Prediction of Isolated Local Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Study.

BACKGROUND: Distinguishing postoperative fibrosis from isolated local recurrence (ILR) after resection of pancreatic ductal adenocarcinoma (PDAC) is challenging. A prognostic model that helps to identify patients at risk of ILR can assist clinicians when evaluating patients' postoperative imaging. This nationwide study aimed to develop a clinically applicable prognostic model for ILR after PDAC resection. PATIENTS AND METHODS: An observational cohort study was performed, including all patients who underwent PDAC resection in the Netherlands (2014-2019; NCT04605237). On the basis of recurrence location (ILR, systemic, or both), multivariable cause-specific Cox-proportional hazard analysis was conducted to identify predictors for ILR and presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A predictive model was developed using Akaike's Information Criterion, and bootstrapped discrimination and calibration indices were assessed. RESULTS: Among 1194/1693 patients (71%) with recurrence, 252 patients (21%) developed ILR. Independent predictors for ILR were resectability status (borderline versus resectable, HR 1.42; 95% CI 1.03-1.96; P = 0.03, and locally advanced versus resectable, HR 1.11; 95% CI 0.68-1.82; P = 0.66), tumor location (head versus body/tail, HR 1.50; 95% CI 1.00-2.25; P = 0.05), vascular resection (HR 1.86; 95% CI 1.41-2.45; P < 0.001), perineural invasion (HR 1.47; 95% CI 1.01-2.13; P = 0.02), number of positive lymph nodes (HR 1.04; 95% CI 1.01-1.08; P = 0.02), and resection margin status (R1 < 1 mm versus R0 ≥ 1 mm, HR 1.64; 95% CI 1.25-2.14; P < 0.001). Moderate performance (concordance index 0.66) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: This nationwide study identified factors predictive of ILR after PDAC resection. Our prognostic model, available through www.pancreascalculator.com , can be utilized to identify patients with a higher a priori risk of developing ILR, providing important information in patient evaluation and prognostication.

Microscopic resection margin status in pancreatic ductal adenocarcinoma - A nationwide analysis.

INTRODUCTION: First, this study aimed to assess the prognostic value of different definitions for resection margin status on disease-free survival (DFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC). Second, preoperative predictors of direct margin involvement were identified. MATERIALS AND METHODS: This nationwide observational cohort study included all patients who underwent upfront PDAC resection (2014-2016), as registered in the prospective Dutch Pancreatic Cancer Audit. Patients were subdivided into three groups: R0 (≥1 mm margin clearance), R1 (<1 mm margin clearance) or R1 (direct margin involvement). Survival was compared using multivariable Cox regression analysis. Logistic regression with baseline variables was performed to identify preoperative predictors of R1 (direct). RESULTS: 595 patients with a median OS of 18 months (IQR 10-32 months) months were analysed. R0 (≥1 mm) was achieved in 277 patients (47%), R1 (<1 mm) in 146 patients (24%) and R1 (direct) in 172 patients (29%). R1 (direct) was associated with a worse OS, as compared with both R0 (≥1 mm) (hazard ratio (HR) 1.35 [95% and confidence interval (CI) 1.08-1.70); P < 0.01) and R1 (<1 mm) (HR 1.29 [95%CI 1.01-1.67]; P < 0.05). No OS difference was found between R0 (≥1 mm) and R1 (<1 mm) (HR 1.05 [95% CI 0.82-1.34]; P = 0.71). Preoperative predictors associated with an increased risk of R1 (direct) included age, male sex, performance score 2-4, and venous or arterial tumour involvement. CONCLUSION: Resection margin clearance of <1 mm, but without direct margin involvement, does not affect survival, as compared with a margin clearance of ≥1 mm. Given that any vascular tumour involvement on preoperative imaging was associated with an increased risk of R1 (direct) resection with upfront surgery, neoadjuvant therapy might be considered in these patients.

