Apexogenesis after initial root canal treatment of an immature maxillary incisor - a case report.

AIM: To present a case where a traumatized, immature tooth still showed capacity for continued root development and apexogenesis after root canal treatment was initiated based on an inaccurate pulpal diagnosis. SUMMARY: Traumatic dental injuries may result in endodontic complications. Treatment strategies for traumatized, immature teeth should aim at preserving pulp vitality to ensure further root development and tooth maturation. A 9-year-old boy, who had suffered a concussion injury to the maxillary anterior teeth, was referred after endodontic treatment was initiated in tooth 21 one week earlier. The tooth had incomplete root length, thin dentinal walls and a wide open apex. The pulp chamber had been accessed, and the pulp canal instrumented to size 100. According to the referral, bleeding from the root made it difficult to fill the root canal with calcium hydroxide. No radiographic signs of apical breakdown were recorded. Based on radiographic and clinical findings, a conservative treatment approach was followed to allow continued root development. Follow-up with radiographic examination every 3rd month was performed for 15 months. Continued root formation with apical closure was recorded. In the cervical area, a hard tissue barrier developed, which was sealed with white mineral trioxide aggregate (MTA). Bonded composite was used to seal the access cavity. At the final 2 years follow-up, the tooth showed further root development and was free from symptoms.

Health technology assessment and implications for clinical practice: the case of prostate cancer screening.

We describe an initiative to disseminate evidence from systematic reviews about the clinical effectiveness of prostate cancer screening to general practitioners and urologists in Norway. The Norwegian Centre for Health Technology Assessment invited The Norwegian Medical Association, The Norwegian Cancer Society, The Norwegian Board of Health, The Norwegian Urological Cancer Group and The Norwegian Patient Association to develop and disseminate clinical practice recommendations. The clinical effectiveness of prostate cancer screening has been assessed in nine independent systematic reviews, which are summarized in a joint INAHTA report. The conclusion was that there is no evidence from appropriately designed trials that early detection and treatment of prostate cancer can reduce mortality, morbidity or improve quality of life. The number of prostate-specific antigen (PSA) tests analysed in Norway increased by 47% [corrected] from 1996 to 1999; at the county level the increase ranged from 12 to 48%. On this background we disseminated leaflets with information about PSA and prostate cancer to 4100 general practitioners and specialists in urology. The main message was, i) PSA should not be taken in healthy men, ii) if the test is wanted, the physician is obliged to give information about the possible consequences. Despite efforts to anchor the information campaign within the mentioned organizations, this met with notable opposition from The Norwegian Urological Society. A survey among agencies within the INAHTA network showed that more than half of the countries within this collaboration have implemented guidelines or recommendations on prostate cancer screening. In conclusion, evidence obtained through an international collaboration such as the INAHTA collaboration may be used to develop and implement national guidelines or recommendations.

Adjuvant endocrine treatment (goserelin vs tamoxifen) in pre-menopausal patients with operable node positive stage II breast cancer. A prospective randomized national multicenter study.

AIMS: To evaluate possible differences in effect on time to recurrence and overall survival in node positive pre-menopausal breast cancer patients (age < or = 50 years) receiving LHRH analogue or tamoxifen as adjuvant endocrine treatment. METHODS: Between January 1989 and July 1994, 320 patients with node positive (pN(+)) and hormone receptor positive or receptor status unknown tumors were included and randomized in a national multicenter study to receive either tamoxifen or goserelin as adjuvant treatment for two years. Primary surgical treatment was employed according to current standards. Final follow-up was completed as of December 2000. Time to events were estimated by the Kaplan-Meier method, and compared by the log rank test. Relative risks were estimated by the Cox's proportional hazards model. RESULTS: No differences in time to first recurrence or overall survival were observed between treatment groups. Proportions of patients in each group having a second breast cancer were also similar. CONCLUSIONS: Standard adjuvant treatment with tamoxifen as compared to adjuvant LHRH analogue therapy employed in this group of breast cancer patients gave similar outcomes, but the number of patients was too small to formally exclude a potentially clinically relevant difference in survival.

[The radiotherapy satellite in Kristiansand--a model for Norwegian regional hospitals?]. / Stråleterapisatellitten i Kristiansand--en modell for norske regionsykehus?

