Nationwide implementation of lenalidomide maintenance in multiple myeloma: A retrospective, real-world study.

Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Pulmonary diffusing capacity for carbon monoxide and nitric oxide after COVID-19: A prospective cohort study (the SECURe study).

Many patients exhibit persistently reduced pulmonary diffusing capacity after coronavirus disease 2019 (COVID-19). In this study, dual test gas diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) metrics and their relationship to disease severity and physical performance were examined in patients who previously had COVID-19. An initial cohort of 148 patients diagnosed with COVID-19 of all severities between March 2020 and March 2021 had a DL,CO,NO measurement performed using the single-breath method at 5.7 months follow-up. All patients with at least one abnormal DL,CO,NO metric (n = 87) were revaluated at 12.5 months follow-up. The DL,CO,NO was used to provide the pulmonary diffusing capacity for nitric oxide (DL,NO), the pulmonary diffusing capacity for carbon monoxide (DL,CO,5s), the alveolar-capillary membrane diffusing capacity and the pulmonary capillary blood volume. At both 5.7 and 12.5 months, physical performance was assessed using a 30 s sit-to-stand test and the 6 min walk test. Approximately 60% of patients exhibited a severity-dependent decline in at least one DL,CO,NO metric at 5.7 months follow-up. At 12.5 months, both DL,NO and DL,CO,5s had returned towards normal but still remained abnormal in two-thirds of the patients. Concurrently, improvements in physical performance were observed, but with no apparent relationship to any DL,CO,NO metric. The severity-dependent decline in DL,NO and DL,CO observed at 5.7 months after COVID-19 appears to be reduced consistently at 12.5 months follow-up in the majority of patients, despite marked improvements in physical performance.

Cat and dog owners' expectations and attitudes towards advanced veterinary care (AVC) in the UK, Austria and Denmark.

Modern veterinary medicine offers a level of care to cats and dogs similar to that available to their owners, including blood transfusions, chemotherapy and MRI scans. The potential benefits to the animals of owners who can afford such care are obvious, but there can also be negative consequences if owners with strong emotional attachments to their pets pursue treatments that significantly reduce the quality of the animal's life while attempting to prolong it. Moreover, caring for a chronically or seriously ill animal can lead to emotional distress and financial and practical challenges for the pet owner. A questionnaire was used to survey cat and dog owners from representative samples of citizens in the UK, Austria and Denmark, to investigate owners' expectations and attitudes towards advanced veterinary care, and the factors that might influence those views. Overall, 58.4% of the pet owners surveyed believed that their pets should have access to the same treatment options as humans, while 51.5% believed that they should have access to the same diagnostic tests as humans. Owners were most likely to be neutral on the question of whether advanced veterinary care has 'gone too far' (45.3%), and to disagree with the statement that advanced care is 'unnecessary' (40.1%). In all three countries, the level of attachment owners had to their pets was most strongly associated with attitudes towards advanced care, with owners scoring higher on Lexington Attachment to Pets Scale (LAPS) being more likely to expect advanced care to be available. Other factors such as owner age, living situation (alone or not), income or possession of pet insurance were less consistently with owner attitudes. Our findings will help inform veterinarians and other health care providers about pet owner expectations and attitudes towards advanced veterinary care, and contribute to the debate on increasing specialisation within the profession.

Identification and management of interstitial lung abnormalities.

Interstitial lung abnormalities (ILA) are incidentally observed specific CT findings in patients without clinical suspicion of interstitial lung disease (ILD). ILA with basal and peripheral predominance and features suggestive of fibrosis in more than 5% of any part of the lung should be referred for pulmonologist review. The strategy for monitoring as described in this review is based on clinical and radiological risk factors. ILA are associated with risk of progression to ILD and increased mortality. Early identification and assessment of risk factors for progression are essential to improve outcome.

Bone marrow adipocytes provide early sign for progression from MGUS to multiple myeloma.

Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient's quality of life, and will have significant socioeconomic implications. Here, we provide evidence that changes in the bone marrow adipose tissue (BMAT) provide an early sign for progression from MGUS to MM. We employed AI-assisted histological analysis of unstained bone marrow biopsies from MGUS subjects with or without progression to MM within 10 years (n = 24, n = 17 respectively). Although the BMAT fraction was not different between the two groups, bone marrow adipocyte (BMAd) density was decreased in MGUS patients who developed MM, compared to non-progressing MGUS patients. Importantly, the distribution profile for BMAd size and roundness was significantly different between the two groups, indicating a shift toward increased BMAd size and roundness in MGUS patients who developed MM. These early changes in the BMAT could serve as valuable early indicators for the transition from MGUS to MM, potentially enabling timely interventions and personalized treatment strategies. Finally, the AI-based approach for histological characterization of unstained bone marrow biopsies is cost-effective and fast, rendering its clinical implementation feasible.

