High Incidence Of Carcinoma Research Articles

Prevalence and oncologic impact of chronic kidney disease for upper tract urothelial carcinoma in endemic area

ObjectiveThis study aimed to assess the impact of preoperative chronic kidney disease (CKD) on the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who underwent standard radical nephroureterectomy (RNU). MethodsA total of 1172 UTUC patients who received RNU at a single center in Taiwan between February 2005 and August 2019 were included. The patients were categorized into two groups based on their preoperative CKD stage: CKD stage ≤3 (811 patients) and CKD stage >3 (361 patients). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula. The study investigated the oncological outcomes, including intravesical recurrence, non-urothelial recurrence, and cancer-specific mortality, stratified by preoperative CKD status. ResultsThe main findings indicated that UTUC patients with CKD stage >3 in Taiwan exhibited a higher proportion of females (p < 0.001), a greater history of concurrent bladder cancer (p = 0.003), more multifocal tumor behavior (p < 0.001), a higher incidence of carcinoma in situ (p = 0.008), increased rates of intravesical recurrence (p < 0.001), a lower prevalence of smoking history (p = 0.003), lower utilization of adjuvant chemotherapy (p < 0.001), reduced occurrence of non-urothelial recurrence (p < 0.001), and lower cancer-specific mortality (p = 0.006) compared to patients with CKD stage ≤3. Multivariate Cox regression analysis revealed significant differences in intravesical recurrence (p = 0.014) and non-urothelial recurrence (p = 0.006) between the CKD stage >3 and CKD stage ≤3 groups. The study also demonstrated that patients with concurrent bladder cancer and variant histology had higher rates of intravesical recurrence, non-urothelial recurrence, and cancer-specific mortality. The CKD stage >3 group exhibited lower rates of intravesical recurrence (p = 0.0014), higher rates of non-urothelial recurrence (p < 0.0001), and increased cancer-specific mortality (p = 0.0091) compared to the CKD stage ≤3 group in the 5-year free survival analysis. ConclusionIn Taiwan, UTUC patients with CKD stage >3 exhibit distinct characteristics compared to the general population with urothelial carcinoma. They are associated with a non-smoking status, a higher proportion of females, and less aggressive pathological features. Additionally, CKD stage >3 can serve as a clinical indicator for intravesical and non-urothelial recurrence. Further investigation into molecular aspects and treatment modifications for these patients is warranted.

Diagnostic Accuracy of Fine Needle Aspiration Cytology (FNAC) in Salivary Gland Lesions with Histopathological Examination (HPE) Correlation in a Tertiary Care Centre in Southern India.

This study aimed to determine the diagnostic yield of fine-needle aspiration cytology (FNAC) in salivary gland lesions compared to histopathological diagnosis. The present study was done on patients above 18years of age, with a palpable swelling, who are clinically diagnosed as salivary gland lesions were evaluated. A total of 31 patients were evaluated in this study. The mean age of the patients was 41years ± 16.08. The male to female ratio of patients evaluated in our study was 1: 1.066, with a marginal preponderance in the female population. There was a higher incidence of carcinoma in females than males. Parotid gland lesions comprised 83.9% of all the salivary gland lesions analyzed, while submandibular gland lesions comprised 16.1%. In our study, the distribution between non-neoplastic, neoplastic benign, and neoplastic malignant lesions was 9.6%, 83.8%, and 6.4%. The overall diagnostic accuracy for non-neoplastic and neoplastic lesions is 90.3%, with a sensitivity of 89% and a specificity of 100%. The segregation of the results into the positive and negative class of diagnostic outcomes shows 80.6% for true positive, 9.7% for true negative, 0% for false-positive, and 9.7% for false-negative reports. Diagnostic accuracy in differentiating non-neoplastic and neoplastic lesions is 90.3%, with a sensitivity and specificity of 89.0% and 100%, respectively. The diagnostic accuracy of FNAC in differentiating benign from malignant lesions in our study is 93.5% (29 out of 31), the sensitivity of FNAC in our study for diagnosing malignancy is poor, and the specificity is 100%. It can be concluded that FNAC is more accurate in diagnosing benign lesions and more specific than sensitive in diagnosing malignant lesions.

