Melanoma in people aged 65 and over in Scotland, 1979-89.

OBJECTIVE--Detailed analysis of primary cutaneous melanoma first diagnosed in Scotland in patients aged 65 and over. DESIGN--Comparison of changing incidence, sex distribution, site, histogenetic type, tumour thickness, and prognosis of all primary cutaneous melanomas in patients aged 65 and over diagnosed in Scotland in the 11 years 1979-89 with similar data for patients aged under 65. SETTING--Data were obtained from the Scottish Melanoma Group''s database, established in 1979, which aims to record detailed clinical, pathological, and surgical follow up details of all primary cutaneous melanomas registered in Scotland. PATIENTS--1430 patients (954 women, 476 men) aged 65 and over; comprising over a third of the 3903 patients with primary melanoma recorded for all age groups in Scotland during this period. RESULTS--The overall incidence of melanoma in patients aged 65 and over increased from 12.2/100,000 in 1979 to 20.7/100,000 in 1989, with the greatest increase seen in older men, from 7.8/100,000 in 1979 to 18.0/100,000 in 1989. The site most commonly affected was the face in both men and women (33% of all tumours). The most common histogenetic type was superficial spreading melanoma. 526 patients (37%) had melanomas with a tumour thickness of 3.5 mm or greater in the older age group, compared with 453 patients (18%) in those aged under 65. The highest proportion of thick tumours was seen in older men. Five year survival figures for 616 patients diagnosed between 1979 and 1984 were 88%, 66%, and 47% for thin, intermediate, and thick tumours respectively. Overall five year survival for the older age group was 64% compared with 78% for the younger age group. CONCLUSION--The increase in melanoma in the elderly and the high proportion of thick tumours, especially in men, require a specific educational programme for both primary and secondary prevention directed towards the older population.     

Opposite regulation of tenascin-C and tenascin-X in MeLiM swine heritable cutaneous malignant melanoma

Interactions between tumour cells and surrounding extracellular matrix (ECM) influence the growth of tumour cells and their ability to metastasise. It is thus interesting to compare ECM composition in tumours and healthy tissues. Using the recently described MeLiM miniature pig model of heritable cutaneous malignant melanoma, we studied the expression of two ECM glycoproteins, the tenascin-C (TN-C) and tenascin-X (TN-X), in normal skin and melanoma. Using semiquantitative RT-PCR, we observed a 3.6-fold mean increase of TN-C RNAs in melanoma compared to normal skin. Both stromal and tumour cells synthesise TN-C. On the contrary, TN-X RNAs decreased 30-fold on average in melanoma. This opposite regulation of TN-C and TN-X RNAs was confirmed at the protein level by indirect immunofluorescence. Whereas pig normal skin displayed a discrete TN-C signal at the dermo-epidermal junction, around blood vessels and hair bulbs, the swine tumour showed enhanced expression of TN-C in these areas and around stromal and tumour cells. In contrast, normal skin showed a strong TN-X staining at the dermo-epidermal junction and in the dermis, whereas this signal almost completely disappeared in the tumour. The results presented here describe a dramatic alteration of the ECM composition in swine malignant melanoma which might have a large influence on tumourigenesis or invasion and metastasis of melanoma cells.     

Metabolic determinants of stemness in medulloblastoma

Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glutathione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.     

Metastases of human tumor cells in immunosuppressed newborn rats

The metastatic ability of human tumour cells can easily be evaluated by using as an experimental model the production of metastases in newborn rats immunosuppressed by an optimal dose of anti-thymocyte serum. Thus, following sub-cutaneous injection of 10(6) cells, a human melanoma cell line, tumorigenic but non metastatic in nude mice, produces within 3 weeks tumours in all inoculated rats and lymph node and pulmonary metastases in 50% of the animals. The cloning of this cell line in semi-solid agar shows its heterogeneity and demonstrates that it contains poorly tumorigenic but highly metastatic cells.     

