Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma.

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Engineering Co-N-Cr Cross-Interfacial Electron Bridges to Break Activity-Stability Trade-Off for Superdurable Bifunctional Single Atom Oxygen Electrocatalysts.

Atomically dispersed metal-nitrogen-carbon (M-N-C) catalysts have exhibited encouraging oxygen reduction reaction (ORR) activity. Nevertheless, the insufficient long-term stability remains a widespread concern owing to the inevitable 2-electron byproducts, H2O2. Here, we construct Co-N-Cr cross-interfacial electron bridges (CIEBs) via the interfacial electronic coupling between Cr2O3 and Co-N-C, breaking the activity-stability trade-off. The partially occupied Cr 3d-orbitals of Co-N-Cr CIEBs induce the electron rearrangement of CoN4 sites, lowering the Co-OOH* antibonding orbital occupancy and accelerating the adsorption of intermediates. Consequently, the Co-N-Cr CIEBs suppress the two-electron ORR process and approach the apex of Sabatier volcano plot for four-electron pathway simultaneously. As a proof-of-concept, the Co-N-Cr CIEBs is synthesized by the molten salt template method, exhibiting dominant 4-electron selectively and extremely low H2O2 yield confirmed by Damjanovic kinetic analysis. The Co-N-Cr CIEBs demonstrates impressive bifunctional oxygen catalytic activity (▵E=0.70 V) and breakthrough durability including 100 % current retention after 10 h continuous operation and cycling performance over 1500 h for Zn-air battery. The hybrid interfacial configuration and the understanding of the electronic coupling mechanism reported here could shed new light on the design of superdurable M-N-C catalysts.

Silencing GMPPB Inhibits the Proliferation and Invasion of GBM via Hippo/MMP3 Pathways.

Glioblastoma multiforme (GBM) is a highly aggressive malignancy and represents the most common brain tumor in adults. To better understand its biology for new and effective therapies, we examined the role of GDP-mannose pyrophosphorylase B (GMPPB), a key unit of the GDP-mannose pyrophosphorylase (GDP-MP) that catalyzes the formation of GDP-mannose. Impaired GMPPB function will reduce the amount of GDP-mannose available for O-mannosylation. Abnormal O-mannosylation of alpha dystroglycan (α-DG) has been reported to be involved in cancer metastasis and arenavirus entry. Here, we found that GMPPB is highly expressed in a panel of GBM cell lines and clinical samples and that expression of GMPPB is positively correlated with the WHO grade of gliomas. Additionally, expression of GMPPB was negatively correlated with the prognosis of GBM patients. We demonstrate that silencing GMPPB inhibits the proliferation, migration, and invasion of GBM cells both in vitro and in vivo and that overexpression of GMPPB exhibits the opposite effects. Consequently, targeting GMPPB in GBM cells results in impaired GBM tumor growth and invasion. Finally, we identify that the Hippo/MMP3 axis is essential for GMPPB-promoted GBM aggressiveness. These findings indicate that GMPPB represents a potential novel target for GBM treatment.

Puerarin improves busulfan-induced disruption of spermatogenesis by inhibiting MAPK pathways.

Male infertility is a global concern, with a noticeable increase in the decline of spermatogenesis and sperm quality. However, there are limited clinically effective treatments available. This study aimed to investigate the potential effectiveness of puerarin in treating male infertility, which leads to gonadal changes. The results obtained from various analyses such as CASA, immunofluorescence, DIFF-Quick, hematoxylin and eosin (H&E), and periodic acid-Schiff (PAS) staining demonstrated that puerarin supplementation significantly alleviated the busulfan-induced reduction in spermatogenesis and sperm quality in both young and adult mice. Furthermore, puerarin exhibited a marked improvement in the damage caused by busulfan to the architecture of seminiferous tubules, causal epididymis, blood-testicular barrier (BTB), as well as spermatogonia and Sertoli cells. Similarly, puerarin significantly reduced the levels of total antioxidant capacity (T-AOC), malondialdehyde (MDA), and caspase-3 in the testes of busulfan-induced mice, as determined by microplate reader analysis. Additionally, RNA-seq data, RT-qPCR, and western blotting revealed that puerarin restored the abnormal gene expressions induced by busulfan to nearly healthy levels. Notably, puerarin significantly reversed the impact of busulfan on the expression of marker genes involved in spermatogenesis and oxidative stress. Moreover, puerarin suppressed the phosphorylation of p38, ERK1/2, and JNK in the testes, as observed through testicular analysis. Consequently, this study concludes that puerarin may serve as a potential alternative for treating busulfan-induced damage to male fertility by inactivating the testicular MAPK pathways. These findings may pave the way for the use of puerarin in addressing chemotherapy- or other factors-induced male infertility in humans.