“A HISTOPATHOLOGICAL STUDY OF TUMORS OF ORAL CAVITY”

Background: The incidence of oral cavity neoplasms in the population has increased manifold over the years. Oral cancer is one of the common cancers in the world, common in India, and also in Bangladesh, Srilanka and Pakistan. Oral cancer is one of the few cancers, whose cause were known and hence it is possible to prevent. The real challenge in oral cancer lies in its prevention and early diagnosis. Objectives: 1.To study the morphological spectrum of neoplasms in oral cavity. 2.To study the age and gender incidence of various neoplasms. 3.To study the commonest sites of various neoplasms. 4.To evaluate or analyse the associated risk factors. Materials and methods: This is a prospective study of the cases attended to Government General Hospital, Vijayawada or Government Dental College Hospital Vijayawada, of oral cavity neoplasms. The biopsy of the tissues was carried out at the Department of Pathology, Siddhartha Medical College, Vijayawada. The study period was from June 2011 to August 2013 over a period of two years and three months. Results: The Study comprises a total of 74 surgical biopsies from oral cavity neoplasms received in the Department of Pathology, 52 of these were malignant lesions and 20 were benign tumour and 2 were premalignant conditions. The invasive squamous cell carcinoma was the most frequent histological type of oral cavity neoplasms. Among the oral cancers, peak age th th incidence was the 5 and 6 decade of life. There was signicant male preponderance. Tongue was the most common site involved. Smokeless tobacco consumption was the commonest associated habit which leads to malignancy. Conclusion:In thisa study we observed that among the oral cavity neoplasms, high incidence of carcinomas are seen, among these squamous cell carcinomas are predominant.

Hürthle cell neoplasms of the thyroid: Pathologic outcomes and ultrasonographic analysis.

BackgroundFine‐needle aspiration (FNA) of thyroid nodules suspicious for Hürthle cell neoplasms (HCN) have uncertain rate of malignancy. We aim to characterize rate and predictors of malignancy at our institution and compare these findings with established literature to help guide management.MethodsSingle tertiary‐referral center, retrospective study of 166 adults who underwent hemithyroidectomy or total thyroidectomy following FNA suspicious for HCN from 1998‐2018. Demographic information and surgical histopathologic results were collected. Preoperative ultrasonography was independently scored on the American College of Radiology Thyroid Imaging Reporting and Data System (TI‐RADS) by a board‐certified head and neck radiologist.ResultsThere were 39 males and 127 females. Overall, 25 (15.1%) patients had carcinoma, with 15 (9%) being Hürthle cell carcinoma (HCC). Men had higher incidence of carcinoma (25.6% v. 11.8%, P = .035), and especially older males. Contralateral carcinoma was seen in 3 of 13 (23.1%) patients that underwent completion thyroidectomy. Patients with carcinoma had larger nodules (average diameter 3.3 cm versus 2.5 cm, respectively, P = .01), but no association with TI‐RADS.ConclusionAdults with nodules suspicious for HCN have significant risk of malignancy consistent with prior studies. Older males and larger nodule diameter are associated with malignancy in this cohort, but TI‐RADS grade is not. These findings provide a framework for management and counseling for lesions suspicious for HCN.

An AFM-Based Nanomechanical Study of Ovarian Tissues with Pathological Conditions.

