Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients.

The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been treated with irinotecan 125 mg/m2 and bevacizumab 10 mg/kg every 2 weeks. The response rate was 37.1% for lom-bev and 30.1% for iri-bev. Median progression-free survival (PFS) was 23 weeks for lom-bev and 21 weeks for iri-bev (p = 0.9). Overall survival (OS) was 37 weeks for lom-bev and 32 weeks for iri-bev (p = 0.5). Lom-bev caused a significantly higher frequency of thrombocytopenia (11.4% grade 3-4) compared to iri-bev (3.5% grade 3-4). Iri-bev patients had more gastrointestinal toxicity with regard to nausea, vomiting, diarrhea, constipation and stomatitis. Within the limitations of the study lom-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision in recurrent GBM therapy as efficacy is equal and no predictive factors for efficacy exist.

Randomised feasibility study of a more liberal haemoglobin trigger for red blood cell transfusion compared to standard practice in anaemic cancer patients treated with chemotherapy.

OBJECTIVES: The primary objective of this feasibility study was to identify quality of life (QoL) scores and symptom scales as tools for measuring patient-reported outcomes (PRO) associated with haemoglobin level in chemotherapy-treated cancer patients. Secondary objectives included comparing QoL and symptoms between randomisation arms. BACKGROUND: Anaemia in cancer patients undergoing chemotherapy is associated with decreased QoL. One treatment option is red blood cell transfusion (RBCT). However, the optimal haemoglobin trigger for transfusion is unknown. METHODS: Patients were randomised to a haemoglobin trigger for RBCT of either < 9·7 g dL-1 (arm A) or < lower normal level, female: 11·5 g dL-1 , male: 13·1 g dL-1 (arm B). Four PROs were used: Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anaemia (FACT-An), a Numeric Rating Scale on symptoms of anaemia and self-reported Performance Status (PS). The association between haemoglobin and PRO variables was assessed using a linear mixed model with random effects. RESULTS: A total of 133 patients were enrolled, of which 86 patients received RBCT (28 in arm A, 58 in arm B). Baseline questionnaires were filled out in 79·7% of cases. Haemoglobin levels were significantly correlated with FACT-An, FACT-An Total Outcome Index (TOI), Functional Well-Being, fatigue and PS. Improvement on several PRO variables was observed in both arms after RBCT, with clinically minimal important differences observed in FACT-G, Physical Well-Being, FACT-An, FACT-An TOI, fatigue and dyspnoea. CONCLUSIONS: QoL scores of physical and functional domains as well as self-reported anaemia-related symptoms correlated well with haemoglobin level in chemotherapy-treated cancer patients.

Hybrid Capture 2 and cobas human papillomavirus assays perform similarly on SurePath samples from women with abnormalities.

OBJECTIVE: In two laboratories (Departments of Pathology, Copenhagen University Hospitals of Herlev and Hvidovre), we compared cobas and Hybrid Capture 2 (HC2) human papillomavirus (HPV) assays using SurePath® samples from women with atypical squamous cells of undetermined significance (ASCUS) at ≥30 years and women after treatment of cervical intraepithelial neoplasia (CIN). METHODS: Samples from 566 women with ASCUS and 411 women after treatment were routinely tested with HC2 and, thereafter, with cobas. Histological outcomes were retrieved from the Danish Pathology Data Base. We calculated the overall agreement between the assays, and compared their sensitivity and specificity for ≥CIN2. RESULTS: In women with ASCUS, HC2 and cobas testing results were similar in the two laboratories. The overall agreement was 91% (95% CI, 88-93). After CIN treatment, the overall agreement was 87% (95% CI, 82-91) at Herlev and 88% (95% CI, 82-92) at Hvidovre. There were no significant differences in the sensitivity for ≥CIN2 between the two tests [Herlev, 98% (95% CI, 89-100) for HC2 versus 94% (95% CI, 82-99) for cobas; Hvidovre, 97% (95% CI, 83-100) for HC2 versus 100% (95% CI, 88-100) for cobas]. The differences were also not significant for specificity. CONCLUSIONS: In women with the studied well-defined clinical indications for HPV testing, cobas and HC2 performed similarly in terms of the detection of HPV and ≥CIN2.

Renal impairment and late toxicity in germ-cell cancer survivors.