MRI-based deep learning model predicts distant metastasis and chemotherapy benefit in stage II nasopharyngeal carcinoma.

Chemotherapy remains controversial for stage II nasopharyngeal carcinoma because of its considerable prognostic heterogeneity. We aimed to develop an MRI-based deep learning model for predicting distant metastasis and assessing chemotherapy efficacy in stage II nasopharyngeal carcinoma. This multicenter retrospective study enrolled 1072 patients from three Chinese centers for training (Center 1, n = 575) and external validation (Centers 2 and 3, n = 497). The deep learning model significantly predicted the risk of distant metastases for stage II nasopharyngeal carcinoma and was validated in the external validation cohort. In addition, the deep learning model outperformed the clinical and radiomics models in terms of predictive performance. Furthermore, the deep learning model facilitates the identification of high-risk patients who could benefit from chemotherapy, providing useful additional information for individualized treatment decisions.

The role of radiologic extranodal extension in predicting prognosis and chemotherapy benefit for T1-2 N1 nasopharyngeal carcinoma: A multicenter retrospective study.

BACKGROUND AND PURPOSE: This multicenter retrospective study aimed to investigated the prognostic value of unequivocal radiologic extranodal extension (rENE) and the efficacy of chemotherapy for stage T1-2 N1 nasopharyngeal carcinoma (NPC) in the IMRT era. MATERIALS AND METHODS: We included 1,082 patients treated in 2005-2017 from three centers. rENE was recorded as G1 (coalescent nodal mass comprising ≥ 2 inseparable nodes) or G2 (invading beyond perinodal fat to frankly infiltrate adjacent structures). Multivariable analysis (MVA) evaluated the prognostic value of rENE. The value of chemotherapy was assessed in rENE-positive (rENE + ) and rENE-negative (rENE - ) subset separately. RESULTS: Centers 1, 2, and 3 had 139/515 (27.0 %), 100/365 (27.4 %), and 43/202 (21.3 %) cN + patients with rENE, respectively. Compared to rENE-, rENE + patients had a worse distant metastasis-free survival (DMFS) and overall survival (OS) (all p < 0.001). MVA confirmed the prognostic of both G1-rENE and G2-rENE for distant metastasis [G1: hazard ratio (HR): 2.933, G2: HR: 6.942, all p < 0.001] and death (G1: HR: 1.587, p = 0.040; G2: HR: 6.162, p < 0.001). There was no significant difference for DMFS and OS between chemo-radiotherapy and radiotherapy alone in rENE + and rENE - groups (all p > 0.1). However, rENE + patients with a cumulative cisplatin/nedaplatin dose (CCND) of > 160 mg/m2 had an improved DMFS (p = 0.033) but no OS (p = 0.197). CONCLUSION: Unequivocal rENE is prognostic in patients with T1-2 N1 NPC. Addition of chemotherapy to radiotherapy did not affect DMFS and OS in rENE - patients. Chemotherapy with a CCND of > 160 mg/m2 improved DMFS in rENE + patients.

Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas.

Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.

Whole-Exome Sequencing Study of Familial Nasopharyngeal Carcinoma and Its Implication for Identifying High-Risk Individuals.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. METHODS: We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218). RESULTS: Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%). CONCLUSIONS: This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.

Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication.