BackgroundDifferent diseases affect both mechanical and chemical features of the involved tissue, enhancing the symptoms.MethodsIn this study, using atomic force microscopy, we mechanically characterized human ovarian tissues with four distinct pathological conditions: mucinous, serous, and mature teratoma tumors, and non-tumorous endometriosis. Mechanical elasticity profiles were quantified and the resultant data were categorized using K-means clustering method, as well as fuzzy C-means, to evaluate elastic moduli of cellular and non-cellular parts of diseased tissues and compare them among four disease conditions. Samples were stained by hematoxylin–eosin staining to further study the content of different locations of tissues.ResultsPathological state vastly influenced the mechanical properties of the ovarian tissues. Significant alterations among elastic moduli of both cellular and non-cellular parts were observed. Mature teratoma tumors commonly composed of multiple cell types and heterogeneous ECM structure showed the widest range of elasticity profile and the stiffest average elastic modulus of 14 kPa. Samples of serous tumors were the softest tissues with elastic modulus of only 400 Pa for the cellular part and 5 kPa for the ECM. Tissues of other two diseases were closer in mechanical properties as mucinous tumors were insignificantly stiffer than endometriosis in cellular part, 1300 Pa compared to 1000 Pa, with the ECM average elastic modulus of 8 kPa for both.ConclusionThe higher incidence of carcinoma out of teratoma and serous tumors may be related to the intense alteration of mechanical features of the cellular and the ECM, serving as a potential risk factor which necessitates further investigation.

Cancer Screening Findings in Korean People with Disabilities: 2016-2017

Background/Objectives: Cancer screening programs are effective in the early detection of several cancers. This study aimed to identify the findings of cancer screenings that were conducted in 2016 and 2017.Methods/Statistical analysis: Sample were obtained from the National Health Insurance Service, and the cancer screening findings among both people with disabilities and those without were compared. Gastric, breast, colon, liver, and cervical cancer were analyze the findings of the screening programs. The findings were categorized as benign, suspicious of malignancy, or other categories (depending on type of cancer). Descriptive statistics and the X2-test were used to analyze the findings among the groups.Findings: The findings were as follows: For gastric cancer screenings, 0.30% in 2016 and 0.35% in 2017 of those screened who had brain injury were found to have gastric cancer, whereas 0.16% in 2016 and 0.15% in 2017 of those screened who were non-disabled where found to have gastric cancer (p<.001). For breast cancer screenings, 0.90% in 2016 and 0.54% in 2017 of those screened who had brain injury had findings that were suspicious of malignancy. For colon cancer screenings, 4.48% in 2016 of those screened who had brain injury were found to have colon cancer, whereas 3.70% in 2016 of those who were non-disabled were found to have colon cancer (p<.001). For liver cancer screenings, people with brain injury had the most findings that were suspicious of liver cancer in 2016 (p<.001), whereas people with physical impairment had the most findings that were suspicious of liver cancer in 2017 (p<.001). The non-disabled group had the highest incidence of carcinoma in situ among groups in 2016 (p<.001) and 2017 (p<.001).Improvements/Applications: Rigorous cancer screening programs should be implemented and expanded to include brain injury and physical impairment disabilities for the early detection of gastric, breast, colon, and liver cancer.

A Rare Cause of Mirizziʼs Syndrome: Cholangiocarcinoma

Introduction: Elevated liver function tests are the most common reason for consultation to a hepatology service, the etiologies of which are varied but most commonly are due to viral hepatitis, toxic, and ischemic injuries. Obstruction due to biliary stones are also a common etiology as well, but we present a more rare case of biliary obstruction that resulted in elevated liver function tests and has a higher incidence of carcinoma. Case Report: A 48-year-old female with no past medical history presents with 1-month history of gradual yellowing of her eyes and skin. Also noted decreased appetite, increasing pruritis, and some subjective weight loss. She denied any abdominal pain, nausea, vomiting, signs of gastrointestinal bleeding, fevers, or chills. She has never experienced this prior. On exam, her vital signs were normal but she had overt jaundice as well as scleral icterus. She had mild tenderness to palpation in the right upper quadrant but negative Murphy's sign. Admission labs revealed a total bilirubin of 14.1 with a direct bilirubin of 10.3. Her AST and ALT were elevated to 112 and 78, respectively, as well as an alkaline phosphatase elevation to 308. Her amylase and lipase were mildly elevated to 146 and 168, respectively. Workup included negative hepatitis serologies and autoimmune panel among other tests. An MRCP was performed which showed a large obstructing cystic duct stone compressing against the common bile duct (CBD) with subsequent biliary tree dilation. An ERCP was performed which confirmed these findings and a CBD stent was placed with effective biliary drainage. She subsequently went for a cholecystectomy. However, 1 month later she presented again with weight loss and jaundice, and was subsequently diagnosed with cholangiocarcinoma after ERCP and further surgical evaluation. Discussion: Mirizzi's syndrome is a rare disorder for which the indication for cholecystectomy is <1%. It is characterized by two different classifications (Csendes or McSherry) based on the presence of and the extent of a cholecystocholedochal fistula. The diagnosis can be made preoperatively with MRCP or ERCP, but often they are diagnosed intraoperatively. The ultimate treatment is surgical cholecystectomy but an ERCP with stent placement can be a temporizing measure. One lesser known association of Mirizzi's syndrome is that there is a higher incidence of gallbladder carcinoma; in one study up to 27%. Thus it is imperative to send the specimen for pathology to evaluate for malignancy and to also expedite any cases of Mirizzi's syndrome for surgical resection. To date, we report the only case of Mirizzi's syndrome associated with cholangiocarcinoma.