BACKGROUND: Treatment with bleomycin-etoposide-cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors. PATIENTS AND METHODS: BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. RESULTS: GFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61]. CONCLUSIONS: Renal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

A randomized pilot study on single-port versus conventional laparoscopic rectal surgery: effects on postoperative pain and the stress response to surgery.

BACKGROUND: Potential benefits of single-port laparoscopic surgery may include improved cosmetic results, less postoperative pain, surgical trauma and faster recovery. Results of randomized prospective studies with a focus on single-port rectal surgery have not yet been presented. The aim of the present study was to compare single-port and conventional laparoscopic surgery for rectal cancer in terms of short-term outcomes including postoperative pain and trauma-induced changes in certain bioactive substances. METHODS: Patients with non-metastasized rectal cancer were prospectively randomized to single-port (n = 20) or conventional laparoscopic rectal surgery (n = 20). Postoperative pain was assessed at rest, at coughing and during mobilization, with a numeric pain ranking score and was recorded at 6 h after the operation and subsequently every morning daily for 4 days. Levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined. Blood samples were collected preoperatively (baseline), and 6, 24, 48, 72 and 96 h after skin incision. RESULTS: Pain scores were significantly reduced in the single-port group on postoperative days 2, 3 and 4 during coughing and mobilization. In addition, the patients in the single-port group suffered significantly less pain at rest at 6 h after surgery and on postoperative days 1, 3 and 4. The levels of the three markers increased significantly after surgery. The increase was similar between groups for plasma IL-6 and TIMP-1 at all time points, while the CRP levels were significantly lower in the single-port group at 6 (p < 0.001) and 24 h (p < 0.05) after skin incision. Abdominal incisions lengths were significantly shorter in the single-port group (p = 0.001). There was no significant difference between groups in operating time and blood loss, morbidity or mortality rate. The short-term oncological outcome in the two groups was similar. CONCLUSIONS: Single-port rectal surgery may reduce postoperative pain. Although CRP levels were lower at some time points, results of the present randomized, pilot study suggest that the trauma-induced inflammatory response of single-port operations may be similar to the trauma-induced inflammatory response of conventional laparoscopic surgery.

Prospective multi-centre randomised trial comparing induction of labour with a double-balloon catheter versus dinoprostone.

This randomised controlled study compared the efficacy of double-balloon catheter versus vaginal prostaglandin E2 (dinoprostone) for induction of labour. In total, 825 pregnant women with cephalic presentation and an unfavourable cervix undergoing induction for conventional indications were randomised to double-balloon or vaginal dinoprostone (3 mg) groups. There was a significantly higher failure rate for labour induction in the balloon group (relative risk: 1.25, 95% confidence interval [CI]: 1.02-1.49). Median induction time was 27.3 h in the balloon group and 29.8 h in the dinoprostone group (difference not significant). After 24 h, 55.3% had given birth in the balloon group versus 54.3% in the dinoprostone group. Additional oxytocin stimulation was used more often in the balloon (46%) compared with that in the dinoprostone (34%) (relative risk: 1.34 (95%CI 1.16 -1.54) group. Caesarean section rates and neonatal outcome were similar. Overall, the two methods for induction were comparable with regard to efficacy and safety.

Pretransplant C-reactive protein as A prognostic marker in allogeneic stem cell transplantation.

We evaluated the prognostic role of baseline levels of C-reactive protein (CRP) as well as CRP levels during conditioning in patients undergoing myeloablative allogeneic stem cell transplantation (SCT). Furthermore, we studied the impact of baseline clinical factors and conditioning regimens on CRP levels in the same period. We conducted a population-based retrospective study of 349 patients undergoing SCT at the National Danish SCT centre between January 2000 and January 2009. CRP levels increased significantly during the conditioning and peaked at day -3 before infusion of the graft. Elevated CRP was associated with older age, non-malignant disease, reduced pretransplant Karnofsky score and high-risk leukaemia. By univariate and multivariate analyses, increased CRP levels (>10 mg/l) before the start of treatment (day -7) and at the day of graft infusion (day 0) were associated with decreased overall survival [HR 1.35 (95%CL) (1.18-1.54); P < 0.0001] and increased treatment-related mortality [1.5 (1.24-1.82); P < 0.0001]. Similar findings were seen for mean CRP levels during the conditioning. CRP was not associated with risk of relapse or aGvHD in multivariate analysis. This study suggests that increased CRP levels before and during the conditioning are associated with baseline clinical factors and that elevated pretransplant CRP levels predict a poorer survival in SCT.