BACKGROUND: Nasopharyngeal carcinoma (NPC) exhibits significant familial aggregation; however, its susceptibility genes are largely unknown. Thus, this study aimed to identify germline mutations that might contribute to the risk of familial NPC, and explore their biological functions. METHODS: Whole-exome sequencing was performed in 13 NPC pedigrees with multiple cases. Mutations co-segregated with disease status were further validated in a cohort composed of 563 probands from independent families, 2,953 sporadic cases, and 3,175 healthy controls. Experimental studies were used to explore the functions of susceptibility genes and their disease-related mutations. FINDINGS: The three rare missense mutations in POLN (DNA polymerase nu) gene, P577L, R303Q, and F545C, were associated with familial NPC risk (5/576 [0·87%] in cases vs. 2/3374 [0·059%] in healthy controls with an adjusted OR of 44·84 [95% CI:3·91-514·34, p = 2·25 × 10-3]). POLN was involved in Epstein-Barr virus (EBV) lytic replication in NPC cells in vitro. POLN promoted viral DNA replication, immediate-early and late lytic gene expression, and progeny viral particle production, ultimately affecting the proliferation of host cells. The three mutations were located in two pivotal functional domains and were predicted to alter the protein stability of POLN in silico. Further assays demonstrated that POLN carrying any of the three mutations displayed reduced protein stability and decreased expression levels, thereby impairing its ability to promote complete EBV lytic replication and facilitate cell survival. INTERPRETATION: We identified a susceptibility gene POLN for familial NPC and elucidated its function. FUNDING: This study was funded by the National Key Research and Development Program of China (2021YFC2500400); the National Key Research and Development Program of China (2020YFC1316902); the Basic and Applied Basic Research Foundation of Guangdong Province, China (2021B1515420007); the National Natural Science Foundation of China (81973131); the National Natural Science Foundation of China (82003520); the National Natural Science Foundation of China (81903395).

Cost-effectiveness of using protons for breast irradiation aiming at minimizing cardiotoxicity: A risk-stratification analysis.

Background: Incidental exposure of the heart to ionizing irradiation is associated with an increased risk of ischemic heart disease and subsequent fatality in patients with breast cancer after radiotherapy. Proton beam therapy can limit the heart dose in breast irradiation to a negligible level. However, compared with conventional photon modality, proton breast irradiation is more expensive. In this study, we performed cost-effectiveness analyses to identify the type of patients who would be more suitable for protons. Methods: A Markov decision model was designed to evaluate the cost-effectiveness of protons vs. photons in reducing the risk of irradiation-related ischemic heart disease. A baseline evaluation was performed on a 50-year-old woman patient without the preexisting cardiac risk factor. Furthermore, risk-stratification analyses for photon mean heart dose and preexisting cardiac risk were conducted on 40-, 50-, and 60-year-old women patients under different proton cost and willingness-to-pay (WTP) settings. Results: Using the baseline settings, the incremental effectiveness (protons vs. photons) increased from 0.043 quality-adjusted life-year (QALY) to 0.964 QALY when preexisting cardiac risk increased to 10 times its baseline level. At a proton cost of 50,000 US dollars ($), protons could be cost-effective for ≤ 60-year-old patients with diabetes and ≤50-year-old patients with grade II-III hypertension at the WTP of China ($37,653/QALY); for ≤ 60-year-old patients with diabetes and ≤ 50-year-old patients with grade II-III hypertension or ≥ 2 major cardiac risk factors at a WTP of $50,000/QALY; and for ≤ 60-year-old patients with diabetes, grade II-III hypertension or ≥ 2 major cardiac risk factors and ≤ 50-year-old patients with total cholesterol ≥ 240 mg/dL at a WTP of $100,000/QALY. Conclusion: Patients' preexisting cardiac risk status was a key factor affecting the cardiac benefits gained from protons and should therefore be a major consideration for the clinical decision of using protons; cost-effective scenarios of protons exist in those patients with high risk of developing cardiac diseases.

Better preservation of erectile function in localized prostate cancer patients with modern proton therapy: Is it cost-effective?

BACKGROUND: Stereotactic body radiation therapy (SBRT) has gradually been recognized as favorable curative treatment for localized prostate cancer (PC). However, the high rate of erectile dysfunction (ED) after traditional photon-based SBRT remains an ongoing challenge that greatly impacts the quality of life of PC survivors. Modern proton therapy allows higher conformal SBRT delivery and has the potential to reduce ED occurrence but its cost-effectiveness remains uninvestigated. METHODS: A Markov decision model was designed to evaluate the cost-effectiveness of proton SBRT versus photon SBRT in reducing irradiation-related ED. Base-case evaluation was performed on a 66-year-old (median age of PC) localized PC patient with normal pretreatment erectile function. Further, stratified analyses were performed for different age groups (50, 55, 60, 65, 70, and 75 years) and threshold analyses were conducted to estimate cost-effective scenarios. A Chinese societal willingness-to-pay (WTP) threshold (37,653 US dollars [$])/quality-adjusted life-year [QALY]) was adopted. RESULTS: For the base case, protons provided an additional 0.152 QALY at an additional cost of $7233.4, and the incremental cost-effectiveness ratio was $47,456.5/QALY. Protons was cost-effective for patients ≤62-year-old at the WTP of China (≤66-year-old at a WTP of $50,000/QALY; ≤73-year-old at a WTP of $100,000/QALY). For patients at median age, once the current proton cost ($18,000) was reduced to ≤$16,505.7 or the patient had a life expectancy ≥88 years, protons were cost-effective at the WTP of China. CONCLUSIONS: Upon assumption-based modeling, the results of current study support the use of proton SBRT in younger localized PC patients who are previously potent, for better preservation of erectile function. The findings await further validation using data from future comparative clinical trials.