CIRCULATING CONCENTRATIONS OF IL-2, IL-6, TNF-ALPHA AND ENDOTOXIN IN PATIENTS OF CARCINOMA GALL BLADDER

Introduction: Gallbladder Cancer represents the most common and aggressive type among the biliary tree cancers (BTCs). Carcinoma Gallbladder has an unusual geographic distribution. The highest incidence of carcinoma of gallbladder is in Chileans, American Indians, and in parts of North India. Objective: The present study was designed to characterise the circulating concentrations of endotoxin and different inflammatory mediators in patients with Carcinoma Gall bladder. Methods and Material: One hundred twenty eight Carcinoma Gall bladder patients were included in the study. Enzyme-linked immunosorbent assay was used for determining the circulating concentrations of Interleukin-2 (IL-2), Interleukin -6 (IL-6), Tumor Necrosis Factor-α (TNF-α)and Endotoxins in human serum. A cross sectional trial was performed. Results: The mean age of the patients was 50.86±12.6 years. The mean duration of jaundice was since last 74.91±50.0 days. Fifty five percent patients had cholelithiasis association with Carcinoma Gall bladder. The mean Body Mass Index (BMI) of Carcinoma Gall bladder patients were 18.33±2.8. The mean circulating concentrations of IL-2 were 33.31±56.6 pg/ml, IL-6 were 167.16±216.4 pg/ml, TNF-α were 56.00±56.7 pg/ml and endotoxin were 0.66±0.2 EU/ml. Conclusions: Mean circulating concentrations of IL-2 and TNF-α were lower and mean circulating concentrations of IL-6 were higher than the previous studies. The mean circulating concentrations of endotoxin were within the normal limits. Which concludes that cytokines may participate in gallbladder carcinogenesis and the study provides evidence for a strong link between chronic inflammation and Carcinoma Gall bladder.

Cryptorchidism-pathophysiology, treatment concept and long-term follow up results

Undescended testes (cryptorchidism), incomplete descent at birth of one or both testes affects 1-3% of boys and is the most common endocrine disease in childhood. If untreated, the undescended testis may develop progressive failure of spermatogenesis and has a higher incidence of carcinoma that may manifest in adolescence and adulthood. Endocrine and primary end organ failures are the two etiological factors most frequently held responsible for the increased incidence of infertility in unilateral and bilateral cryptorchidism. The cryptorchid testis has a typical histology showing depletion of germ cells and impaired maturation of gonocytes accompanied by intestinal fibrosis and Leydig cell atrophy. In 70% of males with isolated cryptorchidism, hypogonadotropic hypogonadism is the cause of undescended testes. The number of Ad spermatogonia that develop in infancy during the period of mini puberty (the stem cells for mature spermatozoa) is severely reduced . The ultimate aim of all therapy for cryptorchidism is to have both testes in the scrotum and to achieve normal fertility. Hormonal treatment is recommended for all patients prior to orchidopexy and those at high risk of infertility (no Ad spermatogonia). Treatment includes Kryptocur for inducing epididymo-testicular descent and Buserelin (LH-RHa) for prevention of infertility. If unsuccessful surgery should be performed before patients second birthday.