Risk of biochemical recurrence and positive surgical margins in patients with pT2 prostate cancer undergoing radical prostatectomy.

BACKGROUND AND OBJECTIVE: To investigate risk factors associated with positive surgical margins (PSM) and biochemical recurrence (BR) in organ confined tumors (pT2) after radical prostatectomy (RP) for localized prostate cancer (PCa). METHODS: Between 1995 and 2011, 1,649 patients underwent RP at our institution. The study includes the 1,133 consecutive patients with pT2 tumors at final histopathology. Logistic regression analysis was used for risk of PSM. Risk of BR, defined as the first PSA ≥ 0.2 ng/ml, was analyzed with Kaplan-Meier and Cox regression analysis. RESULTS: Median follow-up was 3.6 years (range: 0.5-15.5 years). In logistic regression, NS surgery was independently associated with an increased risk of pT2 PSM (OR = 1.68, 95% CI: 1.3-2.0, P = 0.01) relative to non-NS surgery. NS surgery was not independently associated with BR but the interaction of PSM and NS surgery trended (P = 0.08) to increase the risk of BR compared to PSM and non-NS surgery. CONCLUSION: Several factors influence the risk of pT2 PSMs in radical prostatectomy. In our cohort pT2 PSM is associated with NS surgery and trend to increase risk of BR compared to non-NS surgery. The optimal selection of candidates for NS surgery is still not clear.

Introducing extended consultations for patients with severe mental illness in general practice: Results from the SOFIA feasibility study.

BACKGROUND: People with a severe mental illness (SMI) have shorter life expectancy and poorer quality of life compared to the general population. Most years lost are due to cardiovascular disease, respiratory disease, and various types of cancer. We co-designed an intervention to mitigate this health problem with key stakeholders in the area, which centred on an extended consultations for people with SMI in general practice. This study aimed to1) investigate general practitioners' (GPs) experience of the feasibility of introducing extended consultations for patients with SMI, 2) assess the clinical content of extended consultations and how these were experienced by patients, and 3) investigate the feasibility of identification, eligibility screening, and recruitment of patients with SMI. METHODS: The study was a one-armed feasibility study. We planned that seven general practices in northern Denmark would introduce extended consultations with their patients with SMI for 6 months. Patients with SMI were identified using practice medical records and screened for eligibility by the patients' GP. Data were collected using case report forms filled out by practice personnel and via qualitative methods, including observations of consultations, individual semi-structured interviews, a focus group with GPs, and informal conversations with patients and general practice staff. RESULTS: Five general practices employing seven GPs participated in the study, which was terminated 3 ½ month ahead of schedule due to the COVID-19 pandemic. General practices attempted to contact 57 patients with SMI. Of these, 38 patients (67%) attended an extended consultation, which led to changes in the somatic health care plan for 82% of patients. Conduct of the extended consultations varied between GPs and diverged from the intended conduct. Nonetheless, GPs found the extended consultations feasible and, in most cases, beneficial for the patient group. In interviews, most patients recounted the extended consultation as beneficial. DISCUSSION: Our findings suggest that it is feasible to introduce extended consultations for patients with SMI in general practice, which were also found to be well-suited for eliciting patients' values and preferences. Larger studies with a longer follow-up period could help to assess the long-term effects and the best implementation strategies of these consultations.

Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis.

AIM: Duodenal adenomatosis in familial adenomatous polyposis results in a cancer risk that increases with age. Endoscopic surveillance has been recommended, but the effect has not yet been documented. The aim of this study was to present the results of long-term duodenal surveillance and to evaluate the risk of cancer development. METHOD: Follow up of patients in a previous study with gastroduodenoscopy in 1990-2010. Statistical analysis included the χ(2) test, actuarial method and Kaplan-Meier analysis. RESULTS: Among 304 patients, 261 (86%) had more than one endoscopy. The median follow up was 14 (interquartile range, 9-17) years. The cumulative lifetime risk of duodenal adenomatosis was 88% (95% CI, 84-93), and of Spigelman stage IV was 35% (95% CI, 25-45). The Spigelman stage improved in 32 (12%) patients, remained unchanged in 88 (34%) and worsened in 116 (44%). Twenty (7%) patients had duodenal cancer at a median age of 56 (range, 44-82) years. The cumulative cancer incidence was 18% at 75 years of age (95% CI, 8-28) and increased with increasing Spigelman stage at the index endoscopy to 33% in Spigelman stage IV (P < 0.0001). The median overall survival was 6.4 years (95% CI, 1.7 to not estimated): 8 years after a screen-detected cancer vs 0.8 years (95% CI, 0.03-1.7) after a symptomatic cancer (P < 0.0001). The location of the mutation in the APC gene did not influence the risk of developing Spigelman stage IV (P = 0.46) or duodenal cancer (P = 0.83). CONCLUSION: The risk of duodenal cancer in familial adenomatous polyposis is considerable, and regular surveillance and cancer prophylactic surgery result in a significantly improved prognosis.

Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer.

BACKGROUND: The aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine and oxaliplatin) as first-line treatment. PATIENTS AND METHODS: One hundred and twenty patients were included. Blood samples were collected before treatment and 3 weeks later before the next treatment cycle. Plasma TIMP-1 and serum CEA levels were correlated to treatment outcome. RESULTS: No significant associations between baseline TIMP-1 or CEA levels and best response to treatment or progression-free survival (PFS) could be demonstrated. In contrast, high baseline plasma TIMP-1 levels were associated with poor overall survival (OS), P = 0.008, hazard ratio (HR) = 1.80 [95% confidence interval (CI): 1.17-2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02-1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0.03). CONCLUSIONS: Both high baseline and subsequent increase in TIMP-1 levels were associated with shorter OS in patients with mCRC receiving XELOX as first-line treatment, whereas baseline TIMP-1 levels were not associated with response or PFS following XELOX treatment.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) genotypes in colorectal cancer.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are key factors of the lectin pathway of complement activation. Polymorphisms of the MBL2 and MASP-2 genes affect serum levels of MBL and MASP-2. In patients with colorectal cancer (CRC), the MBL and MASP-2 serum levels are increased and high MASP-2 levels are associated with recurrence and poor survival, whereas low MBL levels predict post-operative pneumonia. It is not known whether these associations are genetically based. In this study, the MBL and MASP-2 genotypes are investigated in 593 patients with CRC and 348 healthy controls. The potential association between genetic profile and infections, recurrence and survival is evaluated. Four single-nucleotide polymorphisms (SNPs) of MBL2 were analysed using TaqMan assays, with characterization of MBL2 wildtype A, variants B, C and D and alleles H/L, Y/X and P/Q. The SNP D120G for MASP-2 was determined. Serum levels of MBL and MASP-2 were measured. The MBL2 and MASP-2 genotype distribution was similar among patients with CRC and healthy controls and MBL2 genotype significantly associated with MBL concentration in serum (P<0.0001). No significant association between MBL2/MASP-2 genotype and post-operative infectious complications (P=0.33 and 0.22), recurrent cancer or survival (P=0.74 and P=0.61 respectively) was found. Thus, the increased serum levels of MBL and MASP-2 found in patients with CRC are not explained for by genetic profiles. In contrast to what has been demonstrated for serum levels of MBL and MASP-2, the genotypes do not predict disease course of the CRC patients.

Intra-operative perforation is an important predictor of local recurrence and impaired survival after abdominoperineal resection for rectal cancer.

AIM: Abdominoperineal resection for rectal cancer is associated with higher rates of local recurrence and poorer survival than anterior resection. The aim of this study was to evaluate the outcome of conventional abdominoperineal resection in a large national series. METHOD: The study was based on the Danish National Colorectal Cancer Database and included patients treated with abdominoperineal resection between 1 May 2001 and 31 December 2006. Follow up in the departments was supplemented with vital status in the Civil Registration System. The analysis included actuarial local and distant recurrence, and overall and cancer-specific survival. Risk factors for local recurrence, distant metastases, overall survival and cancer-specific survival were identified using multivariate analyses. RESULTS: A total of 1125 patients were followed up for a median of 57 (25-93) months. Intra-operative perforation was reported in 108 (10%) patients. The cumulative 5-year local recurrence rate was 11% [95% confidence interval (CI), 7-13)], overall survival was 56% (95% CI, 53-60) and cancer-specific survival was 68% (95% CI, 65-71). Multivariate analysis showed that perforation, tumour stage and nonradical surgery were independent risk factors for local recurrence; tumour fixation to other organs, perforation and tumour stage were independent risk factors for distant metastases; and risk factors for impaired overall survival and cancer-specific survival were age, tumour perforation, tumour stage, lymph node metastases and nonradical surgery. CONCLUSION: Intra-operative perforation is a major risk factor for local and distant recurrence and survival and therefore should be avoided.