A Nomogram to Predict Survival in Patients With Locoregional Recurrent Nasopharyngeal Carcinoma Receiving Comprehensive Treatment.

Objective: This study aimed to establish a prognostic stratified model of chemotherapy-based comprehensive treatment for patients with locoregional recurrent nasopharyngeal carcinoma (lrNPC), to help individualized treatment decision-making. Materials and Methods: This study retrospectively reviewed patients with lrNPC who received chemotherapy-based comprehensive treatment from January 1, 2010, to December 31, 2018. A total of 422 eligible patients were divided into test (n = 338) and validation (n = 84) cohorts. A LASSO cox regression model was used to identify significant prognostic factors for overall survival (OS) in the test cohort. A nomogram was then developed based on a combined consideration of clinically meaningful prognostic factors and statistically significant prognostic factors. The performance of the nomogram was assessed with Harrell's concordance index (C-index) and calibration plots. Results: Five significant factors were identified: age, albumin (ALB), T stage after recurrent (rT), neutrophil to lymphocyte ratio (NLR), and systematic immune-inflammation index (SII). The nomogram was established with these five factors. C-index was 0.636 in the test cohort and 0.610 in the validation cohort. The calibration curves for the OS rate at 3, and 5 years showed an excellent agreement in both cohorts. In addition, the corresponding risk classification system successfully classified patients into low- and high-risk groups and performed well in stratification (P < 0.001). Conclusions: The nomogram shows well prognostic performance for lrNPC patients receiving chemotherapy-based comprehensive treatment.

Prognostic Biomarkers for Survival in Nasopharyngeal Carcinoma: A Systematic Review of the Literature.

This systematic review aims to identify prognostic molecular biomarkers which demonstrate strong evidence and a low risk of bias in predicting the survival of nasopharyngeal carcinoma (NPC) patients. The literature was searched for on PubMed to identify original clinical studies and meta-analyses which reported associations between molecular biomarkers and survival, including ≥150 patients with a survival analysis, and the results were validated in at least one independent cohort, while meta-analyses must include ≥1000 patients with a survival analysis. Seventeen studies fulfilled these criteria-two studies on single nucleotide polymorphisms (SNPs), three studies on methylation biomarkers, two studies on microRNA biomarkers, one study on mutational signature, six studies on gene expression panels, and three meta-analyses on gene expressions. The comparison between the hazard ratios of high-risk and low-risk patients along with a multivariate analysis are used to indicate that these biomarkers have significant independent prognostic values for survival. The biomarkers also indicate a response to certain treatments and whether they could be used as therapeutic targets. This review highlights that patients' genetics, epigenetics, and signatures of cancer and immune cells in the tumor microenvironment (TME) play a vital role in determining their survival.

Coupling fine Pt nanoparticles and Co-Nx moiety as a synergistic bi-active site catalyst for oxygen reduction reaction in acid media.

Fabricating high-efficiency catalysts of Pt nanoparticles coupled with single-atom sites (MNC) attracts intensive attention to accelerate the oxygen reduction reaction (ORR). Here we rationally design the low-Pt hybrid catalyst containing fine Pt nanoparticles coupled with Co-Nx moieties via a microwave-assisted heating process. The well-dispersed Pt nanoparticles are anchored by CoNC supports because of the metal-support interaction. Furthermore, the Co-Nx moiety acts as an electron donor to regulate the electronic structure of Pt through the electron synergistic effect, moderating the adsorption energy of oxygen intermediates on Pt sites, and then increasing the intrinsic activity of Pt. In addition, the overflow effect from CoNC to Pt facilitates a nearly four-electron process and enhances the kinetics of ORR. In acid media, the optimized 10% Pt/CoNC hybrid catalysts with Pt nanoparticles size (2.18 nm) exhibit improved ORR activity and robust durability, delivering a half-wave potential (E1/2) of 0.886 V and negligible loss after accelerated durability test, exceeding the best-in-class commercial Pt/C. The finding of the synergy between CoNC supports and Pt nanoparticles offers a novel ideation to construct various low-loading Pt-based hybrid catalysts.