Does choroid plexus tumour differ with age?

Choroid plexus neoplasms are rare intracranial neoplasms. Significant differences exist in their presentation and management in paediatric and adult populations. The present study aims to study the differences among the paediatric and adult population, various factors affecting the outcome, and the clinical and histological correlation. This is a retrospective study of 47 patients with choroid plexus neoplasms managed at NIMHANS from 1984 to 2004. The case records and images were retrieved and reviewed. The various histopathological features were outlined and histopathology reviewed accordingly. For follow-up, patients were contacted by letter or telephone and the necessary information obtained. Follow-up was available in 41 out of 47 patients. Sixty per cent patients were in the paediatric age group and 40% were adults. Forty-three per cent of children with tumours were less than 1 year of age. The lateral ventricle was the most common site of involvement in the paediatric group compared with the fourth ventricle in adults. Calcification is seen on CT scan more often in papillomas and in adult tumours. Invasion of surrounding parenchyma may be seen in both papillomas and carcinomas. However, in papillomas it is by nests of tumour cells compared with carcinomas wherein invasion is by individual tumour cells. Hydrocephalus is present irrespective of location and size of the tumour. Gross total excision is more feasible in adults. Large tumour size, excessive blood loss, higher incidence of carcinomas result in partial excision of these tumours in the paediatric group. Subdural collections and tumour bed haematomas are more common complications in the paediatric group after resection of tumour. These tumours have significant differences among paediatric and adult groups. Carcinomas are predominantly seen in younger children. Invasion of brain parenchyma by nests of cells does not carry a poor prognosis. The outcomes are better in adults.

Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis

Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2), a transcription factor that regulates inducible expression of detoxifying enzymes, is critical in preventing N-nitrosobutyl(4-hydroxybutyl)amine (BBN)-induced urinary bladder carcinogenesis. To explore whether Nrf2 and the tumor suppressor p53 cooperatively act in tumor prevention, we investigated the susceptibility of Nrf2-/-::p53+/- mice to BBN-induced urinary bladder carcinogenesis. The incidence of BBN-induced urinary bladder carcinoma was 63.0% in Nrf2-/- mice (P = 0.115), 75.8% in p53+/- mice (P < 0.01) and 89.6% in Nrf2-/-::p53+/- mice (P < 0.01) compared with 37.9% in wild-type. Higher incidence of carcinoma was observed in Nrf2-/-::p53+/- mice when compared with either Nrf2-/- (P < 0.01) or p53+/- mice (P = 0.382). Similarly, muscular invasive carcinoma incidence was higher in Nrf2-/-::p53+/- mice (62.0%) than either wild-type (6.9%, P < 0.01), p53+/- (38.0%, P = 0.110) or Nrf2-/- mice (3.7%, P < 0.01). Furthermore, urinary concentrations of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN, were only increased when Nrf2 but not p53 was disrupted. These results demonstrate that tumor susceptibility is synergistically exacerbated in Nrf2-/-::p53+/- mice due to poor detoxification and accelerated proliferation in comparison with either single mutant alone. BBN administration increased p53-mediated expression of p21, Mdm2 and Bax, and the inducible expression of p21 was significantly enhanced in Nrf2-/- mice. Conversely, modest increases in NAD(P)H dehydrogenase, quinone 1 (NQO1) and uridine diphosphate (UDP) glucuronosyltransferase 1A6 (UGT1A6) expression were observed in p53+/- compared with those of wild-type mice after BBN exposure. These results thus reveal potential interactions between p53 and Nrf2 and their gene batteries, and indicate that both factors cooperatively contribute to tumor prevention.