The Association of Olfactory Function with BMI, Appetite, and Prospective Weight Change in Dutch Community-Dwelling Older Adults.

OBJECTIVES: The olfactory decline that often accompanies aging is thought to contribute to undernutrition in older adults. It is believed to negatively affect eating pleasure, appetite, food intake and subsequently nutritional status. We have evaluated the associations of olfactory function with BMI, appetite and prospective weight change in a cohort of Dutch community-dwelling older adults. DESIGN: Cross-sectional cohort study. PARTICIPANTS: Dutch community-dwelling older adults from the ongoing Longitudinal Aging Study Amsterdam (LASA). Measurements and setting: In 2012-2013, the 40-item University of Pennsylvania Smell Identification Test (UPSIT) was administered to 824 LASA participants to evaluate their olfactory function. Body weight, height, appetite, comorbidity, cognitive status and socio-demographic factors were also assessed. Follow-up weight was measured after three years. RESULTS: 673 participants (aged 55-65 years) were included in the regression analyses. Median UPSIT-score was 33. When adjusted for potential confounders, lower UPSIT-score (indicative of poorer olfactory function) was not associated with poor appetite (OR = 1.062, p = 0.137) or prospective weight change (B = -0.027, p = 0.548). It was, however, associated with lower BMI in smokers (B = 0.178, p = 0.032), but not in non-smokers (B = -0.015, p = 0.732). CONCLUSION: Lower olfactory function scores were associated with lower BMI in community-dwelling older adults who smoke, but not with appetite or prospective weight change. Therefore, smoking older adults with olfactory impairments may pose as a vulnerable group with respect to developing undernutrition.

Yield of staging laparoscopy before treatment of locally advanced pancreatic cancer to detect occult metastases.

INTRODUCTION: Locally advanced pancreatic cancer (LAPC) is found in 35% of patients with pancreatic cancer. However, these patients often have occult metastatic disease. Patients with occult metastases are unlikely to benefit from locoregional treatments. This study evaluated the yield of occult metastases during staging laparoscopy in patients with LAPC. METHODS: Between January 2013 and January 2017 all patients with LAPC underwent a staging laparoscopy after a recent tri-phasic CT-scan of the chest and abdomen. Data were retrospectively reviewed from a prospectively maintained database. Univariate and multivariable logistic regression analysis was conducted to predict metastasis found at laparoscopy. RESULTS: A total of 91 (41% male, median age 64 years) LAPC patients were included. The median time between CT-scan and staging laparoscopy was 21 days. During staging laparoscopy metastases were found in 17 patients (19%, 95% CI: 12%-28%). Seven (8%) patients had liver-only, 9 (10%) patients peritoneal-only, and 1 (1%) patient both liver and peritoneal metastases. Univariate logistic regression analysis showed that CEA (OR 1.056, 95% CI 1.007-1.107, p = 0.02) was the only preoperative predictor for occult metastases. In a multivariable logistic regression analysis of the preoperative risk factors again only CEA was an independent predictor for occult metastatic disease (p = 0.03). Patients with a CEA above 5 µg/L had a risk of occult metastasis of 91%. FOLFIRINOX was given to 69 (76%) of the patients with a median number of cycles of 8. Subsequent radiotherapy was given to 44 (48%) patients after the FOLFIRINOX treatment. Six (14%) patients underwent a resection after FOLFIRINOX and radiotherapy. The overall 1-year survival was 53% in patients without occult metastasis versus 29% with occult metastasis (p = 0.11). The 1-year OS for patients that completed FOLFIRINOX and radiotherapy was 84%. CONCLUSION: The yield of staging laparoscopy for occult intrahepatic or peritoneal metastases in patients with locally advanced pancreatic cancer was 19%. Staging laparoscopy is recomended for patients with LAPC for accurate staging to determine optimal treatment.

Molecular diagnosis of chronic granulomatous disease.

Patients with chronic granulomatous disease (CGD) suffer from recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, liver, brain and bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia and Salmonella species. CGD is a rare (∼1:250 000 births) disease caused by mutations in any one of the five components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes. Molecular diagnosis of CGD involves measuring NADPH oxidase activity in phagocytes, measuring protein expression of NADPH oxidase components and mutation analysis of genes encoding these components. Residual oxidase activity is important to know for estimation of the clinical course and the chance of survival of the patient. Mutation analysis is mandatory for genetic counselling and prenatal diagnosis. This review summarizes the different assays available for the diagnosis of CGD, the precautions to be taken for correct measurements, the flow diagram to be followed, the assays for confirmation of the diagnosis and the determinations for carrier detection and prenatal diagnosis.

Glomus jugulare tumours: a 15 year radiotherapy experience in South Australia.

Glomus jugulare tumours (GJT) are one of a family of benign hypervascular neoplasms that arise from chief cells of the paraganglionic tissue from the dome of the jugular bulb. Historically, these tumours have primarily been managed surgically but radiation is an alternative treatment modality. The purpose of this retrospective review was to determine the patient survival, tumour control, clinical control rates and long term toxicity of GJT treated with radiation in South Australia. Between 1996 and 30 June 2012, 15 patients with GJT (16 tumours) were managed with radiotherapy. Twelve patients were female and the median age was 62 years. Thirteen patients (87%) were treated with conventional external beam radiotherapy and two patients (13%) with stereotactic radiosurgery. The mean duration of follow-up was 4 years (range 1 month-15 years 4 months). The close-out date for survival analyses was 31 October 2012. Crude overall survival, tumour control, clinical control and long term grade >2 toxicity rates were 100%, 94% (15/16), 94% and 7% (1/16), respectively. The Kaplan-Meier 5 and 10 year clinical and tumour control rates were both 93% (95% confidence interval: 61-99%). Radiation is an effective treatment modality for GJT. With comparable patient survival, arguably improved tumour and clinical control rates relative to surgery, minimal toxicity and ongoing advances in radiotherapy technologies, radiation should be strongly considered for the primary management of GJT.

Systematic review of perioperative selective decontamination of the digestive tract in elective gastrointestinal surgery.

BACKGROUND: Studies on selective decontamination of the digestive tract (SDD) in elective gastrointestinal surgery have shown decreased rates of postoperative infection and anastomotic leakage. However, the prophylactic use of perioperative SDD in elective gastrointestinal surgery is not generally accepted. METHODS: A systematic review of randomized clinical trials (RCTs) was conducted to compare the effect of perioperative SDD with systemic antibiotics (SDD group) with systemic antibiotic prophylaxis alone (control group), using MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. Endpoints included postoperative infection, anastomotic leakage, and in-hospital or 30-day mortality. RESULTS: Eight RCTs published between 1988 and 2011, with a total of 1668 patients (828 in the SDD group and 840 in the control group), were included in the meta-analysis. The total number of patients with infection (reported in 5 trials) was 77 (19.2 per cent) of 401 in the SDD group, compared with 118 (28.2 per cent) of 418 in the control group (odds ratio 0.58, 95 per cent confidence interval 0.42 to 0.82; P = 0.002). The incidence of anastomotic leakage was significantly lower in the SDD group: 19 (3.3 per cent) of 582 patients versus 44 (7.4 per cent) of 595 patients in the control group (odds ratio 0.42, 0.24 to 0.73; P = 0.002). CONCLUSION: This systematic review and meta-analysis suggests that a combination of perioperative SDD and perioperative intravenous antibiotics in elective gastrointestinal surgery reduces the rate of postoperative infection including anastomotic leakage compared with use of intravenous antibiotics alone.

Radiotherapy for optic nerve sheath meningioma: a case for earlier intervention?

