Abstract Objectives Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high rates of morbidity and mortality, largely because of its late diagnosis and metastatic potential. Lactate metabolism and protein lactylation are thought to play roles in NPC pathogenesis by modulating the tumor microenvironment and immune evasion. However, research specifically linking lactate-related mechanisms to NPC remains limited. This study aimed to identify lactate-associated biomarkers in NPC and explore their underlying mechanisms, with a particular focus on immune modulation and tumor progression. Methods To achieve these objectives, we utilized a bioinformatics approach in which publicly available gene expression datasets related to NPC were analysed. Differential expression analysis revealed differentially expressed genes (DEGs) between NPC and normal tissues. We performed weighted gene coexpression network analysis (WGCNA) to identify module genes significantly associated with NPC. Overlaps among DEGs, key module genes, and lactate-related genes (LRGs) were analysed to derive lactate-related differentially expressed genes (LR-DEGs). Machine learning algorithms can be used to predict potential biomarkers, and immune infiltration analysis can be used to examine the relationships between identified biomarkers and immune cell types, particularly M0 macrophages and B cells. Results A total of 1,058 DEGs were identified between the NPC and normal tissue groups. From this set, 372 key module genes associated with NPC were isolated. By intersecting the DEGs, key module genes, and lactate-related genes (LRGs), 17 lactate-related DEGs (LR-DEGs) were identified. Using three machine learning algorithms, this list was further refined, resulting in three primary lactate-related biomarkers: TPPP3, MUC4, and CLIC6. These biomarkers were significantly enriched in pathways related to "immune cell activation" and the "extracellular matrix environment." Additionally, M0 and B macrophages were found to be closely associated with these biomarkers, suggesting their involvement in shaping the NPC immune microenvironment. Conclusion In summary, this study identified TPPP3, MUC4, and CLIC6 as lactate-associated clinical modelling indicators linked to NPC. linked to NPC, providing a foundation for advancing diagnostic and therapeutic strategies for this malignancy.
To the Editor: In China, multiple myeloma (MM) has a crude prevalence of 7 per 100,000 population and an incidence of 1.6 per 100,000 population.[1] The term "1q21 abnormality" refers to genetic alterations including deletions, duplications, and amplifications in the 1q21 region of chromosome 1. Gain or amplification 1q21 (1q21+), which refers to an additional copy or multiple copies of genetic material in the long arm of chromosome 1 at position 21, is a well-documented abnormality that correlates with adverse clinical outcomes in patients with MM and has been demonstrated to be associated with poor prognosis, drug resistance, and disease progression in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM).[2] However, treatment options specifically for 1q21+ patients have seldom been recommended in guidelines due to the lack of clinical data, except for the 2018 Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) 3.0, which makes recommendations for transplant-eligible NDMM patients. This study aimed to evaluate the effectiveness of treatment regimens for RRMM with 1q21+ and to review relevant studies. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) extension statement and was registered in the PROSPERO database (No. CRD42023401904). PubMed, EMBASE, and the Cochrane CENTRAL Database were searched on September 8, 2022 (details are provided in Supplementary Materials, https://links.lww.com/CM9/C264). Randomized controlled trials (RCTs) of patients aged 18 years or older with a diagnosis of RRMM and 1q21+ were considered. We included patients who were treated with either single or combined pharmacological therapy using the following drugs regardless of dose and frequency. (1) Anti-CD38 monoclonal antibodies (mAbs): Daratumumab (dara) and isatuximab (Isa), (2) exportin-1 (XPO1) inhibitor: Selinexor, (3) antibody–drug conjugate (ADC): Belantamab, (4) anti-signaling lymphocytes activating molecule factor 7 (SLAMF7) mAbs: Elotuzumab (E), (5) protease inhibitors (PIs): Ixazomib (I) and carfilzomib (K), (6) immunomodulatory imide drug (IMiD): Pomalidomide (P). In addition, we included intervention with bortezomib (V) plus lenalidomide (R) plus dexamethasone (d). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall survival (OS), overall response rate (ORR), which was calculated as rate of complete response (CR) plus rate of very good partial response (VGPR), duration of response (DOR), and time to progression (TTP). Two reviewers extracted the following data from each study: Trial characteristics, participant characteristics, intervention information, and outcome information. Comparative data were synthesized using RevMan 5.3 (https://test-training.cochrane.org/online-learning/core-software-cochrane-reviews/review-manager-revman/download-revman-5). We calculated the hazard ratio (HR) and its 95% confidence interval (CI) for dichotomous outcomes, and the mean difference (MD) and its 95% CI for continuous outcomes. We synthesized single-group data and performed a proportional meta-analysis in R version 4.1.0 (https://www.r-project.org) with a meta-analysis package using the restricted maximum likelihood (REML) method. A fixed-effects model was used to synthesize data. Where significant heterogeneity was identified, namely I2 >50%, we explored the sources of heterogeneity through subgroup analysis of clinical, methodological, and statistical variations, and employed a random-effects model to pool data. We described the results of individual studies' when a meta-analysis was inappropriate due to clinical or methodological heterogeneity. The quality of the included RCTs was assessed independently by two reviewers using the Cochrane Collaboration Risk of Bias 2.0 tool for randomized studies. Any disagreements were resolved by discussion. More details of methods are given in Supplementary Materials, https://links.lww.com/CM9/C264. Finally, five studies with nine references[3–11] were included [Supplementary Figure 1, https://links.lww.com/CM9/C264]. The five included RCTs (2094 patients) all enrolled 1q21+ patients (n = 926, 44.2%) as a subgroup. Two studies (n = 619) reported that the HRs (95% CI) for OS of elotuzumab plus lenalidomide plus dexamethasone (ERd) and ixazomib plus lenalidomide plus dexamethasone (IRd) exhibited no significant differences from those with Rd, with values of 0.81 (0.61–1.06)[8] and 0.86 (0.66–1.12).[9] Two studies (n = 255) reported no significant difference in the HR (95% CI) for OS of IsaPd or IsaKd compared with that of Pd or Kd (HR 0.76, 95% CI 0.56–1.04) [Supplementary Figure 2A, https://links.lww.com/CM9/C264].[5,10] The HR for PFS was reported in five studies (n = 789) [Supplementary Figure 2B, https://links.lww.com/CM9/C264].[3–7] The results revealed that the addition of isatuximab to Pd or Kd lowered the risk of progression or death by 54% compared with that for Pd or Kd alone (two studies, n = 255, HR 0.46, 95% CI 0.33–0.66).[3,5] The addition of elotuzumab lowered the risk by 29% compared with that of Pd or Rd alone (two studies, n = 362, HR 0.71, 95% CI 0.55–0.93).[4,6] The addition of ixazomib lowered the risk by 22% compared with that of Rd alone (one study, n = 172, HR 0.78, 95% CI 0.49–1.24).[7] A higher ORR was observed for IsaPd than for Pd in one study (n = 48, 51.9% vs. 9.5%, P = 0.0011).[5] VGPR was higher for IsaPd than for Pd, as reported in one study (n = 48, 33.3% vs. 0, P = 0.0018).[5] Additionally, one study[7] that compared IRd and Rd reported the CR rate, DOR, and TTP [Supplementary Figure 3, https://links.lww.com/CM9/C264]. The overall quality assessment result for each study is given in Supplementary Figure 4, https://links.lww.com/CM9/C264. One study[7,9] was rated as having some concerns of bias due to a lack of information on randomization methods and allocation concealment, but the other four studies were rated as having low risk. Our findings indicated that the addition of isatuximab to Pd or Kd was associated with a significant benefit in PFS compared with Pd or Kd alone. Benefits of isatuximab were also observed in ORR and VGPR. Moreover, the addition of isatuximab, ixazomib, and elotuzumab to Kd, Pd, or Rd significantly reduced the risk of disease progression compared with Kd, Pd, or Rd alone. However, the benefits of isatuximab, ixazomib, and elotuzumab were not significant for OS. In the present study, the lowest proportion of disease progression or death was observed for IsaKd (35%), followed by IRd (45%); Kd (50%); IsaPd (54%); EPd, ERd, and Rd (60%); and Pd (75%), suggesting that isatuximab-based combinations are more beneficial for RRMM patients with 1q21+ than ixazomib- and elotuzumab-based combinations. Notably, we did not identify eligible RCTs of daratumumab, another anti-CD38 mAb, which was approved by the Food and Drug Administration in 2015 for MM patients and for RRMM patients with 1q21+. A previous study reported a median PFS of 6.0 months for RRMM patients with 1q21+ (vs. 25.2 months for patients without 1q21+) who were treated with daratumumab as a monotherapy or a combination with PIs and IMiDs,[12] indicating that chromosome 1q status might be a prognostic factor for relapse/refractory patients. Another study reported a longer median PFS (24.5 months) for RRMM patients with 1q21+ who received a daratumumab-based regimen (compared with 23.5 months in RRMM patients without 1q21+) than that reported by Parrondo et al[13]. The similar PFS outcomes indicate that daratumumab-based therapy may abrogate the poor outcomes associated with the presence of 1q21+. Improved ORR and VGPR were generally observed for IsaKd compared with IsaPd and IRd. However, the results should be interpreted carefully due to the variation in baseline characteristics. First, the age range varied among the studies involving IsaKd,[3] IRd,[7] and IsaPd.