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Abstract Blocking oncogenic signaling induced by the BRAFV600E mutation is a promising approach for melanoma treatment. We tested the anti-tumor effects of a specific inhibitor of Raf protein kinases, PLX4032/RG7204, in melanoma cell lines. PLX4032 decreased signaling through the MAPK pathway only in cell lines with the BRAFV600E mutation. Seven out of 10 BRAFV600E mutant cell lines displayed sensitivity based on cell viability assays and three were resistant at concentrations up to 10 μM. Among the sensitive cell lines, four were highly sensitive with IC50 values below 1 μM, and three were moderately sensitive with IC50 values between 1 and 10 μM. There was evidence of MAPK pathway inhibition and cell cycle arrest in both sensitive and resistant cell lines. Genomic analysis by sequencing, genotyping of close to 400 oncogeninc mutations by mass spectrometry, and SNP arrays demonstrated no major differences in BRAF locus amplification or in other oncogenic events between sensitive and resistant cell lines. However, metabolic tracer uptake studies demonstrated that sensitive cell lines had a more profound inhibition of FDG uptake upon exposure to PLX4032 than resistant cell lines. In conclusion, BRAFV600E mutant melanoma cell lines displayed a range of sensitivities to PLX4032 and metabolic imaging using PET probes can be used to assess sensitivity.

Background: Since allelic loss of genes involved in the development of colorectal cancer could serve as prognostic markers, we examined the correlation between loss of markers linked to the hMSH2/hMSH6 (2p21-16.3), hMLH1 (3p21.3), APC (5q21-22), p53 (17p13.1) and DCC (18q21.3) loci and survival in a series of 64 consecutively collected colorectal cancers., Methods: The association between allelic loss and survival was analysed by univariate and multivariate tests to identify independent variables of survival., Results: Loss of chromosome 2p21-16.3 reduced the overall 5-year survival from 52% to 15% (P = 0.0003). The prognostic significance was evident in patients with Dukes' A + B as well as Dukes' C tumours. A multivariate analysis comparing Dukes' staging, age at diagnosis, tumour localization, sex, loss of chromosome 2p21-16.3, 3p21.3, 5q21-22, 17p13.1 or 18q21.3 and microsatellite instability showed that only Dukes' staging (hazard ratio 3.0; 1.4-6.5 with 95% confidence interval, P = 0.0065) and loss of 2p21-16.3 (hazard ratio 6.2; 2.3-16.8 with 95% confidence interval, P = 0.0006) were independent variables of survival. Loss of 2p21-16.3 was, moreover, associated with increased loss of the other tumour suppressor loci (P = 0.012)., Conclusions: The results show that loss of 2p21-16.3 is an independent indicator of survival in patients with colorectal cancer.

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome characterized by the development of colorectal cancer (CRC) and other carcinomas. Our aim was to evaluate tumour parameters and survival in HNPCC., Methods: One hundred and eight Danish HNPCC patients were compared with 870 patients with sporadic colorectal cancer., Results: The median age at CRC diagnosis was 41 years in the HNPCC group. HNPCC patients had significantly more carcinomas located to the right colon (68% against 49% in controls), more synchromous tumours (7% versus 1%), more metachronous CRC after 10 years (29% versus 5%), more localized carcinomas (62% versus 39%), and significantly higher crude cumulative 5-year survival (56% versus 30%)., Conclusions: CRC in HNPCC behaves differently compared to sporadic cases concerning age of onset, frequency of multiple lesions, and location. The metastatic tendency is less than in sporadic CRC and the survival is better.

To investigate the familial aggregation of colorectal cancer in Denmark, parents and siblings of colorectal cancer patients diagnosed below age 60 years in the years 1982-1984 were identified through population registries. For 1,470 probands with families eligible for tracing, 1,376 mothers, 1,303 fathers and 3,259 siblings were identified. They contributed 222,634 person-years, and 325 cases of colorectal cancer were observed during the follow-up period 1943-1992. All data were retrieved from population registries and consequently were free from any reporting bias. The overall standardized morbidity ratio (SMR) compared with the Danish population was 2.02 (95% confidence interval [CI] 1.81-2.25), significantly different between the parents (1.78, 95% CI 1.55-2.04) and the siblings (2.65, 95% CI 2.21-3.17). A strong dependence on the proband's age at diagnosis was seen for the sibling risk; siblings of probands less than 50 years old at diagnosis had a 5-fold risk compared with the general population. This dependence was not seen for parents, but the risk tended to be higher for parents of younger ages. No other factor was seen to influence the relative risk. The observation of an 80% increased risk among the parents and a 170% increased risk among the siblings indicates that the genetic component is one source, but probably not the only one, of familial aggregation of colorectal cancer. The cost benefit of screening siblings of colorectal cancer patients is substantially higher than that for the total population.

In order to investigate the frequency of congenital hypertrophy of the retinal pigment epithelium (CHRPE) in sporadic colorectal cancer, ophthalmoscopy was carried out in 34 patients with colorectal carcinoma without known familial disposition. CHRPE is one of the most frequent extracolonic manifestations in familial adenomatous polyposis. None of the patients showed any sign of CHRPE. It is concluded that although genetic factors are presumably of importance in the development of sporadic colorectal cancer, CHRPE cannot be used as a marker for future risk of colorectal carcinoma except in polyposis families.

Pantomography of the mandible was performed in 98 patients with sporadic colorectal adenocarcinoma. Twenty-eight patients (29%) had osteomas versus 5% in a control group (P < 0.001). Mandibular osteomas are found in most patients with the premalignant dominant syndrome familial adenomatous polyposis. Sporadic colorectal cancer examinations of married couples have shown that diet has only a moderate influence on the development of colorectal cancer, whereas pedigree studies indicate a genetic component. On this basis we conclude that mandibular osteomas are probably genetic markers of the development of sporadic colorectal carcinoma.

Hereditary non-polyposis colorectal cancer (HNPCC) probably constitutes 5% of all the cases of sporadic colorectal cancer. At present, the diagnosis can only be established on the basis of a family history which should fulfill the "Amsterdam criteria": 1) Colorectal cancer in at least three family members, 2) One family member must be a close relative of the other two, and 3) The diagnosis must have been established prior to the age of 50 years in at least one relative. Other forms of cancer also occur in the HNPCC syndrome, particularly endometrial cancer. The syndrome has a dominant inheritance and, therefore, all close relatives should be submitted to control examinations for the most important forms of cancer associated with the syndrome.

In order to investigate the influence of a possible genetic factor on the development of colorectal cancer (KRC), a cohort investigation was carried out among parents of patients with KRC. A total of 1,542 patients participated in the investigation. These patients were under the age of 60 years and registered in The Danish Cancer Register as cases of KRC during the period 1982-1984. 96% of the parents of these patients were identified by means of the administrative registers. The parents were then sought in The Danish Cancer Register for cancer during the period 1943-1986. The incidence rates for the Danish population were employed to calculate anticipated number of cases of KRC among these parents. significantly increased frequencies of KRC were found among both the mothers and the fathers, as the standardised incidence ratio was 1.62 in mothers and 1.87 among fathers. As a Danish investigation of spouses of patients with KRC has not demonstrated any increased frequency of KRC among spouses, it is concluded that this finding indicates a possible genetic factor in the etiology of KRC.

A retrospective study of 325 consecutive patients suffering colorectal adenocarcinoma, allowed in 141, the determination of the influence of blood transfusion upon the risk of recurrence/metastases over a minimum observation period of 6 months. Of 29 patients not receiving blood transfusion, 6 were subjected to recurrence/metastases. Of 112 patients receiving blood transfusion, 45 suffered recurrence/metastases. No significant difference in the risk of developing recurrence/metastases was seen when the primary tumor was Dukes' class A and C. When the primary tumor was Dukes' class B, a significantly higher risk of recurrence/metastases was seen in the group receiving blood transfusion. A constrained use of blood transfusion in connection with colorectal surgery is recommended until definitive immunological studies determined the influence of blood transfusion upon the risk of recurrence/metastases.

To investigate the genetic factor in the development of colorectal cancer, a cohort study was undertaken of parents of patients with this disease. All 1,524 patients, who were diagnosed with colorectal cancer in Denmark in 1982-84 and were below the age of 60 years, were selected from the National Cancer Register. The parents of these patients were identified from the public population registers. The index persons had a total of 1,478 eligible mothers, of whom 96% were successfully traced, and a total of 1,414 eligible fathers, of whom 96% were traced. These parents were sought in the Cancer Register for cancer cases diagnosed in the period January 1, 1943 to December 31, 1986. The incidence rates for the Danish population were used to estimate the expected numbers of colorectal cancer cases among the parents. Both the mothers and the fathers exhibited an increased risk of colorectal cancer. The standardized incidence ratios were 1.62 (95% CI 1.31-2.01) and 1.87 (95% CI 1.54-2.27), respectively. In a previous study we found that spouses of patients with colorectal cancer in Denmark did not have an increased risk of this disease. The increased risk found in the present study among the parents of patients therefore indicates that a possible genetic factor is present in the aetiology of colorectal cancer, and that it is of importance in the general population.

Familial adenomatous polyposis is a dominant hereditary disease which includes early development of up to several thousand colorectal adenomas and subsequent development of colorectal adenocarcinoma in all of the untreated cases. In addition, various extracolonic manifestations may be observed. These include epidermoid cysts, osteomas, desmoids and gastroduodenal polyps. Conventional proctosigmoidoscopy is employed as the primary diagnostic method as all of the patients have rectal adenomata. Thereafter colonoscopic examination is undertaken and gastroduodenoscopy is performed on account of the risk of development of duodenal adenomas. Treatment consists of prophylactic colectomy at about the age of 15 years. An ileorectal anastomosis is most frequently made but construction of an ileoanal reservoir may be considered in selected cases. Regular prophylactic control examinations of first degree relatives of affected family members should commence at the age of ten years. Recent demonstration of a specific gene for polyposis on chromosome 5 will, together with demonstration of retinal pigmentation permit early preclinical diagnosis in future. Establishment of the Polyposis Register has resulted in earlier tracing and treatment of the condition and an improved prognosis.

One hundred and seventy-six individuals with various colorectal diseases were investigated simultaneously for increased in vitro tetraploidy in dermal fibroblast cultures and for occult mandibular osteomas. In only 10 of the 176 persons were both presumed markers of colorectal genetic predisposition present in the same individual. No evidence was found that these traits are causally associated. A combination of the two presumed markers showed a tendency towards occurrence in individuals with a positive family history of colorectal cancer among first-degree relatives.

Orthopantomography of the mandible was carried out on 50 patients with colorectal cancer without known familial disposition. Twelve patients (24%) had osteomas, as against 5% in the control group (P less than 0.001). Since an increased occurrence of mandibular osteomas has earlier been demonstrated in cases of familial polyposis coli and the family cancer syndrome, we must conclude that genetic factors are presumably of more importance in the development of colorectal cancer than previously assumed.

The beneficial effect of renal artery embolization on flank pain in a patient with terminal colon cancer is described. The indications for the procedure are discussed, including its use in similar cases for temporary improvement of the quality of life.

Orthopantomography of the mandible (OTM) showed osteomas in 3 of 34 non-affected sibs and children of the probands in 14 families with polyposis coli. The observed to expected ratio with osteomas was 0.35, which is not significantly lower than 1.0 and in accordance with the frequency in the normal population. Although the result does not enable a definite evaluation of the diagnostic value of OTM, the finding suggests that this method may be used as a supplement to regular proctosigmoidoscopic screening of first-degree relatives of polyposis patients.

Orthopantomography of the mandible was carried out on 50 patients with colorectal adenoma(s) without carcinoma or any known familial disposition. Four patients (8%) had osteomas, and we advance the hypothesis that individuals with both osteomas and adenomas represent a separate type of adenoma patient. Further studies are needed to evaluate the prognostic value of the association of adenomas and mandibular osteomas.

In a follow-up study of 32 patients with duodenal ulcer complicated by pyloric stenosis treated by highly selective vagotomy and dilatation of the stricture, we found an ulcer recurrence rate of 19% and a restenosis rate of 7.6% after a minimum of six years of observation. It is concluded, that dilatation can be used as an alternative to former surgical procedures in the treatment of pyloric stenosis and that highly selective vagotomy is still justified in the treatment of some cases of duodenal ulcer.

A 33-year-old man had a three-year history of ulcerative colitis. After 14 months of treatment he developed localized colitis cystica profunda mimicing a stenosating cancer of the rectum. The process developed over a short period. The diagnosis is based on a histological examination revealing benign submucosal cysts lined by columnar epithelium. A conservative surgical attitude is recommended.

A total of 26 patients with familial polyposis coli without extracolonic manifestations were examined by gastroduodenoscopy. Histologically verified polyps were found in 18 patients (69 percent, 95 percent confidence limits 48-86). Gastric adenoma was diagnosed in one patient, fundic gland polyposis in six patients, and duodenal adenomas in 12 patients. It is concluded that the incidence of gastroduodenal polyps is independent of the clinical presence of other extracolonic manifestations. It is advisable that polyposis patients should be followed with gastroduodenoscopy and biopsy of polyps.

Twenty-four patients with malignant pelvic mass had diverting ureterocutaneostomy. Four patients (17%) developed necrosis and one (4%) required surgical correction due to stenosis. The remaining patients had a well-functioning ureterocutaneostomy until the death which occurred median 174 days later. We find that good palliation can be achieved using this simple operation, and therefore recommend it as the urinary diverting procedure to patients with obstructing pelvic malignancy.

Orthopantomograms of the mandible were performed on 46 patients with familial polyposis coli having no clinical signs of Gardner's syndrome and on 46 control patients matched according to age and sex. Thirty-five patients (76.1 per cent) and two (4.3 per cent) controls had osteomas (P less than 0.0005). It is concluded that orthopantomography of the mandible is a valuable diagnostic supplement to prophylactic proctosigmoidoscopic examination of first-degree relatives of polyposis patients. Due to the frequent occurrence of mandibular osteomas in polyposis patients without clinically detectable extracolonic manifestations, it is suggested that "Gardner's syndrome" is no longer considered a clinical entity.

In a follow-up study of 40 patients operated on for a bleeding vessel in a duodenal ulcer by means of ligation, pyloroplasty and vagotomy, we found that 9 patients (23%) suffered from recurrent bleeding, with a fatal outcome in 7 cases (78%). We conclude therefore that this method is unsuccessful, and if haemostasis is not achieved by endoscopic electrocoagulation operative resection is suggested. Where resection indicates too high a risk to the patient, we suggest that the operative procedure is reduced to ligation of the bleeding vessel combined with a medical vagotomy in the form of an H2-receptor antagonist.

In a four-year-old boy perforation of a peptic ulcer occurred in a Meckel's diverticulum located on a duplication of the small intestine. Complications in connection with Meckel's diverticulum and intestinal duplication are discussed, and also the indications for surgery. If the duplication is too large for resection, continuity of passage must be ensured.

Hydroceles in children less than one year old should only be treated surgically when discomfort occur, as spontaneous remission is to be expected in this age group. Surgery is nearly always indicated in older children. In a consecutive series of 83 children operated for hydrocele, a follow-up study found a 2% recurrence rate, after an average of 5 years observation, despite the ligation of the processus vaginalis at the anulus inguinalis profundus. In that only 7% of the children developed a contralateral hydrocele, routine exploration on this side is deemed unnecessary.

One hundred and seventy-two patients (76 patients with colorectal cancer, 46 with adenoma of the colon or rectum, and 50 controls) were investigated for in vitro tetraploidy in dermal fibroblast monolayer cultures. The incidence of increased in vitro tetraploidy (IVT) among patients with adenoma or carcinoma was significantly different from that of controls. There was no difference in the incidence of IVT between the adenoma patients and those with colorectal cancer. IVT was investigated among different subgroups of adenoma and colorectal cancer patients and was only found to be related to an inherited tendency to colorectal cancer.

Forty-seven Danish and 50 Finnish patients with familial adenomatous polyposis coli (FPC) were studied by panoramic tomography (PTG) of the mandible, which showed dental abnormalities in 17% of the cases. Eleven patients (11%) had supernumerary teeth and/or compound osteomas, and nine patients (9%) had impacted permanent teeth. The frequency of the dental anomalies was statistically significantly higher in FPC patients than in the normal population; it is therefore concluded that this dental abnormality should be included in the list of extracolonic manifestations that may occur in any FPC patient. The frequency of dental anomalies was higher in Finnish than in Danish patients, probably owing to a higher frequency of extracolonic manifestations in the Finnish series.

One hundred and seven patients (57 patients with ulcerative colitis and 50 controls) were investigated for in vitro tetraploidy (IVT) in dermal fibroblast monolayer cultures. There was no difference in incidence of IVT between patients with ulcerative colitis and controls. We advance the hypothesis that the genetic background of the colorectal cancer type found in ulcerative colitis differs from that found in the colon cancer syndromes and in non-hereditary colorectal cancers. Colorectal cancer in ulcerative colitis is probably only dependent on the degree of inflammatory lesions of the colonic mucosa.

Orthopantomography of the mandible in 50 consecutive patients with ulcerative colitis showed mandibular osteomas in 2 patients (4%), which is the same frequency as found in the normal population. Since earlier investigations have shown an increased frequency of mandibular osteomas in familial polyposis coli, the cancer family syndrome, and colorectal cancer without known familial disposition, it is concluded that the etiology of colorectal carcinoma in ulcerative colitis is not, as for these diseases, a combination of the same genetic and environmental factors but probably only a function of the duration and involvement of the disease.