AIMS: To assess tumour control, visual outcomes and toxicity after radiotherapy for all patients with optic nerve sheath meningiomas (ONSM) treated by a single radiation oncologist at a single institution over a 15 year period. To explore potential predictors of outcomes. MATERIALS AND METHODS: All patients underwent ophthalmological and radiological assessments before radiotherapy. These were repeated at regular intervals after treatment. A retrospective analysis of clinical, dosimetric and radiological data was carried out. Patients with useful vision before radiotherapy were divided into two groups - those with maintained or improved vision and those with a deterioration in vision. The groups were compared using the Mann-Whitney U-test with regard to eight potential predictors of outcome. RESULTS: Seventeen patients with 18 ONSM were treated with fractionated radiotherapy (46.8-55.8 Gy in 26-31 fractions). No evaluable tumours grew after treatment: control rate 100% (95% confidence interval 82-100%). Using the most common definition of visual function described in the literature, vision was maintained or improved in 89% (95% confidence interval 67-97%) of cases. In those with useful vision before treatment (13 evaluable eyes), visual acuity was maintained or improved in eight (62%, 95% confidence interval 36-82%). There was a suggestion that the time from the onset of symptoms to radiotherapy may influence outcome. Those with stable or better visual acuity after radiotherapy had been observed for a shorter time compared with those who had worse visual acuity (median of 18 months versus 62 months). Acute and late toxicity from radiotherapy was manageable. CONCLUSION: Radiotherapy is an extremely effective modality in arresting the growth of ONSM. A longer time from symptom onset to the start of radiotherapy may predict for poorer outcomes.

Cost-effectiveness of perioperative selective decontamination of the digestive tract versus placebo in elective gastrointestinal surgery.

OBJECTIVE: We compared the routine use of perioperative selective decontamination of the digestive tract (SDD) for elective gastrointestinal surgery with placebo in a randomized controlled trial. Alongside this trial, a cost-effectiveness analysis from a provider perspective was performed. METHODS AND RESULTS: A total of 289 patients undergoing elective surgery of the digestive tract were randomized to either SDD (143 patients) or placebo (146 patients). Routine use of SDD led to less patients with an infectious complication compared with placebo (p = 0.028). Mean total costs per patient were slightly less (EUR 2,604; 95% CI -6,292 to 1,084) in patients randomized to SDD (EUR 12,031) compared to patients randomized to placebo (EUR 14,635). Costs of hospitalization were the main determinant of the cost difference between the groups. The incremental cost-effectiveness ratio per prevented occurrence of ≥1 infectious complications per patient was -EUR 23,164, indicating the superiority of SDD over placebo. CONCLUSION: This study shows that in patients undergoing elective gastrointestinal surgery, the routine use of SDD is less expensive and economically more efficient than placebo in reducing the number of patients with infectious complications.

Genetical analysis of all Danish patients diagnosed with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system caused by a defect in NADPH oxidase, leaving the granulocytes unable to kill invading microorganisms. CGD is caused by mutation in one of the five components gp91phox, p22phox, p47phox, p67phox and p40phox, encoded by the X-linked CYBB gene and the autosomal CYBA, NCF1, NCF2 and NCF4 genes respectively. We have collected samples from all Danish patients with known CGD followed in the clinic or newly diagnosed during a 5-year period, a cohort of 27 patients, and characterized them genetically. The cohort includes 10 male patients with X-linked CGD and one female with extremely lyonized expression of a defective CYBB allele. Six patients had mutation in CYBA. Seven of 10 patients with a defect in NCF1 were homozygous for the common GT deletion, one was compound heterozygous for the GT deletion and a splice-site mutation, and two patients were homozygous for a nonsense mutation in exon 7. Three novel mutations were detected, a deletion of exon 6 in CYBA, a duplication of exon 8-13 in CYBB and a splice site mutation in intron 7 of NCF1.

Current application of selective decontamination of the digestive tract, perioperative antibiotics and mechanical bowel preparation in surgical departments in the Netherlands.

OBJECTIVE: To study the current application of selective decontamination of the digestive tract (SDD), the use of preoperative antibiotics and mechanical bowel preparation (MBP) in elective gastrointestinal (GI) surgery in surgical departments in the Netherlands. METHODS: A point prevalence survey was carried out and an online questionnaire was sent to GI surgeons of 86 different hospitals. RESULTS: The response rate was 74%. Only 4/64 (6.3%) of the Dutch surgical wards are currently using perioperative SDD as a prophylactic strategy to prevent postoperative infectious complications. The 4 hospitals using SDD on their surgical wards also use it on their ICUs. All hospitals make use of perioperative intravenous antibiotic prophylaxis in elective GI surgery. In most hospitals, a cephalosporin and metronidazole are applied (81.3 and 76.6%). MBP was used in 58 hospitals (90.6%) mainly in left colonic surgery. CONCLUSIONS: Perioperative SDD is rarely used in elective GI surgery in the Netherlands. Perioperative intravenous antibiotic prophylaxis is given in all Dutch hospitals, conforming to guidelines. Although the recent literature does not recommend MBP before surgery, it is still selectively used in 90.6% of the Dutch surgical departments, mainly in open or laparoscopic left colonic surgery (including sigmoid resections).

Randomized clinical trial of perioperative selective decontamination of the digestive tract versus placebo in elective gastrointestinal surgery.

BACKGROUND: This randomized clinical trial analysed the effect of perioperative selective decontamination of the digestive tract (SDD) in elective gastrointestinal surgery on postoperative infectious complications and leakage. METHODS: All patients undergoing elective gastrointestinal surgery during a 5-year period were evaluated for inclusion. Randomized patients received either SDD (polymyxin B sulphate, tobramycin and amphotericin) or placebo in addition to standard antibiotic prophylaxis. The primary endpoint was postoperative infectious complications and anastomotic leakage during the hospital stay or 30 days after surgery. RESULTS: A total of 289 patients were randomized to either SDD (143) or placebo (146). Most patients (190, 65·7 per cent) underwent colonic surgery. There were 28 patients (19·6 per cent) with infectious complications in the SDD group compared with 45 (30·8 per cent) in the placebo group (P = 0·028). The incidence of anastomotic leakage in the SDD group was 6·3 per cent versus 15·1 per cent in the placebo group (P = 0·016). Hospital stay and mortality did not differ between groups. CONCLUSION: Perioperative SDD in elective gastrointestinal surgery combined with standard intravenous antibiotics reduced the rate of postoperative infectious complications and anastomotic leakage compared with standard intravenous antibiotics alone. Perioperative SD.D should be considered for patients undergoing gastrointestinal surgery. REGISTRATION NUMBER: P02.1187L (Dutch Central Committee on Research Involving Human Subjects).

Chronic granulomatous disease of childhood: an unusual cause of recurrent uncommon infections in a 61-year-old man.

Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency that affects 1 : 250,000 of the population, which is characterized by recurrent bacterial and fungal infections and by granuloma formation. We investigated a 61-year-old man presented with a 20-year history of a relapsing skin rash appearing as mildly pruritic and erythematous plaques affecting various body regions. Cutaneous biopsies were taken and sent for histology and tissue culture. Leucocyte function was assessed by determining the generation of reactive oxygen species. Bactericidal activity was assessed in the presence of autologous and homologous sera. Western blotting was performed for protein analysis of the reduced nicotinamide adenine dinucleotide phosphate oxidase system, and mutation screening was carried out using PCR amplification and sequence analysis. Examination of biopsies obtained from lesional skin indicated a suppurative granulomatous process. Tissue cultures grew Aspergillus nidulans and Aspergillus fumigatus (confirmed by PCR). A. nidulans has often been associated with CGD, and the leucocyte function tests supported this diagnosis. Direct DNA sequencing led to the identification of a hemizygous missense novel mutation in CYBB (c.907C>T), which predicts a p.His303Tyr amino-acid substitution in gp91-phox, thus confirming the diagnosis of CGD. In conclusion, we report a case of a rare inherited immunodeficiency, CGD, in a 61-year-old man, and describe the novel hemizygous missense mutation underlying the condition. Mild forms of usually fatal immunodeficiencies should be considered when assessing the occurrence of unusual infectious diseases in apparently healthy people.

Radiosurgery versus surgery, both with adjuvant whole brain radiotherapy, for solitary brain metastases: a randomised controlled trial.

AIMS: This randomised non-inferiority trial was designed to assess whether radiosurgery plus adjuvant whole brain radiotherapy (RS + WBRT) is as effective as surgery plus whole brain radiotherapy (S + WBRT) for cancer patients with a solitary brain metastasis, with respect to overall survival and quality of life. MATERIALS AND METHODS: Major inclusion criteria were a history of systemic cancer within 5 years and enhanced magnetic resonance imaging-confirmed solitary brain metastasis suitable for both radiosurgery and surgery. All patients were to receive WBRT (30 Gy in 10 fractions). Between February 2003 and April 2009, 40 patients were considered eligible, 22 consented to randomisation and 21 were analysed (11 RS + WBRT, 10 S + WBRT). The trial was closed early due to slow accrual. RESULTS: The estimated median overall survival times for RS + WBRT and S + WBRT patients were 6.2 and 2.8 months, respectively (hazard ratio 0.53, 95% confidence interval 0.20-1.43, P = 0.20). Corresponding median failure-free survival times were 3.1 and 1.7 months (P = 0.20). For 19 'per protocol' patients, 2/10 in the RS + WBRT arm had distant intracranial failure (one also had local failure) and 3/9 S + WBRT patients had distant intracranial failure (no local failures). There were no grade 3-4 late radiation toxicities. Two months after starting treatment there were no significant differences in quality of life between the arms. CONCLUSION: This randomised trial encountered the accrual difficulties and consequent low statistical power commonly associated with interdisciplinary studies drawing from a small eligible population, but can contribute to future overviews on the management of solitary brain metastases.

Different characteristics of patients with gastro-oesophageal reflux disease on their path through healthcare: a population follow-up study.

BACKGROUND: Only a minority of patients with gastro-oesophageal reflux symptoms (GORS) seek medical advice. Little is known about patient characteristics associated with consultation in primary care and referral to secondary care. AIMS AND METHODS: We compared the characteristics of patients with GORS in the general population, those who consulted their general practitioner (GP) and those referred to secondary care for upper endoscopy. We aimed to identify differences between patients with short term (<90 days) and chronic symptoms, and differences between patients with symptoms in primary and secondary care. The study was performed in a primary care based prospective dynamic population. RESULTS: In total, 16% of 7237 adult patients were identified with GORS. Twenty-five percent of these patients consulted the GP, of whom 40% were referred for endoscopy. Patients with chronic GORS were older, had a higher body mass index, were more often referred for upper endoscopy (all P<0.001) and more frequently had relevant findings during endoscopy (oesophagitis: 50% and Barrett's oesophagus: 10%). Patients referred for upper endoscopy were older than nonreferred patients (P<0.001). CONCLUSION: Only a minority of people with GORS visit their GP. After consulting referral for endoscopy occurs relatively often. Underlying endoscopic abnormalities are frequently found in patients with chronic GORS.

International variations in radiotherapy fractionation for bone metastases: geographic borders define practice patterns?

Although it may be argued that single fraction (SF) radiotherapy (RT) should be regarded as the standard palliative treatment for pain due to uncomplicated bone metastases, its widespread clinical use is still underexploited. In this chapter, the authors discuss a number of surveys investigating doctors and patients' preferences for palliative RT schedules, discuss the possible reasons for this phenomenon, and suggest potential strategies to increase the use of SF.

Four different NCF2 mutations in six families from Turkey and an overview of NCF2 gene mutations.