[5] Although the studies had similar median ages of patients (65–68 years old), Loiseau et al[7] and Moreau et al[3] enrolled patients with wider age ranges (38–91 years old and 55–70 years old, respectively) than Harrison et al[5] (60–74 years old). Considering the possible impact of age, the inclusion of younger patients may have contributed to the better responses in the studies of Moreau et al[3] and Loiseau et al[7]. In addition, different prior treatments may have influenced the results.[14] The results may also have been affected by the efficacy of lenalidomide and pomalidomide on their own or in combination with other drugs. The different ORR (17% vs. 68% vs. 83%) and VGPR (2% vs. 40% vs. 52%) of Pd, Rd, and Kd observed in this review provide indirect support to this argument. Overall, we reviewed RCT data from 1q21+ subgroup analysis, provided clinical suggestions, and filled the gap in the treatment options for the difficult-to-treat subgroup of patients with 1q21+ RRMM. The addition of isatuximab may significantly improve survival for RRMM patients with 1q21+. More studies are needed to validate the present results. Acknowledgments We acknowledge all authors who are solely responsible for content and editorial decisions. Conflicts of interest Zhanzhi Xie is a Sanofi employee and may hold shares and/or stock options in the company. This work was supported by Sanofi.
ABSTRACT Background This study compares the efficacy and safety of single autologous stem cell transplantation (ASCT) versus tandem ASCT for multiple myeloma (MM) patients in the era of novel agents. Methods A total of 112 high‐risk MM patients were included (single ASCT, (n = 57) or tandem ASCT (n = 55) in this retrospective multicenter study. Responses and outcomes were evaluated. Results At 100 days after ASCT1 and ASCT2, 36 (63.2%) versus 45 (81.8%) patients achieved sCR/CR, 16 (28.1%) versus 7 (12.7%) patients achieved VGPR, and 5 (8.8%) versus 1 (1.8%) patient achieved PR, respectively, in the single and tandem ASCT cohorts. The 3‐year cumulative incidence of non‐relapse mortality and disease progression was 0% versus 7.3% ( p = 0.083), and 45.8% versus 25.8% ( p = 0.039), respectively, for the single and tandem ASCT cohort. The tandem ASCT cohort showed a trend of better 3‐year probability of PFS (58.1% vs. 64.7%, p = 0.064) compared with the single ASCT cohort. In multivariate analysis, ultra high‐risk and achieving<VGPR response after ASCT1 were associated with an inferior PFS. Ultra high‐risk was also associated with an inferior OS. Conclusions Tandem ASCT demonstrated improved outcomes compared to single ASCT in high‐risk MM patients receiving triplet or quadruplet induction and maintenance therapy. However, patients with ultra high‐risk cytogenetics may require innovative therapeutic approaches, as tendem ASCT does not overcome their adverse prognosis.
AbstractObjective: We aimed to explored the efficacy and safety of XVRD protocol in newly diagnosed multiple myelomawith extramedullary disease. Methods: This is a single-arm, open, observational clinical study. For induction/consolidation(21-day cycles), patients (pts) received 8 cycles of XVRd (Selinexor 60 mg PO weekly, Bortezomib 1.3 mg/m2 SC days1, 4, 8, 11, Lenalidomide 25 mg PO days 1-14, and Dexamethasone 40 mg PO weekly). In maintenance (28-day cycles), pts received XR (Selinexor+Lenalidomide) at least 2 years until disease progression, death or withdrawal. The primary endpoint was overall response rates and minimal residual disease negative rates. Results: The median age of the 10 pts was 62 (range 55-81) years. R-ISS stage 3 was present in 2 (20%) pts. 3 pts had high risk cytogenetic and 1 patient with plasma cell leukocyte. According to IMWG criteria, the ORR of 10 pts with NDMM was 100%, including 2 stringent complete response (sCR), 2 complete remission (CR), 4 very good partial response (VGPR) and 2 partial response (PR). Median progression-free survival and overall survival were not achieved. The most common grade 3-4 treatment-emergent adverse events (occurring in 10% of pts) were thrombocytopenia. The most common non-hematological adverse events were grade 1 or 2, including nausea (30%), fatigue (40%), and anorexia (20%). Overall, the severe toxicities are manageable. Conclusion: The XVRd regimen has good efficacy and tolerance in newly diagnosed multiple myelomawith extramedullary disease.