The SOFIA pilot trial: a cluster-randomized trial of coordinated, co-produced care to reduce mortality and improve quality of life in people with severe mental illness in the general practice setting.

BACKGROUND: People with severe mental illness (SMI) have an increased risk of premature mortality, predominantly due to somatic health conditions. Evidence indicates that primary and tertiary prevention and improved treatment of somatic conditions in patients with SMI could reduce this excess mortality. This paper reports a protocol designed to evaluate the feasibility of a coordinated co-produced care program (SOFIA model, a Danish acronym for Severe Mental Illness and Physical Health in General Practice) in the general practice setting to reduce mortality and improve quality of life in patients with severe mental illness. METHODS: The SOFIA pilot trial is designed as a cluster randomized controlled trial targeting general practices in two regions in Denmark. We aim to include 12 practices, each of which is instructed to recruit up to 15 community-dwelling patients aged 18 and older with SMI. Practices will be randomized by a computer in a ratio of 2:1 to deliver a coordinated care program or usual care during a 6-month study period. A randomized algorithm is used to perform randomization. The coordinated care program includes educational training of general practitioners and their clinical staff educational training of general practitioners and their clinical staff, which covers clinical and diagnostic management and focus on patient-centered care of this patient group, after which general practitioners will provide a prolonged consultation focusing on individual needs and preferences of the patient with SMI and a follow-up plan if indicated. The outcomes will be parameters of the feasibility of the intervention and trial methods and will be assessed quantitatively and qualitatively. Assessments of the outcome parameters will be administered at baseline, throughout, and at end of the study period. DISCUSSION: If necessary the intervention will be revised based on results from this study. If delivery of the intervention, either in its current form or after revision, is considered feasible, a future, definitive trial to determine the effectiveness of the intervention in reducing mortality and improving quality of life in patients with SMI can take place. Successful implementation of the intervention would imply preliminary promise for addressing health inequities in patients with SMI. TRIAL REGISTRATION: The trial was registered in Clinical Trials as of November 5, 2020, with registration number NCT04618250 . Protocol version: January 22, 2021; original version.

Attenuated familial adenomatous polyposis: results from an international collaborative study.

AIM: The study aimed to describe genetical and clinical features of attenuated familial adenomatous polyposis (AFAP) and to propose clinical criteria and guidelines for treatment and surveillance. METHOD: A questionnaire study was carried out of polyposis registries with data on patients with presumed AFAP, defined as having ≤ 100 colorectal adenomas at age ≥ 25. RESULTS: One hundred and ninety-six patients were included. The median number of adenomas was 25 (0-100) with a uniform distribution of colorectal adenomas and carcinomas (CRC). Age at CRC diagnosis was delayed by 15 years compared with classic FAP. Eighty-two patients had a colectomy and an ileorectal anastomosis and 5/82 (6%) had a secondary proctectomy. The location of the mutation in the APC gene was known in 69/171 (40%) tested patients. Only 15/29 (52%) of mutations in APC were found in parts of the gene usually associated with AFAP (the 5' end, exon 9 and 3' end). CONCLUSIONS: A subset of FAP patients with a milder phenotype does exist and treatment and surveillance had to be modified accordingly. The mutation detection rate is lower than in classic FAP and mutations in AFAP patients are located throughout the APC gene. We propose the following clinical diagnostic criteria for AFAP: a dominant mode of inheritance of colorectal adenomatosis and <100 colorectal adenomas at age 25 or older. Colonoscopy had to be preferred to sigmoidoscopy and surveillance had to be life-long. In the majority of patients, prophylactic colectomy and ileorectal anastomosis are recommended at the age of 20-25 years.

Delayed dental maturity in dentitions with agenesis of mandibular second premolars.