Addition of chemoradiotherapy to palliative chemotherapy in de novo metastatic nasopharyngeal carcinoma: a real-world study.

BACKGROUND: To determine whether concurrent chemotherapy is necessary during locoregional radiotherapy (RT) after palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (mNPC). METHODS: A total of 746 patients with mNPC from 2000 to 2017 at our hospital were retrospectively reviewed. Among them, 355 patients received PCT followed by RT. Overall survival (OS) and progression-free survival (PFS), including locoregional progression-free survival (LRPFS) and distant progression-free survival (DPFS) were estimated with the Kaplan-Meier method and log-rank test. Cox proportional-hazards models, landmark analyses, propensity score matching, and subgroup analyses were used to address confounding. RESULTS: Of the patients included in our study, 192 received radiotherapy alone after PCT (PCT + RT), and 163 received concurrent chemoradiotherapy after PCT (PCT + CCRT). The prognosis of PCT + CCRT was significantly better than that of PCT + RT (5 year OS, 53.0 vs 36.2%; P = 0.004). After matching, the 5 year OS rates of the two groups were 55.7 and 39.0%, respectively (P = 0.034) and the median DPFS were 29.4 and 18.7 months, respectively (P = 0.052). Multivariate Cox regression analysis indicated that PCT + CCRT was an independent favorable prognostic factor (P = 0.009). In addition, conducting concurrent chemoradiotherapy after 4-6 cycles of PCT or conducting concurrent chemotherapy with single-agent platinum was associated with significant survival benefit in the matched cohort (5 year OS rate, 60.4 or 57.4%, respectively). The survival difference between groups remained significant when evaluating patients who survived for ≥ 1 year (P = 0.028). CONCLUSIONS: The optimal treatment strategy of mNPC is the combination of PCT followed by concurrent chemoradiotherapy. More specifically, concurrent chemoradiotherapy with single-agent platinum after 4-6 cycles of PCT is suggested.

Driver mutations in ADGRL3 are involved in the evolution of ependymoma.

Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.

Intensity-modulated proton radiation therapy as a radical treatment modality for nasopharyngeal carcinoma in China: Cost-effectiveness analysis.

BACKGROUND: Compared to conventional intensity-modulated photon radiation therapy (IMRT), intensity-modulated proton radiation therapy (IMPT) has potential to reduce irradiation-induced late toxicities while maintaining excellent tumor control in patients with nasopharyngeal carcinoma (NPC). However, the relevant cost-effectiveness remains controversial. METHODS: A Markov decision tree analysis was performed under the assumption that IMPT offered normal tissue complication probability reduction (NTCP reduction) in long-term dysphagia, xerostomia, and hearing loss, compared to IMRT. Base-case evaluation was performed on T2N2M0 NPC of median age (43 years old). A Chinese societal willingness-to-pay threshold (33558 US dollars [$])/quality-adjusted life-year [QALY]) was adopted. RESULTS: For patients at median age and having NTCP reduction of 10%, 20%, 30%, 40%, 50%, and 60%, their incremental cost-effectiveness ratios were $102684.0/QALY, $43161.2/QALY, $24134.7/QALY, $13991.6/QALY, $8259.8/QALY, and $4436.1/QALY, respectively; IMPT should provide an NTCP reduction of ≥24% to be considered cost-effective. CONCLUSIONS: IMPT has potential to be cost-effective for average Chinese NPC patients and should be validated clinically.

How to Improve the Effect of Microvascular Decompression for Hemifacial Spasm: A Retrospective Study of 32 Cases with Unsuccessful First Time MVD.

