Exploring the factors influencing evidence-based approaches to advanced chronic kidney disease: a qualitative study involving nurses and physicians.

BACKGROUND: Advanced chronic kidney disease (ACKD) is associated with a high risk of adverse cardiovascular and renal events and has a significant impact on quality of life and life expectancy. Several studies have identified areas for improvement in their management in primary care. Some professional and environmental factors can act as key barriers to appropriate care. OBJECTIVE: To analyse attitudes, subjective norms, and perceived behavioural control among primary care professionals related to the implementation of an evidence-based approach for individuals with ACKD in primary care. METHODOLOGY: This was a qualitative study using an interpretative phenomenological approach based on the theory of planned behaviour. Two aspects of the evidence-based approach were explored: the implementation of clinical practice guidelines and the utilisation of electronic kidney disease records within the scope of this study. Primary care nurses and physicians participated in a previous pilot interview and five focus groups. Subsequently, a thematic analysis of the gathered data was conducted. FINDINGS: Thirty-three primary care professionals participated. The emerging themes included: experiences in the management of ACKD (highlighting a distinct profile of older, frail patients with comorbidities masking CKD and a CKD follow-up primarily focused on analytical monitoring and drug adjustment); factors in the professional environment influencing the use of scientific evidence (such as time constraints, excessive electronic health records, and unfamiliar reference guidelines); attitudes towards the application of recommendations on ACKD (recognising limitations of computer systems despite considering them as guidance); and capacities to implement evidence-based recommendations (acknowledging formative needs and challenges in coordinating care with nephrology services). CONCLUSIONS: Several psychological elements identified through the TBP hinder the adequate implementation of an evidence-based approach for individuals with CKD. Attitudes have been identified as factors modulating the use of standardised electronic records. Instead, subjective norms (influences from the professional environment) and perceived behavioral control (perception of capabilities) acted as barriers to the proper application of clinical practice guidelines and standardised records. IMPLICATIONS FOR PRACTICE: Strategies aimed at optimising the management of people with ACKD should focus not only on training but also on improving attitudes, organisational structures, IT systems and coordination between primary care and nephrology.

Text messaging as a tool to improve cancer screening programs (M-TICS Study): A randomized controlled trial protocol.

BACKGROUND: Short message service (SMS) based interventions are widely used in healthcare and have shown promising results to improve cancer screening programs. However, more research is still needed to implement SMS in the screening process. We present a study protocol to assess the impact on health and economics of three targeted SMS-based interventions in population-based cancer screening programs. METHODS/DESIGN: The M-TICs study is a randomized controlled trial with a formal process evaluation. Participants aged 50-69 years identified as eligible from the colorectal cancer (CRC) and breast cancer (BC) screening program of the Catalan Institute of Oncology (Catalonia, Spain) will be randomly assigned to receive standard invitation procedure (control group) or SMS-based intervention to promote participation. Two interventions will be conducted in the CRC screening program: 1) Screening invitation reminder: Those who do not participate in the CRC screening within 6 weeks of invite will receive a reminder (SMS or letter); 2) Reminder to complete and return fecal immunochemical test (FIT) kit: SMS reminder versus no intervention to individuals who have picked up a FIT kit at the pharmacy and they have not returned it after 14 days. The third intervention will be performed in the BC screening program. Women who had been screened previously will receive an SMS invitation or a letter invitation to participate in the screening. As a primary objective we will assess the impact on participation for each intervention. The secondary objectives will be to analyze the cost-effectiveness of the interventions and to assess participants' perceptions. EXPECTED RESULTS: The results from this randomized controlled trial will provide important empirical evidence for the use of mobile phone technology as a tool for improving population-based cancer screening programs. These results may influence the cancer screening invitation procedure in future routine practice. TRIAL REGISTRATION: Registry: NCT04343950 (04/09/2020); clinicaltrials.gov.

False-Positive Results in a Population-Based Colorectal Screening Program: Cumulative Risk from 2000 to 2017 with Biennial Screening.