BACKGROUND: One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the NCF2 gene, which encodes the polypeptide p67(phox), a key cytoplasmic protein in the phagocyte NADPH oxidase system. NCF2 is localized on chromosome 1q25, encompasses 40 kb and contains 16 exons. MATERIALS AND METHODS: We report here the clinical and molecular characterization of six patients with CGD from six consanguineous Turkish families. The ages of the five female patients were between 3 and 22 years and a male patient was 2 years old; all patients showed clear clinical symptoms of CGD. RESULTS: The mothers of the patients did not show a bimodal histogram pattern specific for X-CGD in the dihydrorhodamine-1,2,3 (DHR) assay. Moreover, p67(phox) protein expression was not detectable using flow cytometric analysis of the patients' neutrophils except in those from patient 6, which had a diminished expression. Mutation analysis of NCF2 revealed four different homozygous mutations: a novel nonsense mutation in exon 3 c.229C>T, p.Arg77X; a novel missense mutation in exon 4 c.279C>G, p.Asp93Glu; a nonsense mutation in exon 4 c.304C>T, p.Arg102X; and a novel missense mutation in exon 6 c.605C>T, p.Ala202Val. The parents were found to be heterozygotes for these mutations. CONCLUSIONS: The prevalence of NCF2 mutant families is approximately 15% in our series of 40 CGD families. This high incidence of A67 CGD in Turkey is undoubtedly caused by the high incidence of consanguineous marriages. We found three new mutations in NCF2 and one previously described. These are presented together with an overview of all NCF2 mutations now known.

Innate immune receptors on neutrophils and their role in chronic lung disease.

Neutrophils, the prototypic cells of the innate immune system, are recruited to infected sites to protect the human body from invading pathogens. To accomplish this function, neutrophils sense pathogens and endogenous damage-associated molecules via innate immune receptors, such as Toll-like receptors (TLRs) and other pattern recognition receptors. This defence function is essential for the pulmonary microenvironment where the host is faced with millions of particles and pathogens inhaled daily. Chronic lung diseases, such as cystic fibrosis or chronic obstructive pulmonary disease are characterized by a neutrophil accumulation and chronic bacterial colonization of the airways. Consequently, insights into the role of TLRs on neutrophils in chronic lung diseases are of high relevance for further diagnostic and therapeutic approaches. Here we summarize and discuss recent advances in the expression, regulation and functional role of TLRs on neutrophils in chronic lung diseases.

Six different CYBA mutations including three novel mutations in ten families from Turkey, resulting in autosomal recessive chronic granulomatous disease.

BACKGROUND: One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the CYBA gene, which encodes the alpha polypeptide of cytochrome b(558), (also known as p22-phox), a key transmembrane protein in the phagocyte NADPH oxidase system. This gene is localized on chromosome 16q24, encompasses 8.5 kb and contains six exons. MATERIALS AND METHODS: We report here the clinical and molecular characterization of 12 AR-CGD patients from 10 consanguineous, unrelated Turkish families with clinical CGD and positive family history. The ages of the six male and six female patients were between 1and 18 years. Before mutation analysis, subgroup analysis of patients was made by flow cytometry with antibodies against NADPH-oxidase components and with the DHR assay (flow cytometric assay of NADPH oxidase activity in leucocytes). RESULTS: Mutation analysis of CYBA showed six different mutations: a frameshift insertion in exon 3 (C after C166); a missense mutation in exon 2 (p.Gly24Arg), a splice-site deletion in intron 1 (4-bp deletion +4_+7 AGTG), a novel nonsense mutation in exon 6 (p.Cys113X), a novel large deletion of exons 3-6 and a novel 1-bp deletion in exon 6 (c.408delC). All mutations were present in homozygous form and all parents investigated were found to be heterozygotes for these mutations. CONCLUSIONS: In our series of 40 CGD families, approximately 25% of the families have p22-phox defects, with six different mutations, including three novel mutations. The high rate of consanguineous marriages seems to be the underlying aetiology.