BACKGROUND: Microvascular decompression (MVD) has become accepted as an effective therapeutic option for hemifacial spasm (HFS); however, the curative rate of MVD for HFS varies widely (50-98%) in different medical centers. This study could contribute to the improvement of the MVD procedure. METHODS: We retrospectively analyzed 32 patients in whom initial MVD failed in other hospitals and who underwent a second MVD at our center. The clinical characteristics, operative findings, outcome of the second MVD, and complications were recorded. RESULTS: There were 18 women and 14 men (56.3 and 43.7%, respectively). The left-to-right ratio was 19:13. The mean age of the patients was 59.8 years. We found an undiscovered conflict site located in zone 4 in 10 patients and in the root entry zone in 8 patients. The initial MVD failed in nine patients because of ignorance of the arterioles that originate from the anterior inferior cerebellar artery. There were no special findings in four patients. No Teflon felts were found in the whole surgical field in one patient. CONCLUSION: Omission of the offending vessel is the most common cause of an unsuccessful MVD. Intraoperative abnormal muscle response associated with the Z-L response is a good measure to correctly identify the involved arterioles.

Treatment and Survival Outcomes Associated With Platinum Plus Low-Dose, Long-term Fluorouracil for Metastatic Nasopharyngeal Carcinoma.

Importance: The treatment of metastatic nasopharyngeal carcinoma (mNPC) is a major challenge because of drug resistance and the toxic effects of chemotherapy. Objective: To evaluate the survival and toxicity outcomes and safety associated with the use of a modified low-dose fluorouracil protocol compared with standard regimens recommended in current guidelines for treatment of mNPC. Design, Setting, and Participants: This retrospective cohort study was based on data retrieved from electronic medical records from Sun Yat-sen University Cancer Center in China for 1397 patients with mNPC diagnosed from January 1, 2006, to December 31, 2017. Data analyses were conducted from October 1, 2020, to May 1, 2021. Exposures: Patients received chemotherapy, including platinum plus low-dose, long-term fluorouracil (PFLL); cisplatin plus standard dose, short-term fluorouracil (PFSS); cisplatin plus gemcitabine (GP); cisplatin plus taxane (TP); and cisplatin plus taxane plus fluorouracil (TPF). Main Outcomes and Measures: The main outcomes included overall survival (OS); subsequent-line, treatment-free survival (sTFS), defined as the period from metastasis to the date requiring subsequent-line treatment or death; and the survival to toxicity ratio (STR), defined as person-year rate of OS divided by person-year rate of severe hematologic toxic effects. Cox regression models were used to compare the outcomes of patients receiving PFLL vs other regimens, adjusting for baseline characteristics. Results: Of 1397 patients with mNPC included in this study (1152 men; median age, 46 years [range, 18-70 years]) 134 received PFLL, 203 received GP, 330 received PFSS, 366 received TP, and 364 received TPF. A total of 764 patients died (75 in treatment group PFLL; 107 in group GP; 204 in group PFSS; 207 in group TP; and 171 in group TPF), and 979 patients had subsequent-line treatment or died, whichever occurred first (PFLL, 77; GP, 144; PFSS, 262; TP, 269; and TPF, 227). The median follow-up was 46.9 months (IQR, 25.4-82.4 months), and the 5-year OS rate among patients who received PFLL was 25.4% (95% CI, 16.7%-38.8%), which was not significantly different from that among patients who did not receive PFLL (30.2%; 95% CI, 27.1%-33.5%; P = .13) or who received GP (25.1%; 95% CI, 18.1%-35.0%; P = .81), PFSS (23.6%; 95% CI, 18.5%-30.0%; P = .80), or TP (28.1%; 95% CI, 22.8%-34.7%; P = .99) but was lower than that for patients who received TPF (40.4%; 95% CI, 34.7%-47.1%; P = .001). The 5-year sTFS among patients who received PFLL (24.1%; 95% CI, 15.4%-37.6%) was significantly higher than that among patients who did not receive PFLL (18.5%; 95% CI, 16.1%-21.3%; P = .005) or who received GP (14.3%; 95% CI, 9.1%-22.5%; P = .001) but similar to that for patients who received TPF (28.0%; 95% CI, 23.0%-34.0%; P = .74). The STR of PFLL was 0.81, substantially better than that of GP (0.41) and TPF (0.65). Conclusions and Relevance: The results of this cohort study suggest that, compared with the use of standard treatment regimens, administration of PFLL was associated with similar OS but prolonged sTFS. PFLL also had better STR than other regimens, which could indicate less severe toxic effects. Thus, PFLL may be an option for first-line treatment of mNPC.