Abstract Cystic fibrosis (CF) is the most common genetic disease in the Caucasion population. Thanks to the CFTR modulators therapy, life expectancy will significantly improve. New therapeutic challenges can be expected, including diseases associated with ageing and higher incidence of cancer, as evidenced by recent epidemiological studies. The increasing incidence of tumors includes also breast cancer. The risk of breast cancer is higher in CF patients compared to the general population. Sex hormones, especially estrogens, also affect on the pathophysiology and immunology of the CF. Previous research, has demonstrated unequivocal survival rates for female CF patients compared to their male counterparts. Is demonstrated, that chemotherapy used for breast cancer affects the CFTR channel and CFTR modulator therapy has frequent side effects on breast tissue. In this review, we focus on the effects of female sex hormones on CF disease, pathophysiological relationships between CF and breast cancer, and the impact of antitumor treatment on both, malignant disease and CF. The potential for further investigation is also discussed.
Introduction: For endobronchial tumor lesions, flexible bronchoscopy is the gold standard technique to obtain material suitable for morphological diagnosis. It has been reported that endobronchial cryobiopsy has higher diagnostic yield compared to forceps biopsy. It remains unclear, if cryobiopsy also shortens time to diagnosis. Aims: Our aim was to assess and compare the diagnostic yield, safety, rate of diagnostic failure and time to diagnosis of both procedures (endobronchial cryobiopsy vs forceps biopsy). Methods: This was a retrospective study. We included all patients with visualized endobronchial tumor lesions that underwent diagnostic bronchoscopy between January 2018 and December 2020 at the Department of Respiratory Diseases, University Hospital Brno, Czech Republic. The Shapiro-Wilk test, Mann-Whitney U test and two-tailed Fisher exact test were used for statistical analyses, using the Statistica software 12.0 (StatSoft Inc., Prague, Czech Rep.). Data presented as median (IQR). P values <0.05 were considered statistically significant. Results: Data of 330 patients were analyzed, of these, 61% underwent endobronchial cryobiopsy and 39% forceps biopsy. There were no differences in age, sex and BMI. Average number of biopsy samples was higher in the forceps group [6 (5-7) vs 4 (3-5); p<0.01], as was time to diagnosis [9 days (7-12) vs 8 (6-10); p<0.01] and rate of patients with diagnosis made after ≥21 days (7% vs 2%; p=0.04). Similarly, repeated biopsy was more frequent in the forceps group (9% vs 2%; p<0.01), while rate of moderate/severe bleeding was comparable in both groups (p=0.12). Conclusions: Endobronchial cryobiopsy shortens the time to histological diagnosis, while proves to be a safe and highly effective method.
•We present two cases of adult CF patients, F508del/3849+10 kb C > T mutation status, who improved the faecal-elastase level after elexacaftor/tezacaftor/ivacaftor initiation.•Exocrine pancreatic insufficiency conversion has been demonstrated so far only in paediatric patients.•We need further studies on whether borderline exocrine pancreatic insufficiency in patients with mild mutation can be saved even in adult age. Cystic fibrosis (CF) is a quality-of-life-limiting disease due to multiorgan complications. Exocrine pancreatic insufficiency (EPI) is one of the most common characteristics of CF. Pancreatic function depends on a CFTR gene mutation's class [[1]Walkowiak J. Herzig K.H. Witt M. et al.Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency.Eur J Clin Investig. 2001; 31: 796-801https://doi.org/10.1046/j.1365-2362.2001.00876.xCrossref PubMed Scopus (47) Google Scholar]. The milder mutation carriers confer a dominant effect on the exocrine pancreatic status. EPI typically occurs in people who carry two severe mutations, while pancreatic sufficiency typically occurs in either both mild or mild + severe mutation carriers [[2]McKay I.R. Ooi C.Y. The exocrine pancreas in cystic fibrosis in the era of CFTR modulation: a mini review.Front Pediatr. 2022; 10914790https://doi.org/10.3389/fped.2022.914790Crossref Scopus (4) Google Scholar]. F508del belongs to a II. class of CFTR pathogenic variant, which leads to reduction of CFTR protein function. 