Background/Purpose
The aim in the present study was to elucidate the diagnostic ability of presepsin for postoperative infectious complications following major hepato‐biliary‐pancreatic (HBP) ...surgery.
Methods
Between 2017 and 2019, 50 patients with major hepatectomy and 55 patients with pancreatoduodenectomy were enrolled. Presepsin, the neutrophil‐to‐lymphocyte ratio (NLR), C‐reactive protein (CRP), and procalcitonin (PCT) were prospectively measured for the first 2 weeks after surgery. The diagnostic abilities of these biomarkers were compared multidirectionally.
Results
All biomarkers returned to normal ranges within 2 weeks after surgery. However, presepsin, unlike the other biomarkers, showed less nonspecific elevation in response to the invasiveness of the surgical procedure immediately after surgery. Receiver operating characteristic curve analysis revealed that presepsin (area under the curve (AUC), 0.959) had a greater ability to discriminate bacterial infection than PCT (AUC, 0.723), CRP (AUC, 0.800), and the NLR (AUC, 0.804). A very high sensitivity of 93.3% and a specificity of 89.2% were achieved at the cutoff value of 620 pg/mL. Multivariable analysis revealed that presepsin on day 3 (P = .013) independently predicted bacterial infection after HBP surgery.
Conclusions
Presepsin may have a better predictive ability than existing biomarkers for infection following major HBP surgery, which may help us achieve faster and more accurate detection of bacterial infections.
Highlight
In this prospective study, Yao and colleagues demonstrated that presepsin may have better predictive ability than existing biomarkers for infection following major hepato‐biliary‐pancreatic surgery. As it shows a rapid and specific increase in response to the presence of bacteria, presepsin may help physicians achieve early and accurate detection of bacterial infections.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Post-radiation fibrosis of the vocal folds is thought to cause vocal impairment. However, the mechanism by which this occurs has been poorly documented, probably because of the lack of an appropriate ...experimental animal model. The purpose of this study was to establish a simple and reproducible mouse model of laryngeal radiation to investigate the development of vocal fold fibrosis over time. C57BL/6 mice individually placed in a lead shield were irradiated with a single dose of 20 Gy. At 1, 2, and 6 months after irradiation, larynges were harvested and subjected to histological examination and gene expression analysis. Irradiated vocal folds showed time-dependent tissue contraction and increased collagen deposition, with no significant difference in the changes in hyaluronic acid levels. Transcriptional analysis revealed upregulated expressions of TGF-β1 and iNOS at 6 months, but downregulated expressions of Acta2, Col1a1, Col3a1, and MMP8. Moreover, elevated TGF-β1 and reduced downstream gene expression levels indicated the existence of an inhibitory factor over the TGF-β/Smad pathway. Discrepancies in histological and transcriptional studies of collagen might suggest that radiation-induced vocal fold fibrosis could be caused by the elongated turnover of collagen. Overall, we established a mouse model of radiation-induced vocal fold fibrosis using a simple protocol. Further investigations are warranted to elucidate the pathogenesis of irradiation-induced fibrosis in vocal folds.
•Post-radiation fibrosis of the vocal folds is thought to cause vocal impairment.•A reproducible mouse model of laryngeal radiation was established.•Irradiated vocal folds showed time-dependent increased collagen deposition.•Transcriptional analysis revealed upregulated and downregulated gene expressions.•Radiation-induced vocal fold fibrosis could result from elongated collagen turnover.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients.
Methods
Patients in group A (aged < 65 years with homologous ...recombination deficiency, HRD, score ≥ 42, or those at any age with germline
BRCA
mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety.
Results
The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%–81%) and 45% (27%–65%) in groups A1 and A2, respectively, and 19% (8%–35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively.
Conclusions
In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen.
Trial registration
:The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (
http://www.umin.ac.jp/ctr/index-j.htm
) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A common method of reporting the result of logistic regression is to provide an odds ratio and its corresponding confidence interval. The results of such statistical analyses cannot be further ...evaluated with respect to the consistency of confidence intervals between the odds ratio and the difference between proportions. In this paper, we propose a simple method to construct the confidence intervals for the difference between binomial proportions based on parameter estimates of logistic regression. Simulation results showed that the score-based confidence interval based on the sample marginal approach is a recommended method for sensitivity analysis in randomized clinical trials.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Adaptive enrichment designs for clinical trials have great potential for the development of targeted therapies. They enable researchers to stop the recruitment process for a certain population in ...mid-course based on an interim analysis. However, adaptive enrichment designs increase the total trial period owing to the stoppage in patient recruitment to make interim decisions. This is a major drawback; it results in delays in the submission of clinical trial reports and the appearance of drugs on the market. Here, we explore three types of patient recruitment strategy for the development of targeted therapies based on the adaptive enrichment design.
We consider recruitment methods which provide an option to continue recruiting patients from the overall population or only from the biomarker-positive population even during the interim decision period. A simulation study was performed to investigate the operating characteristics by comparing an adaptive enrichment design using the recruitment methods with a non-enriched design.
The number of patients was similar for both recruitment methods. Nevertheless, the adaptive enrichment design was beneficial in settings in which the recruitment period is expected to be longer than the follow-up period. In these cases, the adaptive enrichment design with continued recruitment from the overall population or only from the biomarker-positive population even during the interim decision period conferred a major advantage, since the total trial period did not differ substantially from that of trials employing the non-enriched design. By contrast, the non-enriched design should be used in settings in which the follow-up period is expected to be longer than the recruitment period, since the total trial period was notably shorter than that of the adaptive enrichment design. Furthermore, the utmost care is needed when the distribution of patient recruitment is concave, i.e., when patient recruitment is slow during the early period, since the total trial period is extended.
Adaptive enrichment designs that entail continued recruitment methods are beneficial owing to the shorter total trial period than expected in settings in which the recruitment period is expected to be longer than the follow-up period and the biomarker-positive population is promising.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Runt-related transcription factor 2
(Runx2
)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (
Usag-1
)-deficient ...mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of
Usag-1
expression can enable the recovery of tooth formation in
Runx2
-deficient mice. Here, we tested whether inhibiting the topical expression of
Usag-1
can reverse arrested tooth formation after
Runx2
abrogation. The results showed that local application of
Usag-1
Stealth small interfering RNA (siRNA) promoted tooth development following
Runx2
siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and
Runx2
-knockout (KO) mouse mandibles, treated with
Usag-1
siRNA, revealing that hindered tooth formation was rescued by
Usag-1
knockdown. Furthermore, topically applied
Usag-1
siRNA partially rescued arrested tooth development in
Runx2
-KO mice, demonstrating its potential for regenerating teeth in
Runx2
-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an adverse event induced by antiresorptive agents (ARAs). The purpose of this study was to evaluate variables, mainly surgery and ...hyperbaric oxygen (HBO) therapy, associated with treatment outcomes in patients with a diagnosis of ARONJ at a single center. We enrolled consecutive patients who presented to our hospital for the management of stage 2 or 3 ARONJ between January 2003 and December 2019. The relationship between potentially predictive factors and outcome variables was examined using statistical analyses, along with a subgroup analysis based on disease stage. Of 252 patients included in this study, 206 had stage 2 ARONJ and 46 had stage 3 ARONJ. There were 119 patients with osteoporosis and 133 with malignant disease. In total, 139 patients were healed, and the healing rate of patients with stage 3 ARONJ was lower than that of patients with stage 2 ARONJ. With regard to the combination of surgery and HBO therapy, most patients underwent HBO before and after surgery. In the univariable analysis, surgery showed a therapeutic effect in both stage 2 and 3 ARONJ, whereas HBO showed a therapeutic effect in stage 2 ARONJ. In the multivariable analysis for stage 2 ARONJ, extensive surgery showed a stronger association with healing than conservative surgery, whereas ≥46 sessions of HBO therapy was less associated with healing than was non-HBO therapy. Our findings suggest that extensive surgery is highly effective against ARONJ regardless of disease stage if there is a sequestrum separation and systemic tolerance, whereas HBO therapy before and after surgical approach can be effective. Further studies are needed to identify treatment strategies for patients with treatment-refractory ARONJ who may be forced to undergo long-term HBO therapy with the expectation of sequestrum separation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective Phosphate is a fundamental element involved in a number of physiological pathways. A previous study showed abnormal laboratory findings and a higher mortality in hypophosphatemic patients ...than in normophosphatemic patients with pneumonia. Sporadic cases of pneumonia due to Legionella spp., Streptococcus pneumoniae, and viruses have been reported; however, the significance of hypophosphatemia in patients with pneumonia has not been adequately studied. We determined whether or not hypophosphatemia in patients with community-acquired pneumonia (CAP) was associated with specific pathogens, patient factors, disease severity, and mortality. Method We retrospectively analyzed 600 patients with CAP who were admitted to our hospital between January 1, 2010, and December 31, 2019. Results Hypophosphatemia was found in 72 (12.0%) of the 600 patients. The most frequent causative microbial agents of CAP in patients with hypophosphatemia were S. pneumoniae, Legionella spp., and influenza virus, whereas in severely ill patients with hypophosphatemia, influenza virus was the most common. Legionella spp., diabetes mellitus, and severe pneumonia were the independent factors for hypophosphatemia in the multivariable analysis. An impaired performance status, severe status on admission, interstitial pneumonia, bacteremia, and guideline-discordant therapy were the independent factors associated with mortality in the multivariable analysis. Hypophosphatemia was not significantly associated with mortality but showed a trend towards higher mortality in the multivariable analysis. Conclusion Hypophosphatemia was not associated with the prognosis in patients with CAP. However, the significance of hypophosphatemia for clinicians lies in the laboratory findings that predict abnormal glucose metabolism, Legionella infection, and severe disease.
We evaluated the hypothesis that grafts from donors with high muscle mass and quality may have a better outcome after living‐donor‐liver‐transplantation (LDLT) than those from usual donors. A total ...of 376 primary adult‐to‐adult LDLT cases were enrolled in this study. Donor skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) were used as markers of muscle mass and quality. In male donor cases (n = 198), those with higher SMI and lower IMAC than age‐adjusted values were defined as the “high muscularity donors” (n = 38) and the others were defined as the “control” (n = 160). The high muscularity donor showed better 1‐year (97% vs 82%, P = .020) and overall graft survival rate (88% vs 67%, P = .024) than the control group after LDLT. Contrastingly, the influence of the muscularity was not observed in female donor cases. Multivariable analysis including donor age confirmed that a high muscularity donor was an independent protective factor for overall graft survival after LDLT (hazard ratio, 0.337; 95% CI: 0.101‐0.838; P = .017). Our study first confirmed that high muscle mass and quality of a male donor is a protective factor of allograft loss after LDLT, independently from donor age.
Grafts from high muscularity male donors, defined as those with higher skeletal muscle mass and lower intramuscular adipose tissue content than age‐adjusted values, were associated with superior graft survival after living donor liver transplantation. See the editorial by Cullen and Goldaracena on page 3281.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is a consensus that portal venous pressure (PVP) modulation prevents portal hypertension (PHT) and consequent complications after adult‐to‐adult living donor liver transplantation (ALDLT). ...However, PVP‐modulation strategies need to be updated based on the most recent findings. We examined our 10‐year experience of PVP modulation and reevaluated whether it was necessary for all recipients or for selected recipients in ALDLT. In this retrospective study, 319 patients who underwent ALDLT from 2007 to 2016 were divided into 3 groups according to the necessity and results of PVP modulation: not indicated (n = 189), indicated and succeeded (n = 92), and indicated but failed (n = 38). Graft survival and associations with various clinical factors were investigated. PVP modulation was performed mainly by splenectomy to lower final PVP to ≤15 mm Hg. Successful PVP modulation improved prognosis to be equivalent to that of patients who did not need modulation, whereas failed modulation was associated with increased incidence of small‐for‐size syndrome (SFSS; P = 0.003) and early graft loss (EGL; P = 0.006). Among patients with failed modulation, donor age ≥ 45 years (hazard ratio HR, 3.67; P = 0.02) and ABO incompatibility (HR, 3.90; P = 0.01) were independent risk factors for graft loss. Survival analysis showed that PVP > 15 mm Hg was related to poor prognosis in grafts from either ABO‐incompatible or older donor age ≥ 45 years (P < 0.001), but it did not negatively affect grafts from ABO‐compatible/identical and young donor age < 45 years (P = 0.27). In conclusion, intentional PVP modulation is not necessarily required in all recipients. Although grafts from both ABO‐compatible/identical and young donors can tolerate PHT, lowering PVP to ≤15 mm Hg is a key to preventing SFSS and consequent EGL with grafts from either ABO‐incompatible or older donors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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