A group of 110 workers in a cotton mill was investigated by questionnaire, skin testing, and the measurement of airway responsiveness through forced expiratory volume for one second(FEV1) by spirometry. The workers were examined before starting work, 10 weeks and one year after exposure. Decreases in FEV1 over shifts were small at 10 weeks and one year, and were slightly higher among people with positive skin reactions to cotton dust extracts. Airway responsiveness, defined as the average decrease in FEV1 after 1.25 mg methacholin, was increased at 10 weeks. It remained about the same after one year, except in the workers with positive skin test. Subjective symptoms of chest tightness and cough with phlegm increased progressively at 10 weeks and one year. Nasal irritation remained unchanged and dry cough decreased in one year. The results suggest that the airway inflammation caused by cotton dust increases with the exposure time and that the changes are more notable in workers with reactivity to cotton dust extract.
Systemic light chain (AL) amyloidosis is a rare and multisystem disease associated with increased morbidity and a poor prognosis. Delayed diagnoses are common due to the heterogeneity of the symptoms. However, real-world insights from Chinese patients with AL amyloidosis have not been investigated.This study aimed to describe the journey to an AL amyloidosis diagnosis and to build an in-depth understanding of the diagnostic process from the perspective of both clinicians and patients to obtain a correct and timely diagnosis.Publicly available disease-related content from social media platforms between January 2008 and April 2021 was searched. After performing data collection steps with a machine model, a series of disease-related posts were extracted. Natural language processing was used to identify the relevance of variables, followed by further manual evaluation and analysis.A total of 2204 valid posts related to AL amyloidosis were included in this study, of which 1968 were posted on haodf.com. Of these posts, 1284 were posted by men (median age 57, IQR 46-67 years); 1459 posts mentioned renal-related symptoms, followed by heart (n=833), liver (n=491), and stomach (n=368) symptoms. Furthermore, 1502 posts mentioned symptoms related to 2 or more organs. Symptoms for AL amyloidosis most frequently mentioned by suspected patients were nonspecific weakness (n=252), edema (n=196), hypertrophy (n=168), and swelling (n=140). Multiple physician visits were common, and nephrologists (n=265) and hematologists (n=214) were the most frequently visited specialists by suspected patients for initial consultation. Additionally, interhospital referrals were also commonly seen, centralizing in tertiary hospitals.Chinese patients with AL amyloidosis experienced referrals during their journey toward accurate diagnosis. Increasing awareness of the disease and early referral to a specialized center with expertise may reduce delayed diagnosis and improve patient management.
follow up a group of newlyemployed workers ina cottonmill, andtoreportchanges insymptoms over time. Methods-Agroupof110millworkers ata cottonmillinShijiazhuang, China, was investigated byquestionnaire, skintest- ing,andspirometric measurements of airway responsiveness throughforced expiratory volumeinone second(FEVy). Theworkers were examinedbefore start- ingwork,at10weeks, andatone year. Results-Decreases inFEVyover shifts were smallat10weeksandone year,and slightly higher among peoplewithskin reactions tocottondustextracts. Airway responsiveness, defined as theaverage decrease inFEV1after1*25mg metha- choline was increased at 10weeks.It remainedaboutthesame after one year, exceptintheworkers positive fortheskin test,inwhom itwas further increased. Subjective symptoms ofchesttightness andcoughwithphlegmincreased pro- gressively at10weeksandone year;nasal irritation remainedunchanged anddry coughdecreased between10weeksand one year. Conclusion-The results suggestthatthe airwayinflammation causedby cotton dustincreases withincreasing exposure timeand thatthechangesare more notable inworkers withreactivity tocot- tondustextract. (Occup Environ Med1995;52:328-331)
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