BACKGROUND: During the first decade of 2000, significant increase of radiotherapy capacity in Norway will take place, as the number of linear accelerators will increase from 24 to 36. In Norway, radiotherapy departments are traditionally located only in university hospitals. However, six of the new accelerators will not be installed in existing radiotherapy centres, but in small, new radiotherapy units, set up in selected county hospitals and organized as satellites of the university hospitals, in order to secure the treatment quality. The university hospital is responsible for both medical and technical standards in the satellite, while the county hospitals have the financial responsibility. RESULTS: The satellite model combines two important aspects of hospital management; treatment is geographically decentralized, while treatment quality is centralized. The first radiotherapy satellite was established in the town of Kristiansand in January 2001. We report our experience with this new concept in radiotherapy. INTERPRETATION: The satellite model should be evaluated also for other medical specialties within the university hospitals.

High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment.

This phase II, multicentre, open-label, clinical trial evaluated antitumoral efficacy, tolerability and endocrine effects following 25 mg of treatment with oral exemestane given daily to postmenopausal women with metastatic breast cancer. Eligibility criteria included oestrogen and/or progesterone positivity or a prior response to hormonal therapy if receptor status was unknown; prior failure to tamoxifen therapy; and progressive disease. Patients were divided into three strata: patients who did not respond to tamoxifen or progressed after disease stabilisation (SD) for less than 6 months (stratum 1); patients who, after an initial response or SD lasting at least 6 months, experienced disease progression whilst on tamoxifen (stratum 2); patients with recurrent metastatic disease during or within 12 months of discontinuing adjuvant tamoxifen (stratum 3). Of the 137 patients who received exemestane, 4 experienced a complete response (CR) and 28 a partial response (PR), for an overall response rate of 23%. Another 33 patients had SD for > or = 24 weeks, resulting in an overall success rate of 47%. The median time to objective response was 16.1 weeks (95% confidence interval (CI) 9.9-24.1). The median response duration was 69.4 weeks, the median duration of overall success 59.1 weeks, the median time to progression (TTP) 25.1 weeks and the median time to treatment failure (TTF) 24 weeks. Response to previous hormonal therapy had little effect on the results, except that there was a trend toward a higher overall success rate in patients who did not respond to previous hormonal therapy. After 8 weeks of therapy, serum levels of oestradiol (E2), oestrone (E1) and oestrone sulphate (E1S) were suppressed to 15.2%, 9.7% and 10.7% of baseline, respectively. The most common adverse events of drug-related or indeterminate cause were hot flushes (14%), dizziness (9%), nausea (8%) and increased sweating (5%). Exemestane had a favourable effect on performance status and tumour-related signs and symptoms, both of which improved or stabilised in approximately 67% and 68% of patients respectively. Exemestane is a unique therapy that is highly active and well tolerated as a new treatment for women with metastatic breast cancer.

Significant difference in p53 and p21 protein immunoreactivity in HPV 16 positive and HPV negative breast carcinomas.

Human papillomavirus (HPV) 16 has previously been found in 19/41 breast carcinomas (46%) in women with a history of HPV 16 positive CIN III lesions. There was no significant difference in distribution of histological subtypes, mean or median tumour diameter or number of regional lymph node metastases in the HPV positive and HPV negative breast carcinoma groups. P53, p21 and c-erbB-2 proteins were analysed by immunohistochemistry in the HPV 16 positive and HPV negative breast carcinomas. There was a significant difference in p53 and p21 protein immunoreactivity between HPV 16 positive and HPV negative breast carcinomas (p = 0.0091 and p = 0.0040), with a significant less detectable p53 and p21 protein immunoreactivity in the HPV 16 positive cases. There was also a significant difference in the coexpression of p53/p21 between the HPV 16 positive and HPV 16 negative breast carcinomas (p = 0.002). No significant difference in immunostaining for c-erbB-2 protein in the two groups was found (p = 0.15), or for the coexpression of p53/c-erbB-2 (p = 0.19). The significantly lower expression of p53 and p21 proteins in HPV 16 positive than in HPV 16 negative breast carcinomas supports the hypothesis of inactivation and degradation of wild-type p53 proteins by HPV 16 E6 and that p53 mutation is not necessary for transformation in the HPV 16 positive cases.

Glutathione modulation changes the penetration of N-[3H]methyl-N-nitro-N-nitrosoguanidine into gastric mucosa of rats.