Management strategies for patients with nipple discharge

The aim of this study was to assess management strategies for patients with nipple discharge (ND). The records of 13,443 women with breast-related complaints who were examined by the same surgeon between 1 January 1960 and 31 December 2000 were retrospectively assessed. Patients with ND were grouped according to whether they had had a spontaneous or provoked discharge. The parameters investigated in each group were age, physical findings, number of pregnancies, duration of lactation, duration of discharge, colour of discharge, and histopathological features. Chi-square and Mann-Whitney U-tests were used for statistical analysis. ND was the presenting symptom in 603 (4.5%) of the cases. Two hundred and eighty-seven (48%) of the 603 patients showed spontaneous nipple discharge (SND group) and the other 316 (52%) showed provoked nipple discharge (PND group). In the SND group, 124 (43%) tissue specimens were obtained by either biopsy or sub-areolar exploration. Histopathological examination revealed that the most frequent causes of ND in these cases were intraductal papilloma (49 patients; 40%), intraductal carcinoma (35 patients; 28%), and cystic disease (15 patients; 12%). Twenty tissue specimens were obtained from the group with PND. In these cases, the most frequently identified causes of ND were cystic disease (seven patients; 35%), intraductal papilloma (six patients; 30%), ductal ectasia (two patients; 10%), and carcinoma (one patient; 5%). The SND and PND groups differed significantly with respect to age (P = 0.001) and duration of ND (P = 0.008). The incidence of cancer was higher in the SND specimens than in the PND specimens (28% vs 5%, respectively; P = 0.01). The number of pregnancies was significantly higher and the duration of lactation was significantly longer in the SND group (P = 0.03 and P = 0.02, respectively). The study confirms previous reports that patients with SND have a higher incidence of carcinoma than those with PND. The results suggest that older age, higher number of pregnancies, and longer duration of lactation may predispose to cancer development in patients with SND. The possibility of breast cancer should also be kept in mind when one is assessing patients with PND. Careful physical examination and close follow-up is the optimal management strategy for patients with any type of ND.

Flies in the colon.

Any regular reader of this column will have noticed a preoccupation with developmental pathology. This is a personal interest, but depends on a conviction that the mechanisms of development, properly understood, are central to the development of most degenerative disease and of much other pathology. The latest surprise is about carcinoma of the colon. The Adenomatous Polyposis Coli (APC) tumour suppressor gene is known to be affected in many families who have a high incidence of carcinoma of the colon and to show truncation mutations in about 80% of colonic adenomas and carcinomas in sporadic cases. The tumour suppressor function of the gene depends on its ability to promote the degradation of β ‐catenin, a protein that functions in intercellular junctions in epithelium. What has this to do with wingless fruit flies? It's all to do with the …

A New Model for the Induction of Tumours in the Forestomach of Rats by N-Methyl-N-Nitrosourea

Background and Aim: Experimental carcinogenesis models provide a useful tool in the study of the aetiopathogenesis and treatment of gastric cancer. We developed a model based on the administration of N-methyl-N-nitrosourea (NMU) in Wistar rats for the induction of maximal yield of gastric carcinomas with a short latency period, and being exclusively localized at the gastric level. Methods: A gastric antiperistaltic fistula was performed in 90 Wistar rats classified into eight different groups. Fifteen days after surgery 5, 10, 15 or 20 mg of NMU/100 g were administered through the fistula once a week for a 3- to 5-week period. Before the administration of NMU, a pyloric blockade was made in order to obtain a temporary isolation of the stomach. At 20 weeks, animals were sacrificed and organs were removed for histological study. Results: All rats treated with 15 mg NMU/100 g once a week for 5 weeks, after pyloric blockade maintained for 1 h, developed well-differentiated carcinomas in the forestomach. Carcinomas were multiple in 11% of cases and appeared with papillomatous lesions in 33% of rats. No tumours were observed in any other organs. In the other groups, no gastric carcinomas were diagnosed. Conclusion: The high incidence of carcinomas in the forestomach, the absence of tumours in other organs and the short latency period represent valuable criteria for the use of our model in chemotherapeutic investigations, as well as in the study of cancer evolution without interferences caused by tumour development in other organs.