BACKGROUND: The aim of this study was to estimate the cumulative risk of a false-positive (FP) result in a fecal occult blood test (FOBT) through 7 screening rounds and to identify its associated factors in a population-based colorectal cancer screening program. METHODS: Retrospective cohort study, which included participants ages 50 to 69 years of a colorectal cancer screening program in Catalonia, Spain. During this period, 2 FOBTs were used (guaiac and immunochemical). A discrete-time survival model was performed to identify risk factors of receiving a positive FOBT with no high-risk adenoma or colorectal cancer in the follow-up colonoscopy. We estimated the probability of having at least 1 FP over 7 screening rounds. RESULTS: During the period of 2000 to 2017, the cumulative FP risk was 16.3% (IC95%: 14.6%-18.3%), adjusted by age, sex, and type of test. The median number of screens was 2. Participants who began screening at age 50 years had a 7.3% [95% confidence interval (CI), 6.35-8.51] and a 12.4% (95% CI, 11.00-13.94) probability of an FP with 4 screening rounds of guaiac-based test and immunochemical test, respectively. Age, the fecal immunochemical test, first screening, and number of personal screens were factors associated with an FP result among screenees. CONCLUSIONS: The cumulative risk of an FP in colorectal screening using FOBT seems acceptable as the colonoscopy, with its high accuracy, lengthens the time until additional colorectal screening is required, while complication rates remain low. IMPACT: It is useful to determine the cumulative FP risk in cancer screening for both advising individuals and for health resources planning.

Communication Channels Used by Women to Contact a Population-Based Breast Cancer Screening Program in Catalonia, Spain.

Communication is a corner stone of population-based breast cancer screening programs that need to invite all the women from their target population and provide them with balanced information on screening to guaranty informed participation. Invited women also need to be able to contact screening programs to get further information on screening procedures and/or cancel and reschedule appointments. This study describes the communication channels used by women invited for breast cancer screening to contact the program. The study population consisted of 141,684 women, aged 50-69 years, who were invited during 2015-2016 for screening by the Catalan Breast Cancer Screening Program (Spain). Multiple logistic regression models were performed to assess the association between age, screening history, socioeconomic status and reasons for contacting the program and the outcome variables (contact with the program; contact through information and communication technology (ICT) channels). Among the 141,684 women invited for BC screening, 22.5% contacted the screening office mainly to reschedule (42.2%) and cancel (29.2%) appointments. While the communication channel mostly used was the telephone, 24.8% of the women used ICT. ICT was more frequently used by women who had never been screened. Women who wanted to change their appointment were 65% (OR 1.65, 95%CI 1.54-1.76) more likely to use ICT than women who wanted to cancel it. This study showed the need to reinforce communication between women and breast cancer screening programs and the importance of offering communication channels suiting all women's needs to facilitate appointments' rescheduling and cancelling and therefore improve screening programs' efficiency.

Longitudinal Adherence to Immunochemical Fecal Occult Blood Testing vs Guaiac-based FOBT in an Organized Colorectal Cancer Screening Program.

Longitudinal adherence is a critical component of the efficacy of stool-based screening programs because they should be repeated every 1-2 years. Few data have been published on the uptake in multiple rounds of fecal occult blood test-based (FOBT) colorectal cancer (CRC) screening. We calculated two measures of longitudinal adherence to biennial FOBT (guaiac fecal occult blood test:gFOBT or fecal immunochemical test:FIT) to better understand its impact on the programmatic effectiveness of a population-based CRC screening program (2000-2017). Ongoing population-based CRC program of men and women aged 50-69 years. Variables: Age at first CRC screening invitation, sex, number of screening invitations, number of screens, deprivation score, and uptake rate. Logistic regression models were used to assess the independent effect of sex, age at first invitation, deprivation, and the type of screening test offered on adherence. The uptake rate for guaiac fecal occult blood test (gFOBT) was 23.9%, and for the fecal immunochemical test (FIT), it was 37.4%. The overall rate of consistently screened invitees after seven rounds of screening was 14.2%, being 20.6% for those individuals who used FIT and 14.3% for those who used gFOBT. Factors associated with continued participation (consistent vs. inconsistent screenees) showed that the longitudinal adherence was associated with age, screening test used, and number of invitations. Continued participation was lower in individuals who were screened using FIT than among those screened using gFOBT [OR, 0.68; 95% confidence interval (CI), 0.57-0.81]. The overall rate of consistently screened invitees for colorectal cancer screening was higher with FIT than gFOBT. Studying the rate of individuals being current for screening may help to anticipate potential benefits before the long-term outcome data are available.