3849+10 kb C > T is in a class V, which is related to reduction in protein quantity. This pathogenic variant is considered mild according to the pancreatic insufficiency prevalence score; carriers of mild genotypes have a significant increase in risk of developing pancreatitis at any age [[3]Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161https://doi.org/10.1053/j.gastro.2010.09.046Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. Carriers of this mutation combination are likely pancreatic sufficient, however, these patients may develop chronic pancreas inflammation and EPI in adulthood [3Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161https://doi.org/10.1053/j.gastro.2010.09.046Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 4Stern R.C. Doershuk C.F. Drumm M.L. 3849+10 kb C–>T mutation and disease severity in cystic fibrosis.Lancet Lond Engl. 1995; 346: 274-276https://doi.org/10.1016/s0140-6736(95)92165-6Crossref PubMed Google Scholar, 5Duguépéroux I. De Braekeleer M. The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype.Eur Respir J. 2005; 25: 468-473https://doi.org/10.1183/09031936.05.10100004Crossref PubMed Scopus (41) Google Scholar]. Fecal elastase (FE-1) 〈 100 μg/g together with the clinical signs is considered as EPI, 100 – 200 μg/g is considered borderline and 〉 200 μg/g indicates sufficient pancreatic function. It is widely thought to be irreversible in adults, and might be restored in the youngest children in the case of targeted therapy use [[2]McKay I.R. Ooi C.Y. The exocrine pancreas in cystic fibrosis in the era of CFTR modulation: a mini review.Front Pediatr. 2022; 10914790https://doi.org/10.3389/fped.2022.914790Crossref Scopus (4) Google Scholar]. The modest improvement of frequency and severity of gastrointestinal symptoms in CF was reported after CFTR modulator use, but to date, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor (ETI) combinations have not been demonstrated to affect exocrine pancreatic function in adults [[6]Schwarzenberg S.J. Vu P.T. Skalland M. et al.Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: report of promise-GI.J Cyst Fibros. 2023; 22: 282-289https://doi.org/10.1016/j.jcf.2022.10.003Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Here, we present 2 cases of adult CF patients who improved their pancreatic function serum values after ETI commencement. The first case is a 38-year-old female who was referred to the CF centre at the age of 16, diagnosed with cystic fibrosis according to genetic testing resulting in F508del/3849+10 kb C > T. Her sweat test value was 82 mmol/l and FE-1 value was 45 μg/g (2/2001). She did not suffer any symptoms of maldigestion (no steatorrhea, bowel movements 1–2 times a day, no failure of thrive, no severe fat-soluble vitamin deficiencies). At this time, her body weight was 51 kg and BMI was at the 68th percentile. Pancreatic enzyme replacement therapy (PERT) was initiated (125,000 UI/day). At the age of 26, the patient was diagnosed with CF-related diabetes with incipient neuropathy. At the age of 35, the combination of tezacaftor/ivacaftor was introduced to her and one year later, at her age 36, she started treatment with the triple combination of ETI. Her body weight at this time was 66 kg, BMI 23.9 kg/m2. We failed to measure the FE-1 before the start of the CFTR modulator and following tezacaftor/ivacaftor initiation. She tolerated the treatment well, with no side effects. After 24 weeks, her sweat test decreased to 12 mmol/l, suggesting a positive response to the treatment. Moreover, after the same interval, the FE-1 increased to 419.4 μg/g, in week 32 even to 442.1 μg/g. She was able to be completely weaned off PERT with no side effects. After PERT withdrawal, her body weight was 2 kg higher than at the time of ETI initiation (68 kg, BMI 24.6 kg/m2). Her gastrointestinal signs remained stable (stable bowel movement, no abdominal discomfort). Inspired by this case, we retested a second patient with the mentioned genotype. A 40-year-old female was diagnosed with CF (genotype F508del/3849 + 10 kb C > T, sweat test 63 mmol/l) at the age of 11. Her first FE-1 value consistent with EPI was at the age of 31 (86.7 μg/g) in 9/2013. She did not suffer from steatorrhea, cramps or abdomen pain, had no signs of failure of thrive, only intermittently bloating and flatulence. At the beginning, she used 75,000 UI/day of PERT. However, after several years, without consulting the CF specialist, she refused to take it anymore, and instead preferred to use alternative medicine treatment (chlorella, barley grass). Although her FE-1 value was in EPI range, without PERT, her gastrointestinal symptoms have not worsened (steatorrhea or any other clinical problems did not appear) and the body weight did not change either (51 kg, BMI 18.7 kg/m2). At the age of 38, she started to use tezacaftor/ivacaftor, and later the triple combination at the age of 39. After 6 months, the sweat test value dropped to 39 mmol/l, after 1 year of use even to 15 mmol/l. This drop to a physiological level indicated a particularly good response to the medication as well. Almost 2 years after initiation of ETI, the FE-1 improved to > 1200 μg/g. She has had no gastrointestinal problems. During this period, her nutritional status has not significantly changed (50 kg, BMI 18.5 kg/m2). Both cases are common in a good sweat test response