Trends in underlying causes of death in allogeneic hematopoietic cell transplant recipients over the last decade.

OBJECTIVES: Improved survival after hematopoietic cell transplantation (HCT) and an increasingly comorbid transplant population may give rise to new trends in the causes of death. METHODS: This study includes all adult allogeneic HCT recipients transplanted at Rigshospitalet between January 1, 2010 and December 31, 2019. Underlying causes of death were determined using the Classification of Death Causes after Transplantation (CLASS) method. RESULTS: Among 802 HCT recipients, 289 died during the study period. The main causes of death were relapse (N = 133, 46.0%), graft-versus-host disease (GvHD) (N = 64, 22.1%) and infections (N = 35, 12.1%). Multivariable analyses showed that with increasing transplant calendar year, a decreased risk of all-cause mortality (HR 0.92, 95% CI 0.87-0.97) and death from GvHD (HR 0.87, 95% CI 0.78-0.97) was identified, but not for other specific causes. Standardized mortality ratios (SMRs) for all-cause mortality decreased from 23.8 (95% CI 19.1-28.5) to 18.4 (95% CI 15.0-21.9) for patients transplanted in 2010-2014 versus 2015-2019, while SMR for patients who died from GvHD decreased from 8.19 (95% CI 5.43-10.94) to 3.65 (95% CI 2.13-5.18). CONCLUSIONS: As risk of all-cause mortality and death from GvHD decreases, death from relapse remains the greatest obstacle in further improvement of survival after HCT.

Anemia in liver transplant recipients: prevalence, severity, risk factors, and survival.

Information about anemia in liver transplant (LTx) recipients is scarce. We investigated the prevalence and severity of anemia before and within the first-year post-LTx, risk factors for having anemia before LTx, and 1-year survival according to anemia status before LTx. This retrospective cohort study received data from The Knowledge Center for Transplantation database at Rigshospitalet, Copenhagen, Denmark. Uni- and multivariate logistic regression were used to investigate factors associated with anemia and a Kaplan-Meier plot to illustrate the probability of survival. We included 346 first-time adult LTx recipients. The median age was 50 years (IQR: 42-57), and 203 (59%) were male. The prevalence of anemia before and 1-year post-LTx were 69 and 45%, respectively. Male sex (aOR 4.0 [95% CI: 2.2-7.2]; p < 0.001) and each unit increase in MELD score (aOR 1.2 [95% CI: 1.1-1.2]; p < 0.001) were positively associated with anemia before LTx. Compared to autoimmune liver diseases, LTx recipients with fulminant hepatic failure (aOR 0.03 [0.00-0.17]; p = 0.001) had lower odds for anemia. The 1-year survival in LTx recipients who had and did not have anemia before transplantation were 93 and 91% (p = 0.47). Anemia was frequent among LTx recipients, and anemia before LTx did not affect 1-year survival.

Seeing the benefits, but not taking advantage of them: Dog and cat owners' beliefs about veterinary telemedicine.

BACKGROUND: Telemedicine offers benefits to clients and their animals, but potential disadvantages are also being debated. METHODS: Using a questionnaire, we investigated dog and cat owners' (N = 2117) use of and beliefs about telemedicine and whether beliefs impact past and expected future use. RESULTS: Although the majority of owners are aware that telemedicine can lead to the risk of something being missed, they see great potential in remote consultation in terms of usefulness for follow-up appointments or improving access to a specialist. However, only 12% of dog owners and 6% of cat owners have used telemedicine, and around 25% of owners who have never used it would be willing to use it in the future. Owners with a larger number of recent veterinary visits were more likely to have used telemedicine. LIMITATIONS: Although a definition of 'telemedicine' was provided, respondents may have had different perceptions of what this meant. CONCLUSION: Owners of dogs and cats recognise the potential benefits of telemedicine, but there is a mismatch with the actual uptake. This not only raises questions about the current availability of telemedicine but also should increase veterinary professionals' understanding of its potential benefits in veterinary practice.

Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial.

BACKGROUND: Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation. METHODS: ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18-70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2-3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05-0·1 mg/kg before transplantation and 0·1-0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27). FINDINGS: Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31-48]) in the ciclosporin group and 16 patients (13% [8-21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15-0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65-81] for ciclosporin vs 79% [70-85] for tacrolimus; HR 0·72 [95% CI 0·41-1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26-0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event. INTERPRETATION: Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation. FUNDING: Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark.

Making decisions for follow-up chemotherapy based on digital patient reported outcomes data in patients with multiple myeloma and other M protein diseases - A mixed method study.

OBJECTIVES: To test if Patient Reported Outcomes (PRO) data can replace physical on-site consultation in determining if patients with multiple myeloma, AL amyloidosis, or plasma cell leukemia are ready for their next bortezomib treatment without dose reduction. METHODS: We developed an online questionnaire addressing common side effects to bortezomib and an algorithm stratifying patients according to their responses and asked them to complete the questionnaire the day before attending the clinic. Applying a mixed-method study design of PRO data, time registrations, and interviews with patients and healthcare professionals, we tested the usability of electronic PRO data forming the basis of decision-making on whether patients are physically fit for the next treatment with an unchanged dose. RESULTS: The questionnaire and the associated algorithm were able to identify patients who were physically fit for treatment without need for further consultation, with a positive predictive value of 98 %. The method proved to be feasible for all groups of patients regardless of age and educational level. Patients and healthcare professionals found the online questionnaire to be advantageous and flexible. CONCLUSION: The use of PRO data to evaluate patients prior to bortezomib treatment is safe and feasible. Patients prefer to report their side effects themselves as it provides them with more freedom during their treatment.

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease.

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.

Do people really care less about their cats than about their dogs? A comparative study in three European countries.

Previous studies have shown that cat owners seem to care less about their cats than dog owners care about their dogs - both in terms of their emotional state of attachment and in their willingness to pay for services that potentially benefit the animals. One study speculated that this difference is "driven by the behavior of the pet" - that the behavior of dogs encourages care more than the behavior of cats - and therefore is a universal phenomenon. However, previous studies mostly relied on convenience sampling of owners and were undertaken in single countries. Based on responses to a questionnaire from cat and dog owners drawn from representative samples of citizens (18 to 89 years of age) in three different European countries, Denmark, Austria and the United Kingdom, we tested the degree to which owners care about their cats and dogs. We used four different measures: Lexington attachment to pets scale (LAPS), possession of pet health insurance, willingness to pay for life-saving treatment, and expectation of veterinary diagnostic and treatment options. Dog owners had higher LAPS scores in all countries. However, the difference between dog and cat owners was greater in Denmark than in Austria and the United Kingdom. More dogs than cats were insured in all three countries, but the ratio was much less skewed in favor of dogs in the United Kingdom compared to Denmark. In terms of expensive life-saving treatment, in every country, more dog owners than cat owners were willing to spend over a certain amount, but the differences were much more pronounced in Denmark compared to the United Kingdom. In Denmark and Austria, dog owners expected more veterinary treatment options to be available, but species made no difference to the expectations of UK owners. People care more about their dogs than their cats in all countries, but with a clear cross-country variation and a very modest difference in the United Kingdom. Therefore, it does not seem to be a universal phenomenon that people care much less about their cats than their dogs. This finding has practical implications for future efforts to expand the level of veterinary services provided for cat owners.

Treatment of primary plasma cell leukaemia with carfilzomib and lenalidomide-based therapy (EMN12/HOVON-129): final analysis of a non-randomised, multicentre, phase 2 study.

