an extreme in vitro liability and an unusual thiol-dependency (most of the activity requires dithiothreitol supply to be determined). These data are at variance with those previously obtained in hepatomas induced by N-2-fluorenylacetamide (E. Gravela et al., (1983) Cancer Res., 42, 2298-2300). The possibility that ODC liability in the 2 hepatomas here studied may result from in vivo exposure to a strong microsomal activity is considered.     

Induction of ornithine decarboxylase activity in rat glandular stomach mucosa by bile acids

A single oral instillation of 1.5 g/kg body weight of sodium taurocholate resulted in a rapid, transient stimulation of ornithine decarboxylase activity in rat glandular stomach mucosa, reaching a peak (10 times the control value) 4 to 6 hr after sodium taurocholate treatment and returning to the control level within 48 hr. The degree of stimulation was dose-dependent. Sodium taurodeoxycholate and sodium taurochenodeoxycholate stimulated the enzyme activity similarly.     

A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine

Purpose

Small intestinal cancer is increasing in the U.S.A, yet little is known about its etiology. Our aim was to prospectively evaluate risk factors for this malignancy by the two main histologic subtypes (adenocarcinomas and carcinoids).

Methods

Hazard ratios and 95 % confidence intervals (CI) were estimated for all incident small intestinal cancers (n = 237), adenocarcinomas (n = 84), and malignant carcinoids (n = 124), by demographic and lifestyle factors among 498,376 men and women.

Results

Age was the only risk factor for adenocarcinomas (HR for ≥65 vs. 50–55 years = 3.12, 95 % CI 1.33, 7.31). Age (HR for ≥65 vs. 50–55 years = 3.31, 95 % CI 1.51, 7.28), male sex (HR = 1.44, 95 % CI 1.01, 2.05), body mass index (BMI, HR for ≥35 vs. 18.5–<25 kg/m² = 1.95, 95 % CI 1.06, 3.58), and current menopausal hormone therapy use (HR = 1.94, 95 % CI 1.07, 3.50) were positively associated with malignant carcinoids. A family history of any cancer or colorectal cancer (HR = 1.42, 95 % CI 0.99, 2.03; 1.61, 0.97, 2.65, respectively), or a personal history of colorectal polyps (HR = 1.51, 95 % CI 0.92, 2.46) produced elevated, but not statistically significant, risks for malignant carcinoids. Race, education, diabetes, smoking, physical activity, and alcohol intake were not associated with either histologic subtype.

Conclusions

Risk factors differed according to cancer subtype; only age was associated with adenocarcinomas, whereas age, male sex, BMI, and menopausal hormone therapy use were positively associated with malignant carcinoids.