OBJECTIVES: To evaluate dental maturity in the mandibular canine/premolar and molar innervation fields in children with agenesis of the 2nd mandibular premolar and to associate these findings with normal control material. SETTING AND SAMPLE POPULATION: Department of Orthodontics, Institute of Odontology, University of Copenhagen. Eighty-three panoramic radiographs (27 girls and 31 boys with agenesis of one mandibular 2nd premolar and 17 girls and eight boys with agenesis of both mandibular 2nd premolars) represented all mandibular second premolar agenesis cases from a material of 2847 radiographs. MATERIAL AND METHODS: On each radiograph, dental maturity of all available mandibular premolars, canines and 2nd molars was evaluated and categorized in maturity stages according to Haavikko whose material served as control material. Descriptive statistics given by sample mean, standard deviation and range for each tooth stratified by gender and agenesis. Ninety-five percentage confidence limits and T-statistics were used. p-values <5% were considered significant. RESULTS: In unilateral agenesis, the canines are specifically delayed in both girls and boys, with a larger delay in girls (p=0.009). The second molar is not delayed in boys (p=0.98) but is in girls (p=0.04). The differences in delay for the canine compared to the second molar are significant for both girls and boys. The results show a considerable delay in tooth maturation within the canine/premolar innervation field predominantly in girls. The 2nd molar is delayed in girls but not in boys.

Sagittal, vertical and transversal dimensions of the maxillary complex in patients with ectopic maxillary canines.

OBJECTIVES: To analyse the craniofacial maxillary complex in cases with labially and palatally located ectopic canines, subgrouped accordingly: Group I: no deviations in the dentition; Group IIa: deviations in the maxillary incisors only; Group IIb: deviations in the dentition in general. SETTING AND SAMPLE POPULATION: Sixty nine patients (mean age 13 years 6 months) with palatally or labially located ectopic canines. MATERIAL AND METHODS: Profile radiographs and dental casts were analysed. The patients were subgrouped according to a previous registration of dental deviations registered radiographically. Maxillary cross-arch transversal width was analysed on dental casts. Sagittal and vertical dimensions were registered cephalometrically on profile radiographs. RESULTS: In the patient sample the maxillary cross-arch transversal width (from first maxillary molar left to first maxillary molar right), was significantly larger than the normal mean (0.65 mm, 95% Cl: 0.02-1.28, p = 0.043). The sagittal length N-S was significantly shorter (-0.97, 95% Cl:-1.72-(-)0.22, p = 0.002). The vertical length ANS-N length was also significantly shorter (-0.79, 95% Cl:-1.65-(-)0.02, p = 0.047). The remaining variables were non-significant. Tests for interaction between groups (I, IIa and IIb) and palatal/labial ectopic location did not demonstrate significance. CONCLUSION: In patients with ectopic maxillary canines, the maxillary complex is shorter sagittally as well as vertically, while it is wider transversally.

Differences between dentitions with palatally and labially located maxillary canines observed in incisor width, dental morphology and space conditions.

AIM: To analyze the interrelationship between incisor width, deviations in the dentition and available space in the dental arch in palatally and labially located maxillary ectopic canine cases. MATERIALS AND METHODS: Size: On dental casts from 69 patients (mean age 13 years 6 months) the mesiodistal widths of each premolar, canine and incisor were measured and compared with normal standards. Dental deviations: Based on panoramic radiographs from the same patients the dentitions were grouped accordingly: Group I: normal morphology; Group IIa: deviations in the dentition within the maxillary incisors only; Group IIb: deviations in the dentition in general. Descriptive statistics for the tooth sizes and dental deviations were presented by the mean and 95% confidence limits for the mean and the p-value for the T-statistic. Space: Space was expresses by subtracting the total tooth sizes of incisors, canines and premolars from the length of the arch segments. RESULTS: Size of lateral maxillary incisor: The widths of the lateral incisors were significantly different in groups I, IIa and IIb (p=0.016) and in cases with labially located ectopic canines on average 0.65 (95% CI:0.25-1.05, p=0.0019) broader than lateral incisors in cases with palatally located ectopic canines. Space: Least available space was observed in cases with labially located canines. The linear model did show a difference between palatally and labially located ectopic canines (p=0.03). Space related to deviations in the dentition: When space in the dental arch was related to dental deviations (groups I, IIa and IIb), the cases in group IIb with palatally located canines had significantly more space compared with I and IIa. CONCLUSION: Two subgroups of palatally located ectopic maxillary canine cases based on registration of space, incisor width and deviations in the morphology of the dentition were identified.

Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.