BACKGROUND: Primary plasma cell leukaemia is a rare and aggressive plasma cell disorder with a poor prognosis. The aim of the EMN12/HOVON-129 study was to improve the outcomes of patients with primary plasma cell leukaemia by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance therapy. METHODS: The EMN12/HOVON-129 study is a non-randomised, phase 2, multicentre study conducted at 19 academic centres and hospitals in seven European countries (Belgium, Czech Republic, Denmark, Italy, Norway, The Netherlands, and the UK) for previously untreated patients with primary plasma cell leukaemia aged 18 years or older. Inclusion criteria were newly diagnosed primary plasma cell leukaemia (defined as >2 ×109 cells per L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Patients aged 18-65 years (younger patients) and 66 years or older (older patients) were treated in age-specific cohorts and were analysed separately. Younger patients were treated with four 28-day cycles of carfilzomib (36 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 8, 9, 15, 16, 22, and 23). Carfilzomib-lenalidomide-dexamethasone (KRd) induction was followed by double autologous haematopoietic stem-cell transplantation (HSCT), four cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 intravenously on days 1, 2, 15, and 16 for the first 12 28-day cycles, and then 56 mg/m2 on days 1 and 15 in all subsequent cycles) and lenalidomide (10 mg orally on days 1-21) until progression. Patients who were eligible for allogeneic HSCT, could also receive a single autologous HSCT followed by reduced-intensity conditioning allogeneic HSCT and then carfilzomib-lenalidomide maintenance. Older patients received eight cycles of KRd induction followed by maintenance therapy with carfilzomib and lenalidomide until progression. The primary endpoint was progression-free survival. The primary analysis population was the intention-to-treat population, irrespective of the actual treatment received. Data from all participants who received any study drug were included in the safety analyses. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350; recruitment is complete and this is the final analysis. FINDINGS: Between Oct 23, 2015, and Aug 5, 2021, 61 patients were enrolled and received KRd induction treatment (36 patients aged 18-65 years [20 (56%) were male and 16 (44%) female], and 25 aged ≥66 years [12 (48%) were male and 13 (52%) female]). With a median follow-up of 43·5 months (IQR 27·7-67·8), the median progression-free survival was 15·5 months (95% CI 9·4-38·4) for younger patients. For older patients, median follow-up was 32·0 months (IQR 24·7-34·6), and median progression-free survival was 13·8 months (95% CI 9·2-35·5). Adverse events were most frequently observed directly after treatment initiation, with infections (two of 36 (6%) younger patients and eight of 25 (32%) older patients) and respiratory events (two of 36 [6%] younger patients and four of 25 [16%] older patients) being the most common grade 3 or greater events during the first four KRd cycles. Treatment-related serious adverse events were reported in 26 (72%) of 36 younger patients and in 19 (76%) of 25 older patients, with infections being the most common. Treatment-related deaths were reported in none of the younger patients and three (12%) of the older patients (two infections and one unknown cause of death). INTERPRETATION: Carfilzomib and lenalidomide-based therapy provides improved progression-free survival compared with previously published data. However, results remain inferior in primary plasma cell leukaemia compared with multiple myeloma, highlighting the need for new studies incorporating novel immunotherapies. FUNDING: Dutch Cancer Society, Celgene (a BMS company), and AMGEN.

Comparative study of per- and polyfluoroalkyl substances (PFAS) removal from landfill leachate.

Landfill leachate is one of the major point sources of per- and polyfluoroalkyl substances (PFAS) pollution. In this study, powdered activated carbon (PAC), granular activated carbon (GAC), anion exchange resin (AIX), nanofiltration (NF), ozonation, and foam fractionation were tested for treatment of the same leachate. These methods were compared in terms of PFAS removal efficiencies and treatment cost. More than 75% removal of long-chain PFAS (6-9 CF2) could be achieved with all the studied methods, though with high resource consumption. It was demonstrated that PFAS breakthrough was up to 27 times faster when the leachate was treated with GAC and AIX compared to groundwater treatment. Nanofiltration was the only method which could be practically applied for removal of PFAS with the shortest fluorinated carbon chain (3-4 CF2). Foam fractionation and AIX offered the most economical treatment, with an estimated cost of < 1 €/m3 for PFOS and PFOA reduction to ≥ 90%. The cost of treatment was shown to increase exponentially if the goal of > 60% ΣPFAS11 removal was applied. It was also discussed that composite parameters that include expected toxicity of different PFAS, such as ΣPFOAeq, should be used to obtain a cost-efficient reduction of PFAS-induced water toxicity.

Acute exacerbation of fibrotic interstitial lung diseases.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and other fibrotic interstitial lung diseases (AE-ILD) is defined by significant acute respiratory worsening and new widespread alveolar damage. This review summarises the current knowledge of diagnosis and treatment of these events. The diagnosis of AE-IPF and AE-ILD is based on typical HRCT findings of new and bilateral ground glass opacification and/or consolidation, and exclusion of fluid overload or cardiac failure. Treatment relies, despite low quality of evidence, on glucocorticoid in addition to supportive and palliative treatment. Despite treatment, the prognosis is poor, with a median survival of 2-4 months.

Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres.

The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.