to the CFTR modulators and a fairly delayed pancreatic insufficiency onset. It might suggest a slower acinar cells function burn out [[7]Krasovskiy S. Usacheva M. Amelina E. Phenotypic characteristics in adult cystic fibrosis (CF) patients carrying 3849+10kbC>T mutation in Russia.Eur Respir J. 2015; 46https://doi.org/10.1183/13993003.congress-2015.PA1311Crossref Google Scholar]. There might be a possibility to rescue borderline pancreatic insufficient patients and individuals with mild mutation with good responses to CFTR modulator therapy. ARRIVAL trial reported the mean absolute change in FE-1 by 164.7 μg/g in children 12 to <24 months old, 6 of 9 patients improved FE-1 to ≥ 200 μg/g level, a value consistent with sufficient pancreatic function [[8]Rosenfeld M. Wainwright C.E. Higgins M. et al.Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.Lancet Respir Med. 2018; 6: 545-553https://doi.org/10.1016/S2213-2600(18)30202-9Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. KIWI trial demonstrated an increase of FE-1 average by 99.8 μg/g in children aged 2–5 years [[9]Davies J.C. Cunningham S. Harris W.T. et al.Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.Lancet Respir Med. 2016; 4: 107-115https://doi.org/10.1016/S2213-2600(15)00545-7Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. 6 of 27 patients converted to exocrine pancreatic sufficient. Included participants all had the gating mutation and were treated with ivacaftor for 24 weeks. Recovery of the pancreatic function was not seen in older children or adults yet. Only a single case of a 48-year-old CF male patient (genotype G551D/R347H) was described to improve the FE-1 from 66 μg/g to 236 μg/g after the ivacaftor initiation [[10]Kounis I. Lévy P. Rebours V. Ivacaftor CFTR potentiator therapy is efficient for pancreatic manifestations in cystic fibrosis.Am J Gastroenterol. 2018; 113: 1058-1059https://doi.org/10.1038/s41395-018-0123-7Crossref PubMed Scopus (14) Google Scholar]. Moreover, in this case, the need for PERT decreased to half of the need. Pathogenic variant R347H is also considered as mild according to the pancreatic insufficiency prevalence score, and might be potentially amenable to the rescue of pancreatic function [[3]Ooi C.Y. Dorfman R. Cipolli M. et al.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology. 2011; 140: 153-161https://doi.org/10.1053/j.gastro.2010.09.046Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. All the presented cases are demonstrated on ivacaftor use. Rescue and restoration of EPI in adult patients with CF appears possible, especially among those who carry at least 1 functionally milder CFTR mutation. Based on the author's case of carriage one mutation of 3849 + 10 kb C > T, especially in cases when EPI has developed over several years, monitoring of EPI should be considered. This especially includes re-evaluation (e.g., by FE-1 testing) among those who are on CFTR modulators and carry at least 1 CFTR mutation with mild pancreatic insufficiency prevalence score, and/or are known to have significant residual function. Symptoms alone do not suffice. Further research needs to determine the effect of ETI on exocrine pancreatic function effect in this specific patient population. The author made no use of generative AI or AI-assisted technologies in the writing process. This research did not receive any specific grant from funding agencies in the public, commercial, or non -profit sectors.
Endobronchial cryobiopsy (ECB) from visualized intraluminal tumor lesions is superior to forceps biopsy (FB) in terms of diagnostic yield, with acceptable safety profile. However, it is not clear, if ECB also shortens the time to morphological diagnosis. Our aim was to assess the diagnostic yield, safety, rate of diagnostic failure, and time to diagnosis of ECB, compared to FB.
Methods
A retrospective single-center study. All patients with visualized endobronchial tumor lesions that underwent diagnostic bronchoscopy between January 1st, 2018 and December 31st, 2020 at the Department of Respiratory Diseases, University Hospital Brno, were included. The Shapiro-Wilk test was used to evaluate normality; Mann-Whitney U test and two-tailed Fisher exact test for group comparisons; p values <0.05 considered statistically significant.
Results
Three hundred and thirty patients were included, of these, 261 (61%) patients underwent ECB. There were no differences in age, sex or BMI. Average number of biopsy samples was higher in the forceps group (4 versus 3; p<0.01), as was the time to diagnosis (9 versus 8 days; p<0.01) and the number of patients with definitive histological diagnosis made after ≥21 days (7% versus 2%; p<0.01). Repeated biopsy was more frequent in the forceps group (9% vs 2%; p<0.01). Post-procedural bleeding was more frequent in the cryobiopsy group; severe bleeding was absent in both groups.