Tumour induction as a consequence of immunosuppression after renal transplantation.

Immunosuppressed recipients of organ transplants have a higher incidence of carcinoma than the general population. A retrospective analysis was made at the Department of Urology of Bonn University, investigating 236 renal allograft recipients as to the incidence of neoplasms before and after transplantation. Eleven patients developed malignant tumours after transplantation. In 4 out of these 11 patients, case history showed pre-existing malignancies. Two of the 4 patients developed a second tumour, while the other two had tumour progression (latency period 21-77 months). Three of the 4 patients died of their tumours 21, 42 and 77 months after transplantation, whereas one female patient is still alive and free of neoplasms 32 months after transplantation. In 7 out of these 11 patients de novo tumours were diagnosed (latency period 3-88 months). All of them are still alive (NED between 15 and 85 months), six of them with good transplant function. There was no difference to be seen in the incidence of malignancies between kidneys supplied by Eurotransplant (n = 40) and ABO compatible kidneys from our own donors (n = 196). The higher incidence rate of neoplasms in transplant recipients requires high standards in preventive measures. Any suspicious change that may occur in the course of a thorough follow-up of transplant recipients must be removed and examined histologically. Patients with previous malignant diseases must be payed special attention, since they frequently tend to develop another malignant tumour and progression of existing tumours, respectively. As far as immunosuppression is concerned, therapeutic guidelines for the treatment of transplant recipients do not differ from those set up for patients on haemodialysis. Since immunosuppression with increased rates of tumour incidence can also be observed in dialysis patients, the mere fact of increased incidence of neoplasms cannot be taken as an argument against transplantation. With a more or less equal risk of tumour incidence the crucial factor should be the higher quality of life for transplant recipients.

The Stereoisomeric Fjord-Region Benzo[c]phenanthrene-3,4-Dihydrodiol 1,2-Oxides Malignantly Transform Rat Liver Epithelial Cells

Abstract The rat liver oval cell line OC/CDE 22 was exposed to each of the four optically active fjord-region dihydrodiol epoxides of benzo[c]phenanthrene to investigate their capacity for malignant transformation of liver cells. All four configurational isomers malignantly transformed OC/CDE 22 cells, resulting in a similar colony-forming efficiency in soft agar. Inoculation of the transformed cells into newborn syngeneic rats produced an extremely high incidence of carcinomas with a short latency period. The induced carcinomas displayed cholangiocellular, adenoid and solid growing structures. Thus, the fjord-region dihydrodiol epoxides of benzo[c]phenanthrene are able to efficiently transform rat liver cells. Furthermore, experimental evidence is presented that proliferation plays a central role in liver cell transformation mediated by polycyclic aromatic hydrocarbons.

Malignant transformation of the liver tumour precursor cell line OC/CDE 22 by the four stereoisomeric fjord region 3,4-dihydrodiol 1,2-epoxides of benzo[c]phenanthrene.

In previous work we established the rat liver oval cell line OC/CDE 22 in order to study in vitro mechanisms of liver cell transformation. We have now exposed OC/CDE 22 cells to each of the four optically active fjord region dihydrodiol epoxides of benzo[c]phenanthrene to investigate their capacity for malignant transformation of liver cells. All four configurational isomers, which are among the most potent carcinogenic metabolites of polycyclic aromatic hydrocarbons tested in murine tumour models, malignantly transform OC/CDE 22 cells at a 2 microM dose level, resulting in a similar colony-forming efficiency in soft agar. Inoculation of the transformed cells into newborn syngeneic rats produced an extremely high incidence of carcinomas with a short latency period. The induced carcinomas displayed cholangiocellular, adenoid and solid growing structures. Neither cell growth in soft agar nor induction of tumor formation in newborn rats were achieved if confluent OC/CDE 22 cell cultures were exposed to each of the four stereoisomers and left in the confluent state for 4 weeks. In contrast, if confluent cells were exposed to the four stereoisomers, immediately split and then subcultured as usual, full transformation was accomplished. Our results indicate that the fjord region dihydrodiol epoxides of benzo[c]phenanthrene are highly efficient transforming agents for rat liver cells and that proliferation plays a pivotal role in the liver cell transformation process induced by polycylic aromatic hydrocarbons.