Glutathione plays a role in gastric mucosal protection and the glutathione level is elevated in some forms of gastritis. We studied the relevance of glutathione for the penetration of N-methyl-N-nitro-N-nitrosoguanidine in the glandular mucosa of the stomach. Male Wistar rats were treated with glutathione (0.5 mmol/kg intravenously), N-acetylcysteine (0.5 mmol/kg intravenously), or L-buthionine-[S,R,]-sulfoximine (BSO, 2 mmol/kg intraperitoneally), before the gastric mucosa was exposed to N-[3H]methyl-N-nitro-N-nitrosoguanidine for 10 min. Penetration of the carcinogen was evaluated by light microscopic identification of cells labeled with bromodeoxyuridine and N-[3H]methyl-N-nitro-N-nitrosoguanidine (double-labeled cells). Thiol substances were quantified by reversed-phase ion-pair liquid chromatography and fluorescence detection. The percentage double-labeled cells was higher in antrum mucosa (11.7 +/- 3.1%) than in corpus mucosa (1.1 +/- 0.2%) (P < 0.05). Total glutathione level was 1853 +/- 101 nmol/g in antrum and 1560 +/- 76 nmol/g in corpus mucosa. BSO administration reduced the amount of glutathione in antrum to 495 +/- 14 nmol/g (P < 0.05) and reduced the percentage double-labeled cells in antrum mucosa to 6.1 +/- 1.3% (P < 0.05). A positive correlation was found between the percentage of double-labeled cells in the antrum mucosa and the total amount of glutathione (r = 0.451, P = 0.002), and the amount of reduced glutathione (r = 0.449, P = 0.002). Glutathione modulation effects the penetration of N-[3H]methyl-N-nitro-N-nitrosoguanidine in the antrum but not in the corpus mucosa. Thiols do not explain the different penetration of carcinogen in antrum and corpus mucosa.

Delayed recruitment of immunocompetent cells in denervated rat periodontal ligament following experimental tooth movement.

It has previously been shown that the number of mononuclear phagocytic cells in the periodontal ligament (PDL) of orthodontically moved rat molars is significantly increased (p < or = 0.05) at 3, 7, and 14 days compared with the controls. Since these changes coincide with increased density of peptidergic nerve fibers, it was of particular interest to investigate a possible relation between the immunocompetent cells and sensory nerve fibers in the PDL of experimentally moved and denervated rat molars. Twenty-two young animals had the first right mandibular molar moved mesially, 7, 14, and 21 days after ipsilateral inferior alveolar nerve axotomy. The left side served as unoperated control. An immunohistochemical procedure was carried out on alternate, serial, cryostat sections with antibodies against CDllb (macrophages, dendritic cells) and class II major histocompatibility complex (MHC) molecules (RT1B). At 7 and 14 days, the number of CD11b+- and RT1B-expressing cells in the denervated PDL showed no significant difference compared with the contralateral side. However, at 21 days, when periodontal tissue re-innervation is established, the number of the investigated immunocompetent cells in the PDL of the denervated and experimentally moved mandibular molars demonstrated a significant difference compared with the contralateral and control molars (p < or = 0.05). It can be concluded that axotomy of the inferior alveolar nerve delays the recruitment of macrophage-like and class II MHC molecule-expressing cells in the PDL of orthodontically moved rat molars. The results further indicate that sensory nerve fibers interact with immunocompetent cells and participate in their mobilization to locally inflamed tissues.

Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III).

Women with both a history of high grade cervical intraepithelial neoplasia (CIN III) and breast carcinoma as second primary cancer were selected for studying the presence of HPV in breast carcinomas. Paraffin embedded material from 38 patients with 41 breast carcinoma cases after CIN III were examined by polymerase chain reaction (PCR) and in situ hybridization. By PCR we detected HPV 16 DNA in 19 out of 41 cases (46%) of the breast carcinomas. One case proved to be HPV 16 positive also by in situ hybridization. HPV 16 was also detected in 32 out of the 38 patients with CIN III (84%). All HPV 16 positive breast carcinomas were HPV 16 positive in their corresponding CIN III lesions. Eight patients with diagnosed breast cancer before the CIN III lesions were used as controls. None of these had HPV positive breast carcinomas. No cases were positive for HPV 11, 18, or 33. HPV 16 was detected in the primary tumours, in local metastases from HPV 16 positive tumours, in a distant HPV 16 positive breast carcinoma metastasis to the colon, and in other primary cancers in patients with HPV 16 positive breast carcinomas and HPV 16 positive CIN III. Estrogen and progesterone receptors were quantified in the HPV positive and HPV negative breast carcinomas, and there was no significant difference in the fraction positive in the two groups. Oncogenic HPV DNA might be transported from an original site of infection to other organs by blood or lymph, and possibly be a factor in the development of cancer in different organs.