Level of satisfaction of critical care patients regarding the nursing care received: Correlation with sociodemographic and clinical variables.

BACKGROUND: The satisfaction of critical care patients regarding the nursing care received is a key indicator of the quality of hospital care. It is, therefore, essential to identify the factors associated with the level of satisfaction of critical care patients. OBJECTIVES: To analyse the level of satisfaction of critical care patients in relation to the nursing care received and to determine the relationship between the level of satisfaction and the sociodemographic and clinical variables. METHODS: This is a prospective and descriptive correlational study. The population were all patients discharged (January 2013 to January 2015) from three intensive care units of a third-level hospital (n = 200). The data on the satisfaction level were collected using the previously validated Nursing Intensive-Care Satisfaction Scale, and the sociodemographic and clinical data were recorded by means of a questionnaire. RESULTS: Mean participants' age in the study (n = 200) was 65.9 years (standard deviation 13.4 years), with a 66% proportion of men (n = 132). There was a very high level of satisfaction regarding the nursing care received during the patients' stay in the intensive care unit, with a rating of 5.73 (standard deviation 0.41). There is no correlation between the level of satisfaction and the sociodemographic variables collected. However, there were statistically significant differences in the average score of the overall level of satisfaction (rho = 0.182, p = 0.010) with respect to the perception of the state of health. CONCLUSION: Critical care patients expressed very high rates of satisfaction, for both the scale as a whole and each of the factors. A high level of satisfaction is strongly influenced by the perception of the state of health.

Meaning-centered psychotherapy integrated with elements of compassion: A pilot study to assess feasibility and utility.

OBJECTIVE: The main objective of this study is to establish emotional benefits of promoting and maintaining meaning in palliative care patients in the final weeks of life and to assess the benefits of including the compassion and self-compassion constructs in the Meaning-Centered Psychotherapy Model (MCP). METHOD: Fifty-one cancer inpatients were randomly assigned to one of the three brief interventions for cancer patients in the end of life: the MCP-palliative care version, the MCP-compassionate palliative care (MCP-CPC), or standard counseling. Feasibility, acceptability, and utility were assessed in each condition. Likewise, patients' opinions about the effectiveness of interventions' elements were also collected.ResultOf the 51 patients that began one of the three interventions, 30 completed the three-session interventional program, as well as the pre- and posttreatment questionnaires. No significant differences were found between therapies in terms of the positive feedback of patients regarding the structure, focus, and length of the all three psychotherapeutic interventions. The most helpful elements or constructs reported by patients were meaning, self-compassion, compassion, legacy, and courage and commitment.Significance of resultsAn abbreviated version of MCP-CPC tailored to the needs of palliative care patients appears to be feasible, acceptable, and helps patients cope with the process of dying. Further research in bigger samples is needed to establish evidence for the feasibility, acceptability, and utility of a brief MCP-CPC for palliative care patients in their last weeks of life. More proposals of further elements are also needed to improve the results. Such research can create or refine previous treatment approaches which improve the quality of life and psychological distress in patients with advanced cancer.

Identifying Coordination and Continuity of Care Indicators for Population-Based Cancer Screening Programs: A Delphi Study.

BACKGROUND: Continuity of care and care coordination are critical issues in virtually all healthcare systems. European guidelines for the quality of screening programs for breast and colorectal cancer describe process, structure, and outcome indicators, but none specifically evaluate coordination and continuity of care during the cancer screening process. OBJECTIVE: The aim of this study was to identify indicators reflecting care coordination and continuity in population-based breast and colorectal cancer screening program. METHODS: A two-round Delphi study was conducted in a sample of 30 cancer screening nurses to identify quality indicators. RESULTS: The final Delphi consensus resulted in six core indicators for the cancer screening program: adequacy of the referral of the target population from the screening program to other health services, waiting time for referral to other health services, understanding of the screening program by professionals involved in the process, effective information flow between professionals involved in the process, participants' perception of the screening program, and, finally, participants' understanding of information about the program. CONCLUSION: The evaluation of indicators is crucial for quality improvement and should allow a measuring system to be established that would allow a comparison of outcomes for all population-based cancer screening programs.