Animal models for the study of prostate carcinogenesis.

Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small, latent carcinoma to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways may exist. The precise etiology and pathogenesis of human prostate cancer remain largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens produces a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. Chronic treatment with testosterone also produces a low prostate carcinoma incidence. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU) and 3,2'-dimethyl-4-aminobiphenyl (DMAB). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU- or DMAB-initiated and/or testosterone-promoted tumors are adenocarcinomas; most originate from the dorsolateral and anterior, but not ventral, prostate lobes. These tumors share a number of important characteristics with human prostate cancer. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. Another high incidence prostate carcinogenesis model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta to rats in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. While it is unknown whether testosterone is a tumor promoter in this system, preliminary studies indicate the formation of a DNA adduct in the target tissue, which suggests that estradiol-17 beta acts as a tumor initiating agent in this system. The high incidence models mentioned earlier are adequate for the study of chemoprevention of prostatic carcinogenesis. Analysis of shifts in the relative incidence of metastasizing carcinoma, grossly apparent but not-metastasizing carcinoma, microscopic-size carcinoma, and carcinoma in situ or atypical hyperplasia may allow study of the modifying effects of potential chemopreventive agents on tumor progression in these animal models of prostatic carcinogenesis.

Uracil-induced calculi and carcinogenesis in the urinary bladder of rats treated simultaneously with N-butyl-N(4-hydroxybutyl)nitrosamine

Urinary bladder carcinogenicity of uracil and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in combination was investigated in male F344 rats. Two experiments were performed: in the first animals were treated with 3.0, 1.0 and 0.3% uracil in the diet and/or 0.005% BBN in the drinking water for 36 weeks followed by a 4 week period without chemicals, the total observation time being 40 weeks; in the second rats received 3.0% uracil in the diet or 0.05% BBN in the drinking water for 4 weeks. In the first experiment, a markedly high incidence of carcinomas was observed in the urinary bladder with both 3.0% uracil alone (11/15, 73%) and 3.0% uracil plus 0.005% BBN (18/20, 90%) treatments. The multiplicity, i.e. numbers of carcinomas induced per 10 cm of basement membrane, was significantly higher with the latter treatment (P less than 0.05), as were proliferative lesions in the renal pelvis. Stone formation was observed in all 3.0% uracil treatment animals. In the second experiment, prostaglandin E2 levels in bladder tissue of uracil-treated animals proved to be significantly higher than in BBN-treated or untreated animals. Thus, the results clearly indicated that calculi associated with 3.0% uracil ingestion can themselves cause carcinoma development in the urinary bladder, while also acting as a potent co-carcinogen agent for BBN carcinogenesis.

Effects of urinary crystals induced by acetazolamide, uracil, and diethylene glycol on urinary bladder carcinogenesis in N-butyl- N-(4-hydroxybutyl)nitrosamine-initiated rats

In order to examine the promoting effect of urinary crystals on urinary bladder carcinogenesis, acetazolamide, uracil, and diethylene glycol, all of which have been reported to cause urinary crystals or calculi, were administered to male F344 rats for 32 weeks after pretreatment with 0.05% N-butyl- N-(4-hydroxybulyl)nitrosamine (BBN) for 4 weeks. A marked increase in urinary crystals was observed in acetazolamide-treated rats and a slight increase in crystals was observed in uracil- and diethylene glycol-treated rats. Histological examination of the urinary bladder revelaed that the BBN-acctazolamide treatment resulted in a higher incidence of carcinoma than BBN-control. Uracil and diethylene glycol did not cause any significant difference compared to the control. Promoting effects by urinary crystals were not clearly shown in the present experiment and, therefore, urinary crystals appear to play a very limited role, if any, in urinary bladder carcinogenesis.