Transplantability and metastatic potential of chemically induced rat brain tumours

From clinical observations it is known that brain tumours in principle do not metastasize. An explanation for this phenomenon is not available. The few described cases of distant metastases from primary brain tumours all occurred after surgery of the central nervous system. Furthermore, the brain does not contain a lymphatic system. The major question in this matter is whether the inability of CNS tumours to metastasize is based on a specific tumour bound property or on specific local factors. Since an experimental model for this situation was not available we induced brain tumours in rats. About 130 WAG/Rij and Sprague Dawley rats (males and females) were treated with the neurocarcinogen ethylnitroso-urea (ENU) within 24 hours after birth. Tumours appeared at the age of 6 to 29 months. All tumours were removed after killing the host and transplanted subcutaneously into syngeneic rats. Histologically the tumours were mostly oligodendrogliomas, schwannomas and several mixed glial tumours. Metastases from these primary tumours were not observed. The transplanted tumours showed distant metastases in 52% of the cases. Metastases occurred mainly in lungs, liver and lymph nodes. From these observations it is concluded that the absence of metastases from primary brain tumours is probably not related to a specific property of brain tumours. Further research is emphasized on specific local factors.     

Immunotherapy of bovine ocular squamous cell carcinoma by repeated intralesional injections of live bacillus Calmette-Guérin (BCG) or BCG cell walls

Summary Thirty cows of the Dutch Friesian and the Maas-Rijn-Ijssel breed with histologically confirmed ocular squamous cell carcinoma were treated by repeated intralesional injection of live bacillus Calmette-Guérin (BCG) (n = 14) or a BCG cell-wall vaccine (n = 16). Complete regression of the primary tumour was observed in 64% and 57% of the animals respectively. In the 2-year follow-up period there was no recurrence of primary tumours. This sharply contrasts with the recurrence frequency (40%–50%) after complete remission induced by a single intralesional injection with BCG, observed in an earlier study. In 1 animal a new primary tumour developed. At necropsy metastases were present in 33% of the treated animals: in 3 of 17 animals that showed complete regression of the primary tumour and in 7 of 13 animals with partial regression or progressive disease. This did not differ significantly from results obtained after a single treatment (27%). Delayed-type hypersensitivity toM. bovis purified protein derivative (PPD) was more persistent in animals showing regression of the primary tumour than in non-responding animals. Of the animals with a positive PPD response 6 months after treatment, 79% showed tumour regression. Regression was observed in only 28% of the animals not responding to PPD after the same period of time. In conclusion: (a) recurrence of the primary tumour was not observed after repeated BCG treatment; (b) the frequency of metastases was not decreased compared to results obtained with a single treatment; (c) regression was correlated with a positive delayed-type hypersensitivity reaction to PPD (P <0.05) 6 months after treatment; (d) no significant differences were observed when the clinical results of treatment with live BCG and the BCG cell wall vaccine were compared.     

Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

Bladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting.The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate.Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.     

Prognostic factors in renal cell carcinoma

We studied 569 cases of renal cell carcinoma in the files of the Department of Pathology of the Norwegian Radium Hospital from 1964 to 1974. A nephrectomy had been performed in all cases. Clinical information on sex, age, survival time and metastases was traced. The histological slides were examined and tumour growth pattern, cell type, cell shape, nuclear atypia, abnormal nucleoli, nuclear grade, vascular invasion and tumour demarcation were all evaluated. Besides well-known prognostic factors such as tumour stage, presence or absence of metastases and vascular invasion, nuclear grade was found to be a useful prognostic factor. Younger patients were found to do better than older, and women better than men. Smaller tumours carried a better prognosis than larger and clear cell tumours had a better prognosis than those composed of eosinophilic or basophilic cells. The presence of spindle cells was a bad prognostic omen.     

