An antibiotic from an uncultured bacterium binds to an immutable target.

Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, lipid II, and lipid IIIWTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.

γ-TuRC asymmetry induces local protofilament mismatch at the RanGTP-stimulated microtubule minus end.

The γ-tubulin ring complex (γ-TuRC) is a structural template for de novo microtubule assembly from α/ß-tubulin units. The isolated vertebrate γ-TuRC assumes an asymmetric, open structure deviating from microtubule geometry, suggesting that γ-TuRC closure may underlie regulation of microtubule nucleation. Here, we isolate native γ-TuRC-capped microtubules from Xenopus laevis egg extract nucleated through the RanGTP-induced pathway for spindle assembly and determine their cryo-EM structure. Intriguingly, the microtubule minus end-bound γ-TuRC is only partially closed and consequently, the emanating microtubule is locally misaligned with the γ-TuRC and asymmetric. In the partially closed conformation of the γ-TuRC, the actin-containing lumenal bridge is locally destabilised, suggesting lumenal bridge modulation in microtubule nucleation. The microtubule-binding protein CAMSAP2 specifically binds the minus end of γ-TuRC-capped microtubules, indicating that the asymmetric minus end structure may underlie recruitment of microtubule-modulating factors for γ-TuRC release. Collectively, we reveal a surprisingly asymmetric microtubule minus end protofilament organisation diverging from the regular microtubule structure, with direct implications for the kinetics and regulation of nucleation and subsequent modulation of microtubules during spindle assembly.

Teixobactin kills bacteria by a two-pronged attack on the cell envelope.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1-3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a ß-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

The structure of the γ-TuRC at the microtubule minus end - not just one solution.

In cells, microtubules (MTs) assemble from α/ß-tubulin subunits at nucleation sites containing the γ-tubulin ring complex (γ-TuRC). Within the γ-TuRC, exposed γ-tubulin molecules act as templates for MT assembly by interacting with α/ß-tubulin. The vertebrate γ-TuRC is scaffolded by γ-tubulin-interacting proteins GCP2-6 arranged in a specific order. Interestingly, the γ-tubulin molecules in the γ-TuRC deviate from the cylindrical geometry of MTs, raising the question of how the γ-TuRC structure changes during MT nucleation. Recent studies on the structure of the vertebrate γ-TuRC attached to the end of MTs came to varying conclusions. In vitro assembly of MTs, facilitated by an α-tubulin mutant, resulted in a closed, cylindrical γ-TuRC showing canonical interactions between all γ-tubulin molecules and α/ß-tubulin subunits. Conversely, native MTs formed in a frog extract were capped by a partially closed γ-TuRC, with some γ-tubulin molecules failing to align with α/ß-tubulin. This review discusses these outcomes, along with the broader implications.

The gamma-tubulin ring complex: Deciphering the molecular organization and assembly mechanism of a major vertebrate microtubule nucleator.

Microtubules are protein cylinders with functions in cell motility, signal sensing, cell organization, intracellular transport, and chromosome segregation. One of the key properties of microtubules is their dynamic architecture, allowing them to grow and shrink in length by adding or removing copies of their basic subunit, the heterodimer αß-tubulin. In higher eukaryotes, de novo assembly of microtubules from αß-tubulin is initiated by a 2 MDa multi-subunit complex, the gamma-tubulin ring complex (γ-TuRC). For many years, the structure of the γ-TuRC and the function of its subunits remained enigmatic, although structural data from the much simpler yeast counterpart, the γ-tubulin small complex (γ-TuSC), were available. Two recent breakthroughs in the field, high-resolution structural analysis and recombinant reconstitution of the complex, have revolutionized our knowledge about the architecture and function of the γ-TuRC and will form the basis for addressing outstanding questions about biogenesis and regulation of this essential microtubule organizer.

Early diagnosis is associated with improved clinical outcomes in benign esophageal perforation: an individual patient data meta-analysis.

BACKGROUND: Time of diagnosis (TOD) of benign esophageal perforation is regarded as an important risk factor for clinical outcome, although convincing evidence is lacking. The aim of this study is to assess whether time between onset of perforation and diagnosis is associated with clinical outcome in patients with iatrogenic esophageal perforation (IEP) and Boerhaave's syndrome (BS). METHODS: We searched MEDLINE, Embase and Cochrane library through June 2018 to identify studies. Authors were invited to share individual patient data and a meta-analysis was performed (PROSPERO: CRD42018093473). Patients were subdivided in early (≤ 24 h) and late (> 24 h) TOD and compared with mixed effects multivariable analysis while adjusting age, gender, location of perforation, initial treatment and center. Primary outcome was overall mortality. Secondary outcomes were length of hospital stay, re-interventions and ICU admission. RESULTS: Our meta-analysis included IPD of 25 studies including 576 patients with IEP and 384 with BS. In IEP, early TOD was not associated with overall mortality (8% vs. 13%, OR 2.1, 95% CI 0.8-5.1), but was associated with a 23% decrease in ICU admissions (46% vs. 69%, OR 3.0, 95% CI 1.2-7.2), a 22% decrease in re-interventions (23% vs. 45%, OR 2.8, 95% CI 1.2-6.7) and a 36% decrease in length of hospital stay (14 vs. 22 days, p < 0.001), compared with late TOD. In BS, no associations between TOD and outcomes were found. When combining IEP and BS, early TOD was associated with a 6% decrease in overall mortality (10% vs. 16%, OR 2.1, 95% CI 1.1-3.9), a 19% decrease in re-interventions (26% vs. 45%, OR 1.9, 95% CI 1.1-3.2) and a 35% decrease in mean length of hospital stay (16 vs. 22 days, p = 0.001), compared with late TOD. CONCLUSIONS: This individual patient data meta-analysis confirms the general opinion that an early (≤ 24 h) compared to a late diagnosis (> 24 h) in benign esophageal perforations, particularly in IEP, is associated with improved clinical outcome.

Risk factors and clinical outcomes of endoscopic dilation in benign esophageal strictures: a long-term follow-up study.

BACKGROUND AND AIMS: Endoscopic dilation (ED) is still the mainstay of therapeutic management of benign esophageal strictures (BESs). This study aimed to establish risk factors for refractory BESs and assess long-term clinical outcomes of ED. METHODS: We performed a retrospective study in 891 patients who underwent ED from 2003 to 2018 for BESs. We searched electronic medical records in 6 tertiary care centers in the Netherlands for data on clinical outcome of ED. Median follow-up was 39 months. The primary endpoint was risk factors for refractory BESs, defined as factors associated with an increased number of ED sessions during follow-up. Secondary endpoints were time from first to last ED session and adverse events. RESULTS: Dilation up to 13 to 15 mm was associated with a higher number of ED sessions than dilation up to 16 to 18 mm (5.0 vs 4.1; hazard ratio [HR], 1.4; P = .001). Compared with peptic strictures, anastomotic (4.9 vs 3.6; HR, 2.1; P < .001), radiation (5.0 vs 3.6; HR, 3.0; P < .001), caustic (7.2 vs 3.6; HR, 2.7; P < .001), and postendotherapy (3.9 vs 3.6; HR, 1.8; P = .005) strictures were associated with a higher number of ED sessions. After 1 year of follow-up, the proportions of patients who remained free of ED was 75% in anastomotic, 71% in radiation, 70% in peptic, 83% in postendotherapy, and 62% in caustic strictures. Esophageal perforation occurred in 23 ED sessions (.4%) in 22 patients (2.4%). CONCLUSIONS: More than 60% of patients with BESs remain free of ED after 1 year of follow-up. Because dilation up to 16 to 18 mm diameter was associated with fewer ED sessions during follow-up, we suggest that clinicians should consider dilation up to at least 16 mm to reduce the number of ED sessions in these patients.

Impact of multidisciplinary tumor board discussion on palliation of patients with esophageal or gastro-esophageal junction cancer: a population-based study.

Background: The Dutch guidelines for esophageal and gastro-esophageal junction (GEJ) cancer recommend discussion of patients by a multidisciplinary tumor board (MDT). Despite this recommendation, one previous study in the Netherlands suggested that therapeutic guidance was missing for palliative care of patients with esophageal cancer. The aim of the current study was therefore to assess the impact of an MDT discussion on initial palliative treatment and outcome of patients with esophageal or GEJ cancer.Material and methods: The population-based Netherlands Cancer Registry was used to identify patients treated for esophageal or GEJ cancer with palliative intent between 2010 and 2017 in 7 hospitals. We compared patients discussed by the MDT with patients not discussed by the MDT in a multivariate analysis. Primary outcome was type of initial palliative treatment. Secondary outcome was overall survival.Results: A total of 389/948 (41%) patients with esophageal or GEJ cancer were discussed by the MDT before initial palliative treatment. MDT discussion compared to non-MDT discussion was associated with more patients treated with palliative intent external beam radiotherapy (38% vs. 21%, OR 2.7 [95% CI 1.8-3.9]) and systemic therapy (30% vs. 23%, OR 1.6 [95% CI 1.0-2.5]), and fewer patients treated with stent placement (4% vs. 12%, OR 0.3 [95% CI 0.1-0.6]) and best supportive care alone (12% vs. 33%, OR 0.2 [95% CI 0.1-0.3]). MDT discussion was also associated with improved survival (169 days vs. 107 days, HR 1.3 [95% CI 1.1-1.6]).Conclusion: Our study shows that MDT discussion of patients with esophageal or GEJ cancer resulted in more patients treated with initial palliative radiotherapy and chemotherapy compared with patients not discussed by the MDT. Moreover, MDT discussion may have a positive effect on survival, highlighting the importance of MDT meetings at all stages of treatment.

Through-the-scope placement of a fully covered metal stent for palliation of malignant dysphagia: a prospective cohort study (with video).

BACKGROUND AND AIMS: To further optimize endoscopic stent placement, an esophageal fully covered self-expandable metal stent with a through-the-scope (TTS) delivery system was designed, providing direct endoscopic control during stent placement. The aim of the study was to assess the feasibility and safety of a TTS stent approach for palliation of malignant dysphagia. METHODS: This multicenter prospective feasibility study included patients with malignant dysphagia undergoing stent placement. The primary outcome was technical success of TTS stent placement. Secondary outcomes included functional outcome, adverse events, and survival. Patients were prospectively evaluated at days 14 and 28, and monthly thereafter, until death or stent removal. RESULTS: In total, 33 stents were placed in 32 patients. TTS stent placement was feasible in 30 (91%) procedures. In the other 3 procedures (9%), no large-channel endoscope could be introduced because of patient discomfort. In 10 (33%) TTS procedures, technical success was achieved because no fluoroscopy and/or guidewire was used, whereas in 20 (67%) TTS procedures, placement was supported by a guidewire (n = 9), or fluoroscopy and a guidewire (n = 11). After 2 weeks, dysphagia scores had improved in 24 (86%) patients. Median dysphagia-free time was 32 days (interquartile range [IQR], 17-76 days). In 20 (63%) patients, 29 serious adverse events (SAEs) occurred. Recurrent dysphagia occurred in 13 (41%) patients due to migration (n = 5), tissue overgrowth (n = 4), and stent deformation (n = 4). Other SAEs included significant retrosternal pain (n = 4), hemorrhage (n = 2), and esophageal perforation (n = 1). No patient died from a stent-related cause. Median survival was 42 days (IQR, 28-91 days). CONCLUSION: Placement of an esophageal TTS stent was feasible in most of the patients with malignant dysphagia. However, stent placement was associated with a relatively high adverse event rate, and in more than one-third of patients, stent placement still required fluoroscopy, which limited optimal benefit of the TTS approach. (Clinical trial registration number: NCT03269903.).

Laboratory Scale X-ray Fluorescence Tomography: Instrument Characterization and Application in Earth and Environmental Science.

A new laboratory scale X-ray fluorescence (XRF) imaging instrument, based on an X-ray microfocus tube equipped with a monocapillary optic, has been developed to perform XRF computed tomography experiments with both higher spatial resolution (20 µm) and a better energy resolution (130 eV @Mn-K(α)) than has been achieved up-to-now. This instrument opens a new range of possible applications for XRF-CT. Next to the analytical characterization of the setup by using well-defined model/reference samples, demonstrating its capabilities for tomographic imaging, the XRF-CT microprobe has been used to image the interior of an ecotoxicological model organism, Americamysis bahia. This had been exposed to elevated metal (Cu and Ni) concentrations. The technique allowed the visualization of the accumulation sites of copper, clearly indicating the affected organs, i.e. either the gastric system or the hepatopancreas. As another illustrative application, the scanner has been employed to investigate goethite spherules from the Cretaceous-Paleogene boundary, revealing the internal elemental distribution of these valuable distal ejecta layer particles.

Healthcare professionals' acceptance of BelRAI, a web-based system enabling person-centred recording and data sharing across care settings with interRAI instruments: a UTAUT analysis.

BACKGROUND: Healthcare and social care environments are increasingly confronted with older persons with long-term care needs. Consequently, the need for integrated and coordinated assessment systems increases. In Belgium, feasibility studies have been conducted on the implementation and use of interRAI instruments offering opportunities to improve continuity and quality of care. However, the development and implementation of information technology to support a shared dataset is a difficult and gradual process. We explore the applicability of the UTAUT theoretical model in the BelRAI healthcare project to analyse the acceptance of the BelRAI web application by healthcare professionals in home care, nursing home care and acute hospital care for older people with disabilities. METHODS: A structured questionnaire containing items based on constructs validated in the original UTAUT study was distributed to 661 Flemish caregivers. We performed a complete case analysis using data from 282 questionnaires to obtain information regarding the effects of performance expectancy (PE), effort expectancy (EE), social influence (SI), facilitating conditions (FC), anxiety (ANX), self-efficacy (SE) and attitude towards using technology (ATUT) on behavioural intention (BI) to use the BelRAI web application. RESULTS: The values of the internal consistency evaluation of each construct demonstrated adequate reliability of the survey instrument. Convergent and discriminant validity were established. However, the items of the ATUT construct cross-loaded on PE. FC proved to have the most significant influence on BI to use BelRAI, followed by SE. Other constructs (PE, EE, SI, ANX, ATUT) had no significant influence on BI. The 'direct effects only' model explained 30.8% of the variance in BI to use BelRAI. CONCLUSIONS: Critical factors in stimulating the behavioural intention to use new technology are good-quality software, interoperability and compatibility with other information systems, easy access to computers, training facilities, built-in and online help and ongoing IT support. These findings can be used by policy makers to maximise the acceptance and the success of new technology. For researchers, the conclusions of the original UTAUT study with regards to the item and scale construction should not be copied blindly across different information systems. A bottom-up approach is preferred when building upon the UTAUT model.

A new antibiotic from an uncultured bacterium binds to an immutable target.

Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid WTA ). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate, but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.

The augmin complex architecture reveals structural insights into microtubule branching.

In mitosis, the augmin complex binds to spindle microtubules to recruit the γ-tubulin ring complex (γ-TuRC), the principal microtubule nucleator, for the formation of branched microtubules. Our understanding of augmin-mediated microtubule branching is hampered by the lack of structural information on the augmin complex. Here, we elucidate the molecular architecture and conformational plasticity of the augmin complex using an integrative structural biology approach. The elongated structure of the augmin complex is characterised by extensive coiled-coil segments and comprises two structural elements with distinct but complementary functions in γ-TuRC and microtubule binding, linked by a flexible hinge. The augmin complex is recruited to microtubules via a composite microtubule binding site comprising a positively charged unordered extension and two calponin homology domains. Our study provides the structural basis for augmin function in branched microtubule formation, decisively fostering our understanding of spindle formation in mitosis.

Breaking the Restriction Barriers and Applying CRISPRi as a Gene Silencing Tool in Pseudoclostridium thermosuccinogenes.

Pseudoclostridium thermosuccinogenes is a thermophilic bacterium capable of producing succinate from lignocellulosic-derived sugars and has the potential to be exploited as a platform organism. However, exploitation of P. thermosuccinogenes has been limited partly due to the genetic inaccessibility and lack of genome engineering tools. In this study, we established the genetic accessibility for P. thermosuccinogenes DSM 5809. By overcoming restriction barriers, transformation efficiencies of 102 CFU/µg plasmid DNA were achieved. To this end, the plasmid DNA was methylated in vivo when transformed into an engineered E. coli HST04 strain expressing three native methylation systems of the thermophile. This protocol was used to introduce a ThermodCas9-based CRISPRi tool targeting the gene encoding malic enzyme in P. thermosuccinogenes, demonstrating the principle of gene silencing. This resulted in 75% downregulation of its expression and had an impact on the strain's fermentation profile. Although the details of the functioning of the restriction modification systems require further study, in vivo methylation can already be applied to improve transformation efficiency of P. thermosuccinogenes. Making use of the ThermodCas9-based CRISPRi, this is the first example demonstrating that genetic engineering in P. thermosuccinogenes is feasible and establishing the way for metabolic engineering of this bacterium.

A distinct mechanism of C-type inactivation in the Kv-like KcsA mutant E71V.

C-type inactivation is of great physiological importance in voltage-activated K+ channels (Kv), but its structural basis remains unresolved. Knowledge about C-type inactivation has been largely deduced from the bacterial K+ channel KcsA, whose selectivity filter constricts under inactivating conditions. However, the filter is highly sensitive to its molecular environment, which is different in Kv channels than in KcsA. In particular, a glutamic acid residue at position 71 along the pore helix in KcsA is substituted by a valine conserved in most Kv channels, suggesting that this side chain is a molecular determinant of function. Here, a combination of X-ray crystallography, solid-state NMR and MD simulations of the E71V KcsA mutant is undertaken to explore inactivation in this Kv-like construct. X-ray and ssNMR data show that the filter of the Kv-like mutant does not constrict under inactivating conditions. Rather, the filter adopts a conformation that is slightly narrowed and rigidified. On the other hand, MD simulations indicate that the constricted conformation can nonetheless be stably established in the mutant channel. Together, these findings suggest that the Kv-like KcsA mutant may be associated with different modes of C-type inactivation, showing that distinct filter environments entail distinct C-type inactivation mechanisms.

Modular assembly of the principal microtubule nucleator γ-TuRC.

The gamma-tubulin ring complex (γ-TuRC) is the principal microtubule nucleation template in vertebrates. Recent cryo-EM reconstructions visualized the intricate quaternary structure of the γ-TuRC, containing more than thirty subunits, raising fundamental questions about γ-TuRC assembly and the role of actin as an integral part of the complex. Here, we reveal the structural mechanism underlying modular γ-TuRC assembly and identify a functional role of actin in microtubule nucleation. During γ-TuRC assembly, a GCP6-stabilized core comprising GCP2-3-4-5-4-6 is expanded by stepwise recruitment, selective stabilization and conformational locking of four pre-formed GCP2-GCP3 units. Formation of the lumenal bridge specifies incorporation of the terminal GCP2-GCP3 unit and thereby leads to closure of the γ-TuRC ring in a left-handed spiral configuration. Actin incorporation into the complex is not relevant for γ-TuRC assembly and structural integrity, but determines γ-TuRC geometry and is required for efficient microtubule nucleation and mitotic chromosome alignment in vivo.

Reconstitution of the recombinant human γ-tubulin ring complex.

Cryo-electron microscopy recently resolved the structure of the vertebrate γ-tubulin ring complex (γ-TuRC) purified from Xenopus laevis egg extract and human cells to near-atomic resolution. These studies clarified the arrangement and stoichiometry of γ-TuRC components and revealed that one molecule of actin and the small protein MZT1 are embedded into the complex. Based on this structural census of γ-TuRC core components, we developed a recombinant expression system for the reconstitution and purification of human γ-TuRC from insect cells. The recombinant γ-TuRC recapitulates the structure of purified native γ-TuRC and has similar functional properties in terms of microtubule nucleation and minus end capping. This recombinant system is a central step towards deciphering the activation mechanisms of the γ-TuRC and the function of individual γ-TuRC core components.

Patient-reported outcomes after external beam radiotherapy versus brachytherapy for palliation of dysphagia in esophageal cancer: A matched comparison of two prospective trials.

BACKGROUND AND PURPOSE: A matched comparison of external beam radiotherapy (EBRT) versus brachytherapy recently demonstrated that EBRT appears at least as effective for palliating dysphagia in patients with incurable esophageal cancer. The aim of this analysis was to compare patient-reported outcomes (PROs) after EBRT versus brachytherapy. MATERIALS AND METHODS: In a multicenter prospective cohort study, patients with incurable esophageal cancer requiring palliation of dysphagia were included to undergo EBRT (20 Gy in 5 fractions). This EBRT cohort was compared to the single-dose 12 Gy brachytherapy cohort of the previously reported SIREC-trial. Propensity score matching was applied to adjust for baseline imbalances. The primary endpoint of dysphagia improvement was reported previously. PROs were secondary outcomes and assessed at baseline and 3 months after treatment using EORTC QLQ-C30 and QLQ-OES18 questionnaires. RESULTS: A total of 115 enrolled EBRT patients and 93 brachytherapy patients were eligible. After matching, 69 well-balanced pairs remained. At follow-up, significant deteriorations in functioning (i.e. physical, role, social), pain, appetite loss, and trouble with taste were observed after brachytherapy. In the EBRT group, such deterioration was observed only for role functioning, while significant improvements in trouble with eating and pain were found. Between-group comparison showed mostly comparable PRO changes, but significantly favored EBRT with regard to nausea, vomiting, pain, and appetite loss. CONCLUSION: Short course EBRT results in similar or better PROs at 3 months after treatment compared to single-dose brachytherapy for the palliation of malignant dysphagia. These findings further support its use and inclusion in clinical practice guidelines.

Low-Dose Versus High-Dose Radiation Therapy for the Palliation of Dysphagia From Esophageal Cancer: A Multicenter Retrospective Cohort Study.

PURPOSE: Clinical evidence regarding optimal radiation dose for palliation of dysphagia from esophageal cancer is generally lacking. In an effort to investigate optimal radiation dose, we assessed 2 different radiation schedules for palliation of dysphagia. METHODS AND MATERIALS: We performed a multicenter, retrospective study comparing low-dose radiation therapy (LR: 5 x 4 Gy external beam radiation therapy [EBRT]) with high-dose radiation therapy (HR: 10 x 3 Gy EBRT and 12-Gy single-dose intraluminal brachytherapy) for palliation of dysphagia in patients with inoperable or metastasized esophageal cancer. Primary outcome was improvement of dysphagia at 6 weeks after start of radiation therapy. Additional outcomes were persistent and recurrent dysphagia during patients' remaining life, severe adverse events, and survival. RESULTS: In total, 292 patients (LR, n = 117; HR, n = 175) were included in this study. After matching, 144 patients (72 in each group) were compared. Improvement of dysphagia at 6 weeks was achieved in 50% of patients after LR and in 66% after HR (P = .071). Persistent or recurrent dysphagia occurred in 64% of patients after LR and in 42% after HR (P = .012). No difference in the rate of severe adverse events was found (P = .889). Median survival was 88 days (95% confidence interval, 64-112) after LR and 177 days (95% confidence interval, 131-223) after HR (P < .001). CONCLUSIONS: This study shows that both LR and HR were well tolerated and effective in short-term relief of dysphagia in patients with inoperable or metastasized esophageal cancer. HR was associated with better long-term relief of dysphagia compared with LR. Our findings suggest that HR could be considered for patients with a longer life expectancy, but prospective studies are required.