Background
Peroral endoscopic myotomy (POEM) is an effective and safe treatment for achalasia, but often leads to posttreatment gastroesophageal reflux disease. The aim of this study was to examine ...the incidence and severity of reflux esophagitis after POEM and to identify associated predictive factors.
Methods
Patients who underwent POEM between August 2011 and December 2022 were included. Multivariate logistic regression was used to assess predictive factors for reflux esophagitis after POEM.
Key Results
In total, 252 patients were included; of which, 46% were female and age ranged between 18 and 87 years. Reflux esophagitis within 1 year after POEM was observed in 131 patients (52%), which was severe in 29 patients (LA grade C/D, 12%). Length of full‐thickness myotomy (cm; OR 1.11, 95% CI 1.02–1.21), Eckardt scores before POEM (OR 0.84, 95% CI 0.74–0.96), previous pneumatic dilation (OR 0.51, 95% CI 0.29–0.91), and previous laparoscopic Heller myotomy (LHM; OR 0.44, 95% CI 0.23–0.86) were associated with reflux esophagitis after POEM. Alcohol use (none vs > 7 units per week; OR 3.51, 95% CI 1.35–9.11) and overweight (BMI ≥25 kg/m2; OR 2.67, 95% CI 1.17–6.09) were positive predictive factors and previous LHM (OR 0.13, 95% CI 0.02–0.95) was a negative predictive factor for severe reflux esophagitis after POEM (LA grade C/D).
Conclusion
About half of the patients develop reflux esophagitis after POEM and 12% is graded as severe. Recognizing predictive factors of reflux esophagitis after POEM treatment leads to better patient selection before POEM and provides an opportunity to take preventive measures or start preemptive treatment.
Reflux esophagitis is commonly observed within 1 year after peroral endoscopic myotomy (POEM) and is severe (grade C/D) in 1 out of 10 patients. Recognizing risk factors for reflux esophagitis after POEM is imperative to select patients for POEM and to take appropriate preventive measures.
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells ...adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.
Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.
Achalasia is a rare esophageal motility disorder characterized by abnormal esophageal peristalsis and the inability of the lower esophageal sphincter to relax, resulting in poor esophageal emptying. ...This can be relieved by endoscopic and surgical treatments; each comes with certain advantages and disadvantages.
This review aims to guide the clinician in clinical decision making on the different treatment options for achalasia regarding the efficacy, safety, and important predictors.
Botulinum toxin injection is only recommended for a selective group of achalasia patients because of the short term effect. Pneumatic dilation improves achalasia symptoms, but this effect diminishes over time and requiring repeated dilations to maintain clinical effect. Heller myotomy combined with fundoplication and peroral endoscopic myotomy are highly effective on the long term but are more invasive than dilations. Gastro-esophageal reflux complaints are more often encountered after peroral endoscopic myotomy. Patient factors such as age, comorbidities, and type of achalasia must be taken into account when choosing a treatment. The preference of the patient is also of great importance and therefore shared decision making has to play a fundamental role in deciding about treatment.
Abstract
Background
Birt-Hogg-Dubé syndrome (BHD) is an inherited disease caused by pathogenic variants in the
FLCN
gene. One of the characteristics is the increased risk for spontaneous ...pneumothorax, likely due to the presence of pulmonary cysts mainly distributed under the carina. Due to variable expression and lack of awareness, BHD is likely to be underdiagnosed
.
We aimed to examine the prevalence of BHD in patients presenting with an apparent primary spontaneous pneumothorax and to evaluate the contribution of chest CT in establishing the diagnosis.
Methods
Patients who presented with apparent primary spontaneous pneumothorax between 2004 and 2017 in a large Dutch teaching hospital were enrolled in this quantitative cross-sectional study. A questionnaire was sent to eligible patients. Patients who completed the questionnaire and consented to further participation were invited to visit the hospital for genetic testing and low dose, volumetric chest CT.
Results
Genetic testing was performed in 88 patients with apparent primary spontaneous pneumothorax. Three patients were found to have a pathogenic variant in the
FLCN
gene (3.4%). No variants of unknown significance were detected. Pulmonary cysts were detected in 14 out of 83 participants with an available chest CT, six had more than one cyst. All three patients with BHD had multiple pulmonary cysts.
Conclusions
Based on previous literature and the present study, we believe that performing a chest CT in every patient presenting with primary spontaneous pneumothorax is justified. Subsequent genetic testing of the FLCN gene should be considered when multiple pulmonary cysts are present.
Trial registration
The study was registered at clinicaltrials.gov with reference NCT02916992.
Summary at a glance
Three out of 88 patients with an apparent primary spontaneous pneumothorax were diagnosed with Birt-Hogg-Dubé syndrome in this study and all three had multiple pulmonary cysts. We believe that performing a chest CT in every patient with an apparent primary spontaneous pneumothorax is justified to identify underlying diseases.
Abstract
Background and study aims Epiphrenic diverticula are rare and mainly occur in patients with underlying esophageal motility disorders. The current standard treatment is surgical ...diverticulectomy often combined by myotomy and is associated with significant adverse event (AE) rates. The aim of this study was to examine the efficacy and safety of peroral endoscopic myotomy in reducing esophageal symptoms in patients with esophageal diverticula.
Patients and methods We performed a retrospective cohort study including patients with an esophageal diverticulum who underwent POEM between October 2014 and December 2022. After informed consent, data were extracted from medical records and patients completed a survey by telephone. The primary outcome was treatment success, defined as Eckardt score below 4 with a minimal reduction of 2 points.
Results Seventeen patients (mean age 71 years, 41.2 % female) were included. Achalasia was confirmed in 13 patients (13 /17, 76.5 %), Jackhammer esophagus in two patients (2 /17, 11.8 %), diffuse esophageal spasm in one patient (1 /17, 5.9 %) and in one patient no esophageal motility disorder was found (1 /17, 5.9 %). Treatment success was 68.8 % and only one patient (6.3 %) underwent retreatment (pneumatic dilatation). Median Eckardt scores decreased from 7 to 1 after POEM (p < 0.001). Mean size of the diverticula decreased from 3.6 cm to 2.9 cm after POEM (p < 0.001). Clinical admission was one night for all patients. AEs occurred in two patients (11.8 %) which were classified as grade II and IIIa (AGREE classification).
Conclusions POEM is effective and safe to treat patients with esophageal diverticula and an underlying esophageal motility disorder.
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt ...to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin sites towards active
cis
-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for circadian clock component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.
Androgen receptor (AR) inhibitors represent the mainstay of prostate cancer treatment. In a genome-wide CRISPR-Cas9 screen using LNCaP prostate cancer cells, loss of co-repressor
conferred resistance ...to AR antagonists apalutamide and enzalutamide. Genes differentially expressed upon
loss share AR as the top transcriptional regulator, and
loss rescued the expression of a subset of androgen-responsive genes upon enzalutamide treatment. GR expression was strongly upregulated upon AR inhibition in a
-negative background. This was consistent with binding of TLE3 and AR at the
locus. Furthermore, GR binding was observed proximal to TLE3/AR-shared genes. GR inhibition resensitized
cells to enzalutamide. Analyses of patient samples revealed an association between TLE3 and GR levels that reflected our findings in LNCaP cells, of which the clinical relevance is yet to be determined. Together, our findings reveal a mechanistic link between TLE3 and GR-mediated resistance to AR inhibitors in human prostate cancer.
Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In ...the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.
Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available.
This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types.
From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.
PDF