Factors related to longitudinal adherence in colorectal cancer screening: qualitative research findings.

BACKGROUND: The effectiveness of screening in colorectal cancer prevention depends on sustained participation rates. The objective of this study was to explore factors related to the longitudinal adherence of screening behavior in the context of a biennial population-based cancer screening program. METHODS: Eight focus groups were conducted with individuals who were invited two or three consecutive times to a population-based colorectal cancer screening program using a fecal occult blood test and who agreed to participate in the program at least once (n = 45). The criteria used to select the study members included adherence to fecal occult blood test maintenance, factors regarding their initial participation in the colorectal cancer screening, sex, and contextual educational level. RESULTS: The participants expressed a high level of satisfaction with the program; however, they showed a low level of understanding with respect to cancer screening. Consulting a general practitioner was cited by all participants as an important factor that mediated their final decision or influenced their behavior as a whole with regard to the program. Fear played a different role in the screening behavior for regular and irregular adherent participants. In the adherent participants, fear facilitated their continued participation in the screening program, whereas for the irregular participants, fear led them to avoid or refuse further screening. Having a close person diagnosed with colorectal cancer was a facilitator for the regular adherent participants. The irregular adherent participants showed some relaxation with respect to screening after a negative result and considered that further screening was no longer necessary. CONCLUSION: Considering the importance of primary healthcare professionals in the decision regarding sustained participation, it is important to better engage them with cancer screening programs, as well as improve the communication channels to provide accurate and balanced information for both health professionals and individuals.

Population-based Cancer Screening: Measurement of Coordination and Continuity of Care.

BACKGROUND: European guidelines for the quality of screening programs for breast and colorectal cancer describe process, structure, and outcome indicators. However, none of them specifically evaluate coordination and continuity of care during the cancer screening process. OBJECTIVES: The aim of this study was to identify and adapt care quality indicators related to the coordination and continuity of the cancer screening process to assess nursing care in cancer screening programs. METHODS: The indicators proposed in this study were selected in 2 phases. The first consisted of a literature review, and the second was made by consensus of an expert group. An electronic literature search was conducted, through June 2016. From a total of 225 articles retrieved, 14 studies met inclusion criteria, and these 14 documents were delivered to the group of experts for evaluation and to propose a final list of agreed-upon indicators. RESULTS: The group of experts selected 7 indicators: adequacy and waiting time derivation of participants, delivery and availability of the report of the process, understanding professionals involved in the process, and satisfaction and understanding of participants. CONCLUSIONS: These indicators should help identify areas for improvement and measure the outcome of coordination and continuity of care. IMPLICATIONS FOR PRACTICE: The results provided a common set of indicators to evaluate the coordination and continuity of care for cancer screening and to consequently assess the contribution of nursing care in cancer screening programs. The identification and adaptation of these quality indicators will help to identify areas for improvement and measure the effect of coordination and continuity of care.

Identifying Nursing Interventions in a Cancer Screening Program Using Nursing Interventions Classification Taxonomy.

PURPOSE: This study aimed to investigate which Nursing Interventions Classification (NIC) labels correspond to specific nursing interventions provided during cancer screening to establish a nursing documentation system. METHOD: This descriptive study was conducted to identify and classify the interventions that cancer screening nurses perform based on an initial list. FINDINGS: The initial list was grouped into 15 interventions that corresponded to four domains and eight classes. CONCLUSION: The study found expert consensus regarding the duties of cancer screening nurses and identified 15 interventions that should be implemented in clinical practice for cancer screening care, according to the NIC taxonomy. IMPLICATIONS: This study is the first step in developing indicators to assess nursing performance in cancer screening, and it helps to establish the core competency requirements for cancer screening nurses.

False-negative rate cannot be reduced by lowering the haemoglobin concentration cut-off in colorectal cancer screening using faecal immunochemical test.