Expression of class III beta-tubulin in neuroendocrine tumours of gastrointestinal tract

Class III b-tubulin is presented as a specific marker for the cells of neuronal origin as well as for the tumours originating from these cells. Its expression is considered one of the earliest events that appear in the cells revealing neuronal differentiation. Using monoclonal antibody TU-20 in an immunohistochemical analysis, we studied the expression of class III b-tubulin in gastrointestinal carcinoid tumours. Paraffin-embedded, formalin-fixed tissue sections from 49 tumour samples obtained from following locations: stomach (4 cases), small intestine (8 cases), appendix (18 cases), rectum (3 cases), pancreas (5 cases), liver metastases (7 cases) and lymph node metastases (4 cases) were used in the study. In 41 of the 49 tumour samples (83.7%), positive staining for class III b-tubulin was detected, while 8 tumour samples (16.3%) were negative. Expression of class III b-tubulin was prominent in all three rectal carcinoids and in three atypical carcinoids located in small intestine. Pancreatic neuroendocrine tumours revealed either weak immunostaining (2 cases), or were negative for this marker (3 cases). The intensity of class III b-tubulin immunolabelling was not related to the degree of tumour differentiation. The results of this study suggest that class III b-tubulin could be a perspective marker for gastrointestinal neuroendocrine tumours. Moreover, the differences in its expression could also elucidate some aspects of histogenetic relationships of neuroendocrine tumours of gastrointestinal tract.     

Research: Is resection of tumours involving the pelvic ring justified? : A review of 49 consecutive cases

INTRODUCTION: Pelvic surgery is challenging and impacts significantly on limb and visceral function, thus, raising the question "is heroic surgery justifiable". This study assessed the functional, oncologic and surgical outcomes following pelvis tumour resections. METHODS: Between 1996-2003, 49 patients (mean age 43 years) underwent pelvic tumour resections- 38 primary malignant tumours, 5 secondary tumours and 6 benign tumours. Bone tumours comprised 5 osteosarcomas, 5 Ewings sarcomas, and 12 chondrosarcomas. Of the soft tumours, 9 were of neural origin. Tumours involved the ilium, acetabulum, pubic bones, sacrum or a combination of these. Functional assessment was performed and no patient had metastases at presentation. RESULTS: There were 41 limb sparing resections and 8 hindquarter amputations. Surgical margins were intralesional (1), marginal (13), wide (26), and radical (3). Of limb sparing surgery, prosthetic reconstructions were performed in 10 patients, biologic reconstructions in 6, a combination of these in 3 and no reconstruction in others. There was 1 intraoperative death, 7 local recurrences and 19 metastases. Death from disease occurred at a mean of 14.2 months with a mean followup of 27 (1-96) months. Amputation and periacetabular resections had worse functional outcomes. Emotional acceptance was surprisingly high. CONCLUSION: Pelvic resections are complex. Functional outcome is significantly affected by surgery. Disease control is similar to limb tumours. Emotional acceptance of surgery in survivors was surprisingly high. Major pelvic resection for malignancy appears justified.     

Spontaneous endometrial tumours of 'Sabra' rats

In a 2 year study of 171 female (101 virgin; 70 multiparous) 'Sabra' rats, spontaneous endometrial tumours were found in 69% of 2 year old animals. Tumour development appeared to be age related, and only virgin females showed tumours before 18 months of age. Polyps were the most prevalent tumour type, followed by adenocarcinomas. The Sabra rat can be included among those rat strains having a high incidence of spontaneous endometrial neoplasia.     