Conclusions
We concluded that ECB from visualized intraluminal tumor lesions may shorten the time to morphological diagnosis, has an excellent diagnostic yield and safety profile.
We present a case report of a 74-years old patient with a finding of bilateral pleural effusion due to a different fluid composition caused by gastric adenocarcinoma. The finding of a bilateral effusion, where the exudate fluid is of a different chemical composition, is a rare phenomenon. While the right-sided exudate had the characteristics of hydrothorax, the left-sided exudate had those of chylothorax. The initial suspicion of a lung tumor was not confirmed, and further examination surprisingly revealed gastric adenocarcinoma. The patient did not benefit from targeted oncological treatment for a long time and the chemotherapy was terminated after 3 cycles. The cause of right-sided hydrothorax is therefore attributed to hypalbuminemia and secondary pneumonia, left-sided chylothorax was a primo-manifestation of gastric adenocarcinoma. There is only a small number of similar case reports of patients with gastric tumor and chylothorax in the literature. While the recorded cases were mostly Asian ethnic patients, the course of their illness - including survival - was almost strikingly similar (and unfavorable).
Introduction: Measurement of ventilatory efficiency for carbon dioxide (VE/VCO2) by cardiopulmonary exercise testing (CPET) has been proposed as a screening method for identification of patients with hyperventilation syndrome (HVS). However, increased VE/VCO2 may be associated with other disorders. Aims: We aimed at finding a more specific marker of HVS by CPET. We hypothesized that ventilatory control during exercise is abnormal in patients with HVS. Methods: HVS patients who underwent CPET at the Department of Respiratory Diseases, University Hospital Brno, Czech Rep. between 2015, Jan 1st and 2017, Dec 31st were retrospectively identified and formed the study group. HVS was defined as dyspnea with respiratory alkalosis (pH >7.45) at peak exercise with absence of acute or chronic respiratory, heart or psychiatric disease. Healthy subjects were selected as controls. Student t-test and Mann-Whitney U test were used for comparison; data are summarized as mean ± SD or median (IQR); significance level: p<0.05. Results: We identified 29 HVS patients and selected 29 controls. At rest, mean PETCO2 was 27 mmHg for HVS patients vs. 30 mmHg in controls (p=0.05). At peak exercise, PETCO2 was also significantly lower (27 mmHg vs. 35 mmHg; p<0.01) and VE/VCO2 higher (38 vs. 31; p<0.01) in patients with HVS compared to controls. In contrast to controls, there were minimal changes of PETCO2 (0.50 mmHg vs. 6.2 mmHg; p<0.01) and VE/VCO2 (0.17 vs. -6.6; p<0.01) during exercise in patients with HVS. The absence of VE/VCO2 and PETCO2 change during exercise was specific for HVS (83% and 93%, respectively). Conclusion: Absence of VE/VCO2 and PETCO2 change during exercise may identify patients with HVS.
Pneumology and phthisiology (respiratory medicine) has undergone dynamic development in the last two decades. The main focus of pulmonology in the past was care for patients with tuberculosis and pneumonia. Since then, respiratory medicine evolved and the current focus is on chronic pulmonary diseases, including chronic obstructive pulmonary disease, bronchial asthma, interstitial lung diseases, but also on acute lung conditions (e.g., pneumonia, pleural diseases, respiratory failure), pneumooncology or highly specialized care for rare lung diseases (e.g., cystic fibrosis, rare interstitial diseases). Bronchology, interventional pneumology and pulmonary function testing are also important components of respiratory medicine. The importance of respiratory medicine was apparent during the COVID-19 pandemic. In this article, we provide a brief overview of the most important news to the field of respiratory medicine in the year 2022, addressing the thematic areas of bronchology, cystic fibrosis, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, pleural diseases, pneumooncology, tuberculosis and non-tuberculous mycobacteria.
Abstract Background Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO 2peak ) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (W peak , VO 2VT1 , VO 2VT2, VO 2 /HR peak , etc.), and helping to better understand the effect of specific treatment (V E , V T , V D /V T etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated. Methods We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients. Results We observed significant improvement in peak workload, VO 2 peak , VO 2VT1 , VO 2VT2 , V E /VCO 2 slope, V E , V T , RQ, VO 2 /HR peak and RR peak. The mean change in VO 2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p = 0.014). VO 2VT1 improved by 15% of the reference value (SD ± 0.1; p = 0.014), VO 2VT2 improved by 0.5 (SD ± 0.4; p = 0.01). There were no differences in other parameters. Conclusion Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.