The aim of this study was to analyse false-negative (FN) results of the faecal immunochemical test (FIT) and its determinants in a colorectal cancer screening programme in Catalonia. We carried out a cross-sectional study among 218 screenees with a negative FIT result who agreed to undergo a colonoscopy. A false-negative result was defined as the detection, at colonoscopy, of intermediate/high-risk polyps or colorectal cancer in a patient with a previous negative FIT (<20 µgHb/g). Multivariate logistic regression models were constructed to identify sociodemographic (sex, age) and screening variables (quantitative faecal haemoglobin, colonoscopy findings) related to FN results. Adjusted odds ratios and their 95% confidence intervals were estimated. There were 15.6% FN FIT results. Faecal haemoglobin was undetected in 45.5% of these results and was below 4 µgHb/g in 94.0% of the individuals with a FN result. About 60% of the lesions were located in the proximal colon, whereas the expected percentage was 30%. Decreasing the positivity threshold of FIT does not increase the detection rate of advanced neoplasia, but may increase the costs and potential adverse effects.

Colorectal Cancer Screening Programme in Spain: Results of Key Performance Indicators After Five Rounds (2000-2012).

Effective quality assurance is essential in any screening programme. This article provides a unique insight into key quality indicators of five rounds of the first population-based colorectal cancer screening programme implemented in Spain (2000-2012), providing the results according to the type of screening (prevalent or first screen and incident or subsequent screen) and test (guaiac or immunochemical). The total crude participation rate increased from 17.2% (11,011) in the first round to 35.9% (22,988) in the last one. Rescreening rate was very high (88.6% in the fifth round). Positivity rate was superior with the faecal immunochemical test (6.2%) than with the guaiac-based test (0.7%) (p < 0.0001) and detection rates were also better with the immunochemical test. The most significant rise in detection rate was observed for high risk adenoma in men (45.5 per 1,000 screened). Most cancers were diagnosed at an early stage (61.4%) and there was a statistically significant difference between those detected in first or subsequent screening (52.6% and 70.0% respectively; p = 0.024). The availability of these results substantially improves data comparisons and the exchange of experience between screening programmes.

[Interval cancers and episode sensitivity in population-based screening programmes for colorectal cancer: a systematic review]. / Cánceres de intervalo y sensibilidad de los programas poblacionales de cribado de cáncer colorrectal.

OBJECTIVE: To describe interval cancers (IC) and the sensitivity of colorectal cancer (CRC) screening programmes. METHODS: A systematic review of the literature was conducted through a MEDLINE (PubMed) search. The search strategy combined the terms 'interval cancer', 'false negative', 'mass screening', 'screening' 'early detection of cancer', 'colorectal cancer' and 'bowel cancer'. Inclusion criteria consisted of population-based screening programmes, original articles written in English or Spanish and publication dates between 1999/01/01 and 2015/02/28. A narrative synthesis of the included articles was performed detailing the characteristics of the screening programmes, the IC rate, and the information sources used in each study. RESULTS: Thirteen articles were included. The episode sensitivity of CRC screening programmes ranged from 42.2% to 65.3% in programmes using the guaiac test and between 59.1% and 87.0% with the immunochemical test. We found a higher proportion of women who were diagnosed with IC and these lesions were mainly located in the proximal colon. CONCLUSION: There is wide variability in the IC rate in CRC programmes. To ensure comparability between programmes, there is a need for consensus on the working definition of IC and the methods used for their identification and quantification.

Fecal hemoglobin concentration as a measure of risk to tailor colorectal cancer screening: are we there yet?

The aim of this paper was to examine the distribution of fecal hemoglobin (f-Hb) concentration in a Spanish colorectal cancer screening population according to sociodemographic characteristics and analyze whether f-Hb was associated with clinical outcomes (type of lesion and its location). From September 2009 to November 2012, we sent 77,744 invitations to individuals aged 50-69 years to provide one sample of feces. f-Hb was measured on samples from 27,606 screenees (35.5%). Colonoscopy findings and pathology data were collected on the 1406 screenees with f-Hb greater than 100 ng Hb/ml (20 mg Hb/g feces). The Mann-Whitney U-test and the Kruskal-Wallis test were used to compare f-Hb (median) according to sociodemographic variables, clinical outcomes, and histological features of adenomas. f-Hb from greater than 100 ng Hb/ml was categorized into quartiles. Regression models were used to determine whether f-Hb was a risk predictor of colorectal lesions. f-Hb was associated directly with the severity of the colorectal lesions. An overlap between individuals with a negative colonoscopy and those with a low-risk adenoma was observed. High-grade dysplasia, villous histology, distal location, and increasing size were all features associated with an increased f-Hb level. f-Hb could be used in individual risk assessment to determine surveillance strategies for colorectal cancer screening.