CYTOKINETICS OF TUMOUR AND ENDOTHELIAL CELLS AND VASCULARIZATION OF LUNG METASTASES IN C3H/HE MICE

A model of lung metastases was developed using intravenous injection of tumour cell aggregates of spontaneous C3H/He mammary tumours in syngeneic mice. the growth rate of lung tumours decreased with increasing tumour volume, with mean host survival of 46 days. the cytokinetics of individual tumours ranging between 0.004 and 4.2 mm³ in volume were studied. the labelling index (LI) ranged between 12 and 17%, the DNA synthesis time (T_s) being 9–10 hr. the growth fraction (GF) ranged between 26 and 38%. the cell cycle time (T_c) was found to be 18–19 hr. the LI and the GF decreased with increasing tumour volume doubling time (T_d). No correlation was found between the tumour volume and T_c. the LI of endothelial cells within these tumours, ranging between 0.004 and 4.2 mm³ in volume was 14–15% and endothelial cell proliferation was not affected by tumour growth. Vascular parameters were also determined for these tumours as a function of tumour volume. Vascular volume increased with increasing tumour size while the percentage of capillary vessels decreased. the cellular volume to capillary volume ratio increased with increasing tumour volume. Necrosis was observed in 0.27 mm³ tumours and increased with increasing tumour size. The results from these studies suggested that the age-dependent decrease in proliferative activity of tumour cells growing in the lung is related to change in effective vascularity.     

Serotonin-producing pancreatic endocrine tumour. Histological, ultrastructural and immunohistochemical study of a case

Serotonin-producing pancreatic endocrine tumours are rare neoplasms which in most cases exhibit malignant biological behaviour. These tumours, in the majority of the well-documented cases, are composed of argyrophil- and argentaffin-positive cells which contain large pleomorphic neurosecretory granules. In contrast, argyrophilic non-argentaffin pancreatic endocrine tumours with tumour cells containing round neurosecretory granules are exceptional. In this study we describe such a tumour not associated with clinical evidence of carcinoid syndrome in a 60-year-old woman. Histological examination revealed tumour extension in pancreatic lymphatic vessels and veins but no evidence of locoregional or distant metastases. Ten months after surgery the patient showed no recurrence of the disease. Immunohistochemistry revealed cytoplasmic serotonin production in the tumour cells which were negative for anti-gastrin, insulin, glucagon, somatostatin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP) and ACTH. This study emphasizes the usefulness of combined ultrastructural and immunohistochemical investigations in order to identify and characterize the rare pancreatic endocrine tumours with serotonin production.     

An endogenous melanocyte-inhibiting tripeptide pyroGlu-Phe-GlyNH2 delays in vivo growth of monoclonal experimental melanoma

The melanocyte-inhibiting tripeptide (MTP) pyroGlu-Phe-GlyNH₂ is present in tissue cultures of non-transformed melanocytes and melanoma cells and influences melanocyte growth in vitro . The objective of the present study was to investigate a possible effect of MTP on the in vivo growth of B16A2, a monoclonal experimental melanoma. The B16A2 clone was established by the limited dilution technique. It has a reduced DNA content and displays slower growth both in vivo and in vitro compared to the parent cell line (B16). B16A2 cells were injected subcutaneously into hairless mice at four sites (300 000 cells in 0.25 ml buffer/site). MTP was given by i.p. injection 3 times a week at two concentrations (1 pmol and 1 nmol/animal). The control animals received the equal volume of solvent. The animals were sacrificed 1 and 2 weeks after tumour transplantation, and all tumours were weighed. One week after transplantation, the animals who received 1 pmol MTP had fewer tumours and a reduced tumour load. Two weeks after the transplantation, the differences between control and treated animals were no longer observed. The results indicate that MTP temporarily delays in vivo tumour growth.     

Protective immunity to UV radiation-induced skin tumours induced by skin grafts and epidermal cells

There is little evidence that cutaneous dendritic cells (DC), including epidermal Langerhans cells (LC), can induce immunity to UV radiation (UVR)-induced skin tumours. Here, it is shown that cells within skin can induce protective antitumour immunity against a UVR-induced fibrosarcoma. Transplantation of the skin overlying subcutaneous tumours onto na?ve recipients could induce protective antitumour immunity, probably because the grafting stimulated the tumour Ag-loaded DC to migrate to local lymph nodes. This suggests that cutaneous APC can present tumour Ag to induce protective antitumour immunity. Previously, it has been shown that immunization of mice with MHC class II+ epidermal cells (EC) pulsed with tumour extracts could induce delayed-type hypersensitivity against tumour cells. Here, this same immunization protocol could induce protective immunity against a minimum tumorigenic dose of UVR-induced fibrosarcoma cells, but not higher doses. Epidermal cells obtained from semiallogeneic donors and pulsed with tumour extract could also induce protective immunity. However, presentation of BSA Ag from the culture medium was found to contribute to this result using semiallogeneic EC. The results suggest that LC overlying skin tumours may be able to induce protective immunity to UVR-induced tumours if stimulated to migrate from the skin.     

Analysis of morphology of adrenal pheochromocytoma as regards their potential malignancy

BACKGROUND: Adrenal pheochromocytoma are diagnosed the most often in patients with arterial hypertension or with thyroid medullar cancer and suspicion of MEN II syndromes. The aim of the study is to analyse the morphology of pheochromocytomas on the basis of Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) in order to estimate their potential malignancy. MATERIAL AND METHODS: Forty tumours were subjected to analysis. Mean patients age was 45.2+/-13.4 years. The diagnosis of pheochromocytoma was establish before surgery in 87.5%. 12.5% of patients were referred to surgery on the basis of tumour diameter (range 70 to 102 mm). In 20.0% of patients MEN II syndromes were diagnosed. RESULTS: In pathological examination benign pheochromo-cytoma was diagnosed in 39 presented patients. In 1 cases malignant form of pheochromocytoma was diagnosed on the basis of lymph nodes metastases. Number of points in PASS was >or=4 in 9 of 40 tumours (22.5%). Among 35 patients operated on more than 12 months ago 2 patients died: 1 patient with malignant pheochromocytoma (PASS=8 points) and 1 patient with MEN IIA syndrome (due to disseminated thyroid medullar cancer). In remaining 7 observed patients with PASS>or=4 points neither recurrence nor metastases were diagnosed within the period of observation (13-90 months). In 1 out of patients with PASS<4 points a local recurrence was surgically removed 82 months after primary operation. CONCLUSION: Analysis of pheochromocytoma in PASS is only of rough character and does not allow for clear-cut histological diagnosis of benign and malignant tumours. The only unquestionable criterion of pheochromocytoma's malignancy remain metastases.     

Hereditary adenocarcinomatosis in 4 generations of a Valais family

An account is given of a family from the Canton of Valais, suffering from hereditary adenocarcinomatosis. The pedigree extends over four generations; the first three comprise 47 individuals (28 males, 19 females), of whom 21 (16 males and 5 females), i.e. 44.6%, are affected with malignant tumours. Of the 32 people in the fourth generation, only one individual is affected to date (a girl aged 21, IV/14). There were 27 tumours in all: 16 adenocarcinomas of the colon, two gastric adenocarcinomas, one duodenal adenocarcinoma, one rectal adenocarcinoma, one papillary carcinoma of the ovary, one osseous sarcoma, one cutaneous fibrosarcoma, a multiform glioblastoma of the basal nuclei of the brain, a basocellular epithelioma, also a cerebral metastasis from an adenocarcinoma, the origin of which has not been established, and a tumour invading the biliary tract. Three members of the family suffered from multiple tumours. In three of the patients, the colonic adenocarcinoma was accompanied by one or two polyps. The average age at the onset for all the tumours was 45 years. It was definitely lower in the third than the second generation (anticipation). The transmission was autosomal dominant, with predilection for the male sex (57.1% male and 26.3% female patients). The penetrance was about 80%. The author finally discusses the diagnostic criteria for hereditary adenocarcinoma and reviews the different familial forms of cancer.     

Results of primary culture of malignant melanoma explants by the so-called compact covering lattices method

Results from primary cultures of malignant melanomas explants can be amplified. The original method is based upon collagen lattices use. The collagen is retracted by human fibroblasts obtained from human angiomas. The cultured tumor fragments are covered by the lattices, which are now adhering to the flask. Six primitive malignant melanomas and three cutaneous metastases were cultured according to the classical method and the new method described here. Compact covering lattices allow a regular melanocytic redifferentiation either in primitive malignant melanomas or in cutaneous metastases. The results point out: the microenvironment's role in tumour growth; the different behaviour of primitive tumours and metastases.     

Changing tumour antigen expression in metastatic hepatocellular carcinoma cells of the guinea pig

Hepatocellular carcinoma cells (Line-10), obtained from ascitic fluid after diethylnitrosamine treatment of Sewall Wright strain-2 guinea pigs, produce solid (primary) tumours, lymph-node and lung metastases and malignant ascites when reinjected into animals of the same strain. Monoclonal antibodies were raised against the tumour cells by immunizing BALB/c mice with viable ascitic hepatocellular Line-10 tumour cells. Three hybridomas producing anti-Line-10 monoclonal antibodies were selected for further studies (10TL1, 10TL40 and 10TL43) and compared with monoclonal antibodies against intermediate filament keratins. The anti-Line-10 monoclonal antibodies did not cross react with Line-1 hepatocellular carcinoma cells, nor with normal guinea pig hepatocytes. When ascitic Line-10 cells form high papillary projections on the peritoneal surface, they significantly reduced their antigen expression of 10TL40 and of 10TL43 defined antigens, while the expression of 10TL1 defined antigens remained unaltered. Invading Line-10 cells in the deep submesothelial stromal tissue, however, lost reactivity with MoAb 10TL43 but not with the MoAb's 10TL40 and 10TL1. The antigens on lung- and lymphnode metastases remained largely unaffected. The reactivity with MoAb's 10TL40 and with 10TL43 was also lost upon prolonged culturing of Line-10 cells. The reactivity of Line-10 and Line-1 cells with all monoclonal antibodies against keratin filaments remained unaltered. Line-1 cells could be distinguished from Line-10 cells by the absence of any reactivity with the MoAb's 10TL1, -40, -43, but also by the fact that 100% of the Line-1 cells were positive with antibodies against keratins 5/8, 18, and 7.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidemiology of central nervous system tumors in Karlovac area (Croatia), 1995-2010

The aim of this study was to provide an overview of the central nervous system (CNS) tumours epidemiology in Karlovac region, over the 1995-2010 period. We analyzed data on 359 patients (194 men and 165 women), diagnosed with CNS tumours according to the World Health Organization's diagnostic criteria, in period 1995-2010. The data were obtained from the Neurology and Neurosurgery Department, including other medical records. The data were analysed with t-test and chi-square test. A total of 359 cases of tumours in CNS were recorded for the period of 1995-2010, with slight predominance of men (194;54.0%) over women (165;46.0%). Under the assumption of gender equality, we did not detect a significant gender difference in tumour diagnosis (p = 0.279). Mean age at the diagnosis was 64.1 +/- 12.6 years, with significant gender difference: mean age at diagnosis for men was 62.8 +/- 11.6 years, while for women it was 65.7 +/- 13.5 (p = 0.029). The commonest type of all tumours was metastases (144;40.1%). When only primary tumours were analysed, the commonest type was glioblastoma (125;58.15%), followed by meningeoma (44;20.5%). The remaining types were much less frequent, with i.e. 5 recorded cases of the following three types: astrocytoma, ependimoma and oligodendroglyoma (2.3%). These results suggest a commonly encountered epidemiological profile in the region, with commonest metastases, and glioblastoma as the most common primary tumour. Due to difficulties related to patient gravitating hospitals admittance and overall small sample size for more detailed analyses, it remains for future studies to determine potential association of the Homeland war (1991-1995) and the occurrence of CNS tumours.