Influence of droloxifene on metastatic breast cancer as first-line endocrine treatment.

The effect of droloxifene (3-hydroxytamoxifen) given as first-line endocrine treatment was evaluated in 39 postmenopausal women with advanced receptor-positive or receptor-unknown breast cancer. The patients had not received any previous anticancer therapy apart from adjuvant treatment. The overall response rate (CR + PR) was 51% (8% CR, 43% PR), 95% confidence interval+/-15.7%. Median time to progression (all patients) was 8 months, the median time to response 2 months, while the median duration of response was 10 months. The drug was well tolerated with no major side effects recorded; 16% of the patients experienced hot flushes. The response to droloxifene recorded in the present study is in accordance with the response rates to tamoxifen as first-line treatment in identical groups of patients.

Effect of gastric secretion on penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine into gastric mucosa of rats.

Clinical conditions with low gastric acid secretion have been associated with increased risk of gastric cancer. There has also been concern about gastric acid inhibition and N-nitroso compound formation in the stomach. This study investigates the effect of gastric acid secretion on the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine, an N-nitroso compound and gastric carcinogen, into the gastric mucosa of rats. Gastric acid secretion was stimulated by pentagastrin (40 microg/kg/hr) and inhibited by omeprazole (40 micromol/kg) before mucosal exposure to N-3H-methyl-N-nitro-N-nitrosoguanidine. Penetration of the carcinogen was evaluated by light microscopic identification of cells in the S-phase labeled with N-3H-methyl-N-nitro-N-nitrosoguanidine. This population of double-labeled cells is considered at risk from N-methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis. The percentage of double-labeled cells was significantly higher in antrum than in corpus mucosa (P < 0.0001). Stimulation or inhibition of gastric acid secretion did not affect the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine in antrum or corpus mucosa. We conclude that modulation of gastric acid secretion does not affect the penetration of the carcinogen into the gastric mucosa nor does it explain the different penetration of the carcinogen into corpus and antrum mucosa.

Effect of inferior alveolar nerve axotomy on periodontal and pulpal blood flow subsequent to experimental tooth movement in rats.

The aims of this study were to evaluate the effect of inferior alveolar nerve (IAN) axotomy on periodontal (PDL) and pulpal blood flow incident to experimental tooth movement and to investigate whether nerve fiber regeneration coincides with blood flow changes. The first right mandibular molar was moved mesially for 3, 7, and 14 days after ipsilateral IAN axotomy in 29 rats. Four rats served as unoperated controls. At the end of each experimental period fluorescent microspheres (FM) were injected into the left ventricle and thereafter counted in serial sections in the PDL and pulp of the right and left first mandibular molars. The number of FM per tissue volume was taken as a measure of blood flow. Re-innervation of nerve fibers was mapped immunohistochemically 7, 14, and 21 days after IAN axotomy in 9 rats that had no orthodontic appliance. The statistical analysis showed no significant differences in the number of FM/mm3 PDL between the denervated and the contralateral side at 3 and 7 days. At 14 days the PDL on the denervated side showed a significant increase in the number of FM/mm3, coinciding with the initial periodontal nerve fiber re-innervation. In the pulp no significant differences were found between the denervated and the contralateral, innervated side in any experimental period. It can be concluded that IAN axotomy postpones an increase in periodontal blood flow until a sensory tissue re-innervation is established, thus indicating that neurogenic mechanisms play an important role in the development of the inflammatory reaction induced by experimental tooth movement.

Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis.

PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN mutations were detected in all of five families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast and thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations were not detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN-coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven PTEN germ-line mutations occurred, five nonsense and two missense mutations, in six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine, breast, and thyroid tumors from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.

Effect of experimental tooth movement on nerve fibres immunoreactive to calcitonin gene-related peptide, protein gene product 9.5, and blood vessel density and distribution in rats.

The effect of experimental tooth movement on nerve fibers immunoreactive to calcitonin gene-related peptide (CGRP) and to protein gene product (PGP) 9.5 were studied, as well as the coincidence of these responses with changes in blood vessel density and distribution in the periodontal ligament (PDL) and pulp of young Wistar rats. The first right maxillary molar was moved mesially by an orthodontic appliance for 3, 7, 14 and 21 days. Sagittal and horizontal serial sections were incubated alternately with antibodies to CGRP, PGP 9.5 and laminin. Nerve and blood vessel density and distribution between the experimental and control sides were compared in the apical and cervical PDL, and in root and coronal pulp. The most pronounced changes occurred in the 7 day group. CGRP and PGP 9.5 immunoreactive nerves in the apical PDL showed increased density, being distributed towards the alveolar bone and frequently found in bone resorption lacunae. Numerous nerve fibres were often present adjacent to hyalinized tissue, but were never found near or within root resorption lacunae. Nerve sprouting was also present both in the root and coronal pulp. Increased nerve and blood vessel density generally coincided with each other. At day 14, periodontal nerves and blood vessels were still disorganized compared with the controls. Tissues near cellular cementum and root resorption lacunae were consistently devoid of nerve fibres. After 21 days, PDL nerve and blood vessel density and distribution were nearly at control level. However, nerve fibres were regularly found inside root resorption areas. In conclusion, experimental tooth movement induces dynamic changes in density and distribution of periodontal and pulpal nerve fibres, indicating their involvement in both early stages of periodontal remodelling and later in the regenerative processes of the PDL, generally occurring in concerted action with modulation of blood vessels.

Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study.

Clinical and endocrinological effects of exemestane (6-methylenandrosta-1,4-diene-3,17-dione; PNU 155971) were evaluated in an open Phase I study. Thirteen postmenopausal women suffering from advanced breast cancer received exemestane in escalating doses over a 12-week period. Starting on 5 mg once daily (o.d.), exemestane was subsequently escalated at 2-week intervals to 10, 25, 50, 100, and 200 mg o.d. Each patient subsequently continued treatment on the highest tolerated dose until time of progression. One patient terminated treatment after 6 days due to diarrhea that was probably not related to drug therapy, although a relationship could not be excluded. Apart from this, no serious side effects were seen during the dose escalation period. Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E2) and estrone (E1) to a mean of 14.6 and 5.8% of pretreatment levels, respectively, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) to 8.9% of pretreatment levels. No fall in adrenal steroid levels was recorded. Exemestane (5 mg o.d.) suppressed urinary E2 and E1 to a mean of 11.9 and 12.2% of pretreatment levels, respectively. Administering exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E1, whereas urinary E2 fell to 6-7% of pretreatment levels. Median time to progression was 63 weeks. We conclude that exemestane is a well-tolerated aromatase inhibitor that effectively suppresses plasma and urinary estrogens in postmenopausal patients with breast cancer.

Immunocompetent cells in rat periodontal ligament and their recruitment incident to experimental orthodontic tooth movement.

The aims of this study were to evaluate the number and distribution of immunocompetent cells in normal rat periodontal ligament (PDL) and to quantify their recruitment incident to experimental tooth movement. 27 young animals had the 1st right maxillary molar moved mesially by an orthodontic appliance for 1, 3, 7 and 14 days, respectively. 4 animals served as untreated controls. An immunohistochemical procedure was carried out on alternate serial cryostat sections, and monoclonal antibodies against CD11b (macrophages, dendritic cells), CD43 (lymphocytes, polymorphs), CD4 (helper T-lymphocytes), and class II MHC molecules were used. Mean counts of the immunolabeled cells in the control group showed the highest number of CD11b+ and class II molecule expressing cells, while CD4+ and CD43+ cells were scarcely found. Significant increase in the number of CD11b+, CD43+ cells and class II molecules was found in the PDL of the experimentally moved 1st molars compared with the contralateral side and the control group, while CD4+ cells showed no significant increase. CD11b+ and cells expressing class II molecules were found around hyalinized tissue, between dentin and cellular cementum and close to Malassez' epithelial cells. In conclusion, normal rat PDL has high number of macrophage and dendritic-like cells, but few lymphocytes and granulocytes. Furthermore, experimental tooth movement leads to significant recruitment of cells belonging to the mononuclear phagocytic system, but has no significant effect on the number of lymphocytes and granulocytes in the rat PDL.