Defining the role of the nurse in population-based cancer screening programs.

Nurses are pivotal in cancer prevention and early detection, but the nurse's role in cancer screening programs has been described only in very general terms without specification of activities needed to develop the role. To identify the set of activities that compose the role of the cancer screening nurse, the authors of the current article performed a critical descriptive literature review to document nursing involvement in cancer screening, covering articles published from 2000-2012. A total of 726 potentially relevant studies were identified, and 22 of those were included in the review. Nurses carry out follow-up, coordinate treatment, ensure continuity throughout the process, provide up-to-date and pertinent information to facilitate patient knowledge and choice, work to ensure coordination among the various levels of care, provide ongoing training, lead research and publications concerning daily practice, and collaborate in investigation oriented toward early detection. The literature revealed that the nurse's role in cancer screening involves case management as the main activity as well as, exceptionally, carrying out diagnostic tests.

First anxiety, afterwards depression: psychological distress in cancer patients at diagnosis and after medical treatment.

OBJECTIVE: The purpose of this study was to assess psychosocial changes at two particular moments: at cancer diagnosis and 2-4 weeks after having finished treatment. MATERIAL AND METHODS: A total of 67 cancer outpatients were assessed in this study. The inclusion/exclusion criteria were as follows: ambulatory cancer patients aged 18 years or older and receiving medical treatment. Patients with a performance status <50 or with cognitive impairment (≥3 errors in the Pfeiffer Questionnaire) were excluded. The inclusion period ranged from 1 April 2005 to 30 April 2007. The scales used were the 14-item Hospital Anxiety and Depression Scale (HADS), which has two subscales for anxiety (seven items) and for depression (seven items), the Quality of Life Short Form 36 Questionnaire, the Mental Adjustment Scale and the Medical Outcomes Study Questionnaire for measuring social support. All data were compared with sociodemographic and medical characteristics. RESULTS: Patients had higher levels of pre-treatment versus post-treatment anxiety (HADS-Anxiety mean, 7.41 versus 6.69), whereas depression scores were higher post-treatment versus pre-treatment (HADS-Depression mean, 3.14 versus 3.89). After medical treatment, patients were more fatigued, with lower performance status (Karnofsky Index), less social support and less quality of life, but no differences in coping styles were found. Women had higher levels of anxiety than men. Patients with psychiatric antecedents had higher levels of distress, but these differences were only observed after diagnosis and not after the treatment. In general, head and neck cancer patients had higher levels of distress, worse coping and worse social functioning. CONCLUSIONS: Cancer patients require special consideration before and after treatment. Anxiety is the symptom that characterizes diagnosis, whereas depression is more common after medical treatment. The head and neck cancer patients were the group with the highest complexity.

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study.

The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.

A mild neurofibromatosis type 1 phenotype produced by the combination of the benign nature of a leaky NF1-splice mutation and the presence of a complex mosaicism.

Here we analyze the genetic and molecular basis responsible for a very benign phenotype observed in an NF1 patient. Quantification of cells carrying the NF1 mutation in different samples derived from the three embryonic layers revealed mosaicism. Furthermore, the construction of a minigene with patient's mutation (c.3198 - 314G>A) confirmed its benign nature due to the leakiness of the splicing mechanism that generated a proportion of correctly spliced transcripts. Hence, we concluded that the mild phenotype observed in this patient is the result of the presence of mosaicism together with the benign nature of a leaky NF1-splice mutation. Finally, with the aim of developing a personalized therapeutic approach for this patient, we demonstrated correction of the splicing defect by using specific antisense morpholino oligomers. Our results provide an example of the molecular complexity behind disease phenotypes and highlight the importance of using comprehensive genetic approaches to better assess phenotype-genotype correlations.

Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: Importance of copy neutral LOH.

Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH-tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ∼80 kb to ∼8 Mb within 17q. In one tumor we identified the first example of a neurofibroma-associated second-hit type-2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation.