Innate-like Cytotoxic Function of Bystander-Activated CD8+ T Cells Is Associated with Liver Injury in Acute Hepatitis A.

Acute hepatitis A (AHA) involves severe CD8+ T cell-mediated liver injury. Here we showed during AHA, CD8+ T cells specific to unrelated viruses became activated. Hepatitis A virus (HAV)-infected cells produced IL-15 that induced T cell receptor (TCR)-independent activation of memory CD8+ T cells. TCR-independent activation of non-HAV-specific CD8+ T cells were detected in patients, as indicated by NKG2D upregulation, a marker of TCR-independent T cell activation by IL-15. CD8+ T cells derived from AHA patients exerted innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. We demonstrated that the severity of liver injury in AHA patients correlated with the activation of HAV-unrelated virus-specific CD8+ T cells and the innate-like cytolytic activity of CD8+ T cells, but not the activation of HAV-specific T cells. Thus, host injury in AHA is associated with innate-like cytotoxicity of bystander-activated CD8+ T cells, a result with implications for acute viral diseases.

Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway.

The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (ΔF508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that ΔF508-CFTR surface expression can be rescued in vitro and in vivo by directing it to an unconventional GRASP-dependent secretion pathway. An integrated molecular and physiological analysis indicates that mechanisms associated with ER stress induce cell surface trafficking of the ER core-glycosylated wild-type and ΔF508-CFTR via the GRASP-dependent pathway. Phosphorylation of a specific site of GRASP and the PDZ-based interaction between GRASP and CFTR are critical for this unconventional surface trafficking. Remarkably, transgenic expression of GRASP in ΔF508-CFTR mice restores CFTR function and rescues mouse survival without apparent toxicity. These findings provide insight into how unconventional protein secretion is activated, and offer a potential therapeutic strategy for the treatment of cystic fibrosis and perhaps diseases stemming from other misfolded proteins.

Mapping the emergence of molecular vibrations mediating bond formation.

Fundamental studies of chemical reactions often consider the molecular dynamics along a reaction coordinate using a calculated or suggested potential energy surface1-5. But fully mapping such dynamics experimentally, by following all nuclear motions in a time-resolved manner-that is, the motions of wavepackets-is challenging and has not yet been realized even for the simple stereotypical bimolecular reaction6-8: A-B + C â†’ A + B-C. Here we track the trajectories of these vibrational wavepackets during photoinduced bond formation of the gold trimer complex [Au(CN)2-]3 in an aqueous monomer solution, using femtosecond X-ray liquidography9-12 with X-ray free-electron lasers13,14. In the complex, which forms when three monomers A, B and C cluster together through non-covalent interactions15,16, the distance between A and B is shorter than that between B and C. Tracking the wavepacket in three-dimensional nuclear coordinates reveals that within the first 60 femtoseconds after photoexcitation, a covalent bond forms between A and B to give A-B + C. The second covalent bond, between B and C, subsequently forms within 360 femtoseconds to give a linear and covalently bonded trimer complex A-B-C. The trimer exhibits harmonic vibrations that we map and unambiguously assign to specific normal modes using only the experimental data. In principle, more intense X-rays could visualize the motion not only of highly scattering atoms such as gold but also of lighter atoms such as carbon and nitrogen, which will open the door to the direct tracking of the atomic motions involved in many chemical reactions.

Alix-normalized exosomal programmed death-ligand 1 analysis in urine enables precision monitoring of urothelial cancer.

Anti-programmed death-ligand 1 (PD-L1) Ab-based therapies have demonstrated potential for treating metastatic urothelial cancer with high PD-L1 expression. Urinary exosomes are promising biomarkers for liquid biopsy, but urine's high variability requires normalization for accurate analysis. This study proposes using the PD-L1/Alix ratio to normalize exosomal PD-L1 signal intensity with Alix, an internal exosomal protein less susceptible to heterogeneity concerns than surface protein markers. Extracellular vesicles were isolated using ExoDisc and characterized using various methods, including ExoView to analyze tetraspanins, PD-L1, and Alix on individual exosomes. On-disc ELISA was used to evaluate PD-L1 and Alix-normalized PD-L1 in 15 urothelial cancer patients during the initial treatment cycle with Tecentriq. Results showed that Alix signal range was relatively uniform, whereas tetraspanin marker intensity varied for individual exosome particles. On-disc ELISA was more reliable for detecting exosomal PD-L1 expression than standard plate ELISA-based measurement. Using exosomal Alix expression for normalization is a more reliable approach than conventional methods for monitoring patient status. Overall, the study provides a practical and reliable method for detecting exosomal PD-L1 in urine samples from patients with urothelial cancer.

Synergistic Effect of Ferroptosis-Inducing Nanoparticles and X-Ray Irradiation Combination Therapy.

Ferroptosis, characterized by the induction of cell death via lipid peroxidation, has been actively studied over the last few years and has shown the potential to improve the efficacy of cancer nanomedicine in an iron-dependent manner. Radiation therapy, a common treatment method, has limitations as a stand-alone treatment due to radiation resistance and safety as it affects even normal tissues. Although ferroptosis-inducing drugs help alleviate radiation resistance, there are no safe ferroptosis-inducing drugs that can be considered for clinical application and are still in the research stage. Here, the effectiveness of combined treatment with radiotherapy with Fe and hyaluronic acid-based nanoparticles (FHA-NPs) to directly induce ferroptosis, considering the clinical applications is reported. Through the induction of ferroptosis by FHA-NPs and apoptosis by X-ray irradiation, the therapeutic efficiency of cancer is greatly improved both in vitro and in vivo. In addition, Monte Carlo simulations are performed to assess the physical interactions of the X-rays with the iron-oxide nanoparticle. The study provides a deeper understanding of the synergistic effect of ferroptosis and X-ray irradiation combination therapy. Furthermore, the study can serve as a valuable reference for elucidating the role and mechanisms of ferroptosis in radiation therapy.

Unveiling a common phase transition pathway of high-density amorphous ices through time-resolved x-ray scattering.

Here, we investigate the hypothesis that despite the existence of at least two high-density amorphous ices, only one high-density liquid state exists in water. We prepared a very-high-density amorphous ice (VHDA) sample and rapidly increased its temperature to around 205 ± 10 K using laser-induced isochoric heating. This temperature falls within the so-called "no-man's land" well above the glass-liquid transition, wherein the IR laser pulse creates a metastable liquid state. Subsequently, this high-density liquid (HDL) state of water decompresses over time, and we examined the time-dependent structural changes using short x-ray pulses from a free electron laser. We observed a liquid-liquid transition to low-density liquid water (LDL) over time scales ranging from 20 ns to 3 µs, consistent with previous experimental results using expanded high-density amorphous ice (eHDA) as the initial state. In addition, the resulting LDL derived both from VHDA and eHDA displays similar density and degree of inhomogeneity. Our observation supports the idea that regardless of the initial annealing states of the high-density amorphous ices, the same HDL and final LDL states are reached at temperatures around 205 K.

Recent Outcomes of Surgical Redo Aortic Valve Replacement in Prosthetic Valve Failure.

BACKGROUND: As redo surgical aortic valve replacement (AVR) is relatively high risk, valve-in-valve transcatheter AVR has emerged as an alternative for failed prostheses. However, the majority of studies are outdated. This study assessed the current clinical outcomes of redo AVR. METHODS AND RESULTS: This study enrolled 324 patients who underwent redo AVR due to prosthetic valve failure from 2010 to 2021 in four tertiary centers. The primary outcome was operative mortality. The secondary outcomes were overall survival, cardiac death, and aortic valve-related events. Logistic regression analysis, clustered Cox proportional hazards models, and competing risk analysis were used to evaluate the independent risk factors. Redo AVR was performed in 242 patients without endocarditis and 82 patients with endocarditis. Overall operative mortality was 4.6% (15 deaths). Excluding patients with endocarditis, the operative mortality of redo AVR decreased to 2.5%. Multivariate analyses demonstrated that endocarditis (hazard ratio [HR]: 3.990, p = 0.014), longer cardiopulmonary bypass time (HR: 1.006, p = 0.037), and lower left ventricular ejection fraction (LVEF) (HR: 0.956, p = 0.034) were risk factors of operative mortality. Endocarditis and lower LVEF were independent predictors of overall survival. CONCLUSION: The relatively high risk of redo AVR was due to reoperation for prosthetic valve endocarditis. The outcomes of redo AVR for nonendocarditis are excellent. Our findings suggest that patients without endocarditis, especially with acceptable LVEF, can be treated safely with redo AVR.

Enhancement and maximum in the isobaric specific-heat capacity measurements of deeply supercooled water using ultrafast calorimetry.

Knowledge of the temperature dependence of the isobaric specific heat (Cp) upon deep supercooling can give insights regarding the anomalous properties of water. If a maximum in Cp exists at a specific temperature, as in the isothermal compressibility, it would further validate the liquid-liquid critical point model that can explain the anomalous increase in thermodynamic response functions. The challenge is that the relevant temperature range falls in the region where ice crystallization becomes rapid, which has previously excluded experiments. Here, we have utilized a methodology of ultrafast calorimetry by determining the temperature jump from femtosecond X-ray pulses after heating with an infrared laser pulse and with a sufficiently long time delay between the pulses to allow measurements at constant pressure. Evaporative cooling of ∼15-µm diameter droplets in vacuum enabled us to reach a temperature down to ∼228 K with a small fraction of the droplets remaining unfrozen. We observed a sharp increase in Cp, from 88 J/mol/K at 244 K to about 218 J/mol/K at 229 K where a maximum is seen. The Cp maximum is at a similar temperature as the maxima of the isothermal compressibility and correlation length. From the Cp measurement, we estimated the excess entropy and self-diffusion coefficient of water and these properties decrease rapidly below 235 K.

Protective effect of the mixture of Lactiplantibacillus plantarum KC3 and Leonurus Japonicas Houtt extract on respiratory disorders.

Air pollutants, such as particulate matter (PM) and diesel exhaust particles (DEP), are associated with respiratory diseases. Therefore, preventive and therapeutic strategies against PM-and DEP (PM10D)-induced respiratory diseases are needed. Herein, we evaluate the protective effects of a mixture of Lactiplantibacillus plantarum KC3 and Leonurus Japonicas Houtt (LJH) extract against airway inflammation associated with exposure to PM10D. To determine the anti-inflammatory effects of the LJH extract, reactive oxygen species (ROS) production and the expression of inflammatory pathways were determined in PM10-induced MH-S cells. For the respiratory protective effects, BALB/c mice were exposed to PM10D via intranasal injection, and a mixture of L. plantarum KC3 and LJH extract was administered orally for 12 days. LJH extract inhibited ROS production and the phosphorylation of downstream factors of NF-κB in PM10-stimulated MH-S cells. The mixture of L. plantarum KC3 and LJH repressed the infiltration of neutrophils, reduced the immune cells number, and suppressed the proinflammatory mediators and cyclooxygenase (COX)-2 expressions in PM10D-induced airway inflammation with reduced phosphorylation of downstream factors of NF-κB. In addition, these effects were not observed in an alveolar macrophage depleted PM10D-induced mouse model using clodronate liposomes. The extract mixture also regulated gut microbiota in feces and upregulated the mRNA expression of Foxp3, transforming growth factor (TGF)-ß1, and interleukin (IL)-10 in the colon. The L. plantarum KC3 and LJH extract mixture may inhibit alveolar macrophage- and neutrophil-mediated inflammatory responses and regulate gut microbiota and immune response in PM10D-induced airway inflammation, suggesting it is a potential remedy to prevent and cure airway inflammation and respiratory disorders.

Map-Based Cloning and Characterization of a Major QTL Gene, FfR1, Which Confers Resistance to Rice Bakanae Disease.

Bakanae disease (BD), caused by the fungal pathogen Fusarium fujikuroi, is a serious threat to rice production worldwide. Breeding elite rice varieties resistant to BD requires the identification of resistance genes. Previously, we discovered a resistant quantitative trait locus (QTL), qFfR1, in a Korean japonica rice variety, Nampyeong. In this study, we fine-mapped qFfR1 with a Junam*4/Nampyeong BC3F3 population and delimited its location to a 37.1 kb region on chromosome 1. Complementation experiments with seven candidate genes in this region revealed that OsI_02728 is the gene for qFfR1. This gene encodes a protein with a typical leucine-rich repeat (LRR) receptor-like protein structure. RNA-sequencing-based transcriptomic analysis revealed that FfR1 induces the transcription of defense genes, including lignin and terpenoid biosynthesis genes, pathogenesis-related genes, and thionin genes. These results may facilitate investigations into the molecular mechanisms underlying BD resistance, including molecular patterns of Fusarium fujikuroi interacting with FfR1 and players working in signal transduction pathways downstream of FfR1, and the breeding of new BD-resistant varieties by providing a BD resistance gene with its precise selection marker. This will contribute to efficient control of BD, which is becoming more prevalent according to temperature rises due to climate change.

A rice seed-specific glycine-rich protein OsDOR1 interacts with GID1 to repress GA signaling and regulates seed dormancy.

Seed dormancy is an important agronomic trait under the control of complex genetic and environmental interactions, which have not been yet comprehensively understood. From the field screening of rice mutant library generated by a Ds transposable element, we identified a pre-harvest sprouting (PHS) mutant dor1. This mutant has a single insertion of Ds element at the second exon of OsDOR1 (LOC_Os03g20770), which encodes a novel seed-specific glycine-rich protein. This gene successfully complemented the PHS phenotype of dor1 mutant and its ectopic expression enhanced seed dormancy. Here, we demonstrated that OsDOR1 protein binds to the GA receptor protein, OsGID1 in rice protoplasts, and interrupts with the formation OsGID1-OsSLR1 complex in yeast cells. Co-expression of OsDOR1 with OsGID1 in rice protoplasts attenuated the GA-dependent degradation of OsSLR1, the key repressor of GA signaling. We showed the endogenous OsSLR1 protein level in the dor1 mutant seeds is significantly lower than that of wild type. The dor1 mutant featured a hypersensitive GA-response of α-amylase gene expression during seed germination. Based on these findings, we suggest that OsDOR1 is a novel negative player of GA signaling operated in the maintenance of seed dormancy. Our findings provide a novel source of PHS resistance.

Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening-based approaches.

Cancer management is major concern of health organizations and viral cancers account for approximately 15.4% of all known human cancers. Due to large number of patients, efficient treatments for viral cancers are needed. De novo drug discovery is time consuming and expensive process with high failure rate in clinical stages. To address this problem and provide treatments to patients suffering from viral cancers faster, drug repurposing emerges as an effective alternative which aims to find the other indications of the Food and Drug Administration approved drugs. Applied to viral cancers, drug repurposing studies following the niche have tried to find if already existing drugs could be used to treat viral cancers. Multiple drug repurposing approaches till date have been introduced with successful results in viral cancers and many drugs have been successfully repurposed various viral cancers. Here in this study, a critical review of viral cancer related databases, tools, and different machine learning, deep learning and virtual screening-based drug repurposing studies focusing on viral cancers is provided. Additionally, the mechanism of viral cancers is presented along with drug repurposing case study specific to each viral cancer. Finally, the limitations and challenges of various approaches along with possible solutions are provided.

Ultrafast photoisomerization mechanism of azaborine revealed by nonadiabatic molecular dynamics simulations.

1,2-Dihydro-1,2-azaborine is an isoelectronic analog of benzene with a B-N substitution, and its unique photoisomerization behavior, which is distinct from that of benzene, has drawn significant attention. To understand the detailed mechanism of azaborine photochemistry considering the dynamical effect and gain a comprehensive understanding of photochemical reactions, we investigated the photoisomerization dynamics of azaborine using nonadiabatic molecular dynamics simulations with Tully's surface hopping algorithm. Herein, the structural and energetic analyses of the trajectories revealed three different paths: direct relaxation (path 1), relaxation via a prefulvene-like intermediate (path 2), and formation of the Dewar isomer as a photoproduct (path 3). Our results confirmed that the photoisomerization of azaborine follows the energetically favored pathway predicted by the previous minimum energy path (MEP) calculations, exclusively forming the Dewar isomer, which is consistent with the experimental observations. Additionally, despite the low quantum yield found in our simulations, the high-level excitation energy calculations support the complete conversion observed in the experiments.

Rapid-Deployment Aortic Valve Replacement in a Real-World All-Comers Population.

BACKGROUND: This study was conducted to evaluate the mid-term outcomes of rapid-deployment aortic valve replacement (AVR) using Edwards Intuity. METHODS: A total of 215 patients underwent rapid-deployment AVR using Edwards Intuity at our institution. The median follow-up duration was 22 months (interquartile range, 8-36). Primary outcomes were overall survival, cumulative incidence of cardiac death, and major adverse cardiac events. Secondary outcomes were early and 1-year hemodynamic performances of the bioprosthetic valve. RESULTS: The mean age was 68.6 ± 10.5 years, and EuroSCORE II was 3.09 ± 4.5. The study population included 113 patients (52.6%) with bicuspid valves (24 patients with type 0 bicuspid valves), 20 patients (9.3%) with pure aortic regurgitation, and 3 patients (1.4%) with infective endocarditis. Isolated AVR was performed in 70 patients (32.4%) and concomitant procedures were performed in 146 patients (67.6%), including aorta surgery (42.3%) and mitral valve procedure (22.3%). Operative mortality was 2.8%. Complete atrioventricular block occurred in 12 patients, but most of them were transient and only 3 patients received permanent pacemaker implantation before discharge. Overall survival at 3 years was 92.3%. Early hemodynamic data showed mean pressure gradients of 15.5 ± 5.0 and 12.7 ± 4.2 mm Hg in the 19 and 21 mm valve, respectively. One-year hemodynamics were also excellent with mean pressure gradients of 14.7 ± 5.3 and 10.7 ± 3.6 mm Hg in the 19 and 21 mm valve, respectively. CONCLUSION: Based on a real-world all-comers population, rapid-deployment AVR using Edwards Intuity could be performed for various indications, including bicuspid valve, pure aortic regurgitation, and infective endocarditis, and the clinical and hemodynamic outcomes were excellent.

Results after Tricuspid Valve Surgery for Preserved and Dysfunctional Right Ventricle.

BACKGROUND: This study aimed to compare long-term outcomes after tricuspid valve (TV) repair (TVr) with those after TV replacement (TVR) by adjusting the right ventricular (RV) volume and function. METHODS: We enrolled 147 patients who underwent TVr (n = 78) and TVR (n = 69) for grade 3 or 4 tricuspid regurgitation and had preoperative cardiac magnetic resonance data. Long-term clinical outcomes were compared between the two groups using inverse probability treatment weighting (IPTW) to adjust for differences in preoperative characteristics between the two groups. Subgroup analyses were performed in patients with preserved and dysfunctional RV (ejection fraction < 50%). RESULTS: There were no significant differences in operative mortality or postoperative complications between the two groups before and after the IPTW adjustment. Five- and 10-year overall survival rates were 84.2 and 67.1%, respectively. Five- and 10-year cumulative incidences of TV-related events (TVREs) were 33.1 and 55.6%, respectively. There were no significant differences in overall survival and cumulative incidence of TVREs after IPTW adjustment (p = 0.236 and p = 0.989, respectively). The risk-adjusted overall survival was marginally higher in the TVr group of patients with preserved RV function (p = 0.054), while no such significant difference was found between the two groups of patients with dysfunctional RV (p = 0.513). CONCLUSION: Adjusted long-term clinical outcomes after TVr and TVR were comparable. TVr might be beneficial for patients with preserved RV function in terms of long-term survival; however, this benefit might disappear in patients with RV dysfunction.

Aortic Valve Replacement in the Era of Transcatheter Aortic Valve Implantation: Current Status in Korea.

BACKGROUND: In the era of transcatheter aortic valve implantation, this study was conducted to investigate the current trend of aortic valve procedures in Korea and to evaluate the early and mid-term outcomes of isolated surgical aortic valve replacement (SAVR) using bioprosthetic valves in contemporary Korea. METHODS: Contemporary outcomes of isolated bioprosthetic SAVR in Korea were analyzed using the datasets on a multicenter basis. Patients who underwent isolated SAVR using bioprostheses from June 2015 to May 2019 were included, and those with concomitant cardiac procedures, SAVR with mechanical valve, or SAVR for infective endocarditis were excluded. A total of 456 patients from 4 large-volume centers were enrolled in this study. Median follow-up duration was 43.4 months. Early postoperative outcomes, mid-term clinical outcomes, and echocardiographic outcomes were evaluated. RESULTS: Mean age of the patients was 73.1 ± 7.3 years, and EuroSCORE II was 2.23 ± 2.09. The cardiopulmonary bypass time and aortic cross-clamp times were median 106 and 76 minutes, respectively. SAVR was performed with full median sternotomy (81.8%), right thoracotomy (14.7%), or partial sternotomy (3.5%). Operative mortality was 1.8%. The incidences of stroke and permanent pacemaker implantation were 1.1% and 1.1%, respectively. Paravalvular regurgitation ≥ mild was detected in 2.6% of the patients. Cumulative incidence of all-cause mortality at 5 years was 13.0%. Cumulative incidences of cardiovascular mortality and bioprosthetic valve dysfunction at 5 years were 7.6% and 6.8%, respectively. CONCLUSION: The most recent data for isolated SAVR using bioprostheses in Korea resulted in excellent early and mid-term outcomes in a multicenter study.

Distal stenting technique for coil embolization of early branch aneurysms of middle cerebral artery.

BACKGROUND AND PURPOSE: Stent-assisted coil embolization of early branch aneurysms of the middle cerebral artery (MCA) can sometimes be challenging due to the small diameter and acute angle of the branches. This study aimed to analyze the treatment results and report the feasibility and outcomes of the distal stenting technique for these aneurysms. MATERIALS AND METHODS: The distal stenting technique was used for 15 wide-neck MCA aneurysms (females, 10; males, 5; mean age, 65.1 years) originating from the early branch between December 2018 and October 2021. The average sizes of the dome, depth, and neck of the aneurysms were 4.17 mm (range: 2.99-6.21 mm), 2.86 mm (range: 1.82-3.72 mm), and 3.42 mm (range: 2.44-4.32 mm), respectively. RESULTS: The average diameter of the stents was 4.0 mm (3.0 mm, 3; 4.0 mm, 6; 4.5 mm, 6). Stents were successfully deployed in all 15 aneurysms (100%). The average length of the procedure was 69 min (range: 45-117 min). On postoperative angiography, nine (60.0%) aneurysms were completely occluded, four (26.7%) had neck remnants, and two (13.3%) had contrast flow in the sac. During the procedure, vasospasm and thrombus formation occurred in one case each, but no neurological sequelae were observed. On follow-up digital subtraction angiography of the 10 aneurysms after an average of 13.7 months (range: 12-18 months), the branches were well preserved, and neck remnants were noted in four aneurysms (40.0%). No thromboembolic events occurred during the clinical follow-up. CONCLUSION: The distal stenting technique using an open-cell stent can be a good option for coil embolization of early branch MCA aneurysms.

First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma.

BACKGROUND: Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma. OBJECTIVE: To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation. METHODS: Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed. RESULTS: A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8+ T cells. LIMITATIONS: Analysis was conducted in a retrospective manner. CONCLUSION: Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

Prognostic impact of neutrophilia and lymphopenia on survival in anal cancer treated with definitive concurrent chemoradiotherapy: a retrospective multicenter study.

PURPOSE: This study evaluated the prognostic value of leukocyte, lymphocyte, and neutrophil counts in anal cancer patients undergoing concurrent chemoradiotherapy (CCRT). METHODS: Multi-institutional retrospective data review included 148 non-metastatic anal cancer patients treated with definitive CCRT with 5-fluorouracil plus mitomycin C between the year 2001 and 2019. The median radiation dose to the primary tumor was 54 Gy with a median pelvic dose of 45 Gy. Median follow-up duration was 56 months, and complete blood cell counts were analyzed from baseline to 1 year after the completion of radiotherapy. RESULTS: Although most patients showed a normal number of blood cells before treatment, 6.1% and 4.1% of patients showed leukocytosis (> 10,000/µl) and neutrophilia (> 7500/µl), respectively. After the initiation of treatment, seven patients (4.7%) displayed grade 4 lymphopenia (< 200/µl) at 1 month. Patients with initial leukocytosis showed inferior progression- and locoregional progression-free survival, and neutrophilia was a prognostic factor in all survival outcomes. Grade 4 lymphopenia at 1 month was also significantly associated with overall, progression-, and distant metastasis-free survival. On multivariate analyses, baseline neutrophilia was associated with 56.8-, 22.6-, 10.7-, and 23.0-fold increased risks of death, disease relapse, locoregional progression, and distant metastasis, respectively. Furthermore, lymphocytes < 200/µl at 1 month was linked to 6.8-, 5.4-, and 6.3-fold increased risks for death, disease relapse, and distant metastasis, respectively. CONCLUSION: The number of leukocytes, lymphocytes, and neutrophils readily acquired from routine blood tests before and during treatment could be an independent prognostic factor of survival in patients with anal cancer.