Objective: Concerns exist regarding the potential development of malignancy and tuberculosis in patients with spondyloarthritis (SpA) treated with biologics. We assessed the extent to which biologic therapy may increase the risk of malignancy and tuberculosis in patients with SpA by meta-analysis to derive estimates of sparse harmful events occurring in Randomized Controlled Trials (RCTs).Methods: A systematic literature search was conducted in PubMed, EMbase, Web of Science, the Cochrane Library, and China Biology Medicine disc for RCTs evaluating the risk of sparse harmful events of biologic therapy in patients with SpA from inception through August 9, 2021. We calculated a pooled Peto OR for malignancy and tuberculosis in biologics-treated patients vs. placebo patients. The risk of bias on the included RCTs was assessed by using Cochrane Risk of Bias tool.Results: In total, 63 studies were included in this meta-analysis, and 83 patients and 7 patients developed malignancy and tuberculosis, respectively. Overall, the risk of malignancy and tuberculosis was increased in SpA patients treated with biologics compared to placebo . Remarkably, compared to placebo, there was higher risk of malignancy for IL-17 inhibitors  and small molecule targeted drugs  in peripheral SpA, and for TNF receptor-Fc fusion protein in axial SpA . Besides, the risk of tuberculosis was higher for anti-TNFα antibody in axial SpA .Conclusion: This meta-analysis showed an elevated risk of malignancy in patients with peripheral SpA treated with biologics, especially for IL-17 inhibitors, and small molecule targeted drugs, a slightly increased risk of malignancy in TNF receptor-Fc fusion protein in axial SpA, and increased risk of tuberculosis in patients with axial SpA treated with anti-TNFα antibody. These findings need to be validated by studies with larger population and longer follow-up. Spondyloarthritis (SpA) is a series of chronic inflammatory conditions that have a range of manifestations, including predominantly axial SpA  and non-radiographic axial SpA (non-axSpA)) and peripheral SpA . People with predominantly axSpA may have additional peripheral symptoms, and vice versa. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), or a combination of both, can usually ameliorate disease activity and retard joint damage, thereby improving quality of life of patients with SpA. However, in a sizeable proportion of patients with SpA, NSAIDs or csDMARDs fail or are not tolerated. For these patients not responding to NSAIDs or csDMARDs, biologics or small molecular targeted drugs can provide clinically important improvement via targeting specific inflammatory mediators in inflammatory pathways, alleviating inflammation, and thus better controlling symptoms and structural destruction. Concerns have been raised about the safety of biologics or small molecular targeted drugs, especially with regard to malignancies and tuberculosis, because they can interfere with the immune system.Cancer is a common event in individuals with rheumatic diseases. A study suggested that about 20% of individuals with rheumatoid arthritis will be diagnosed with malignancy during their remaining lifetimes . When anTuberculosis is an important infectious disease worldwide, which is related to a significant morbidity and mortality, especially in developing countries. More and more biologics are used in the treatment of individuals with SpA, which is a matter of great concern, particularly for the individuals having previously suffered from tuberculosis. Studies in Taiwan have shown a 2.28-fold increase in the risk of tuberculosis in patients with rheumatoid arthritis than that in the general population , while pAt present, many RCTs have reported the safety of biologics and small molecular targeted drugs in the treatment of SpA. However, RCTs are inadequate for detecting and quantifying rare events, such as malignancies and tuberculosis. A meta-analytic approach is considered useful to overcome the inherent limitations of individual RCTs in the assessment of safety outcomes. The main objective of the systematic review is to summarize and contextualize the risk of malignancies and tuberculosis accompanying biologics and small molecular targeted drugs use in RCTs and long-term extension studies using meta-analysis.We strictly followed PRISMA  guidelines and the recommendations from the Cochrane Collaboration to conduct this systematic review and meta-analysis.An experienced medical librarian and information specialist was invited to conduct a comprehensive literature search with input from the study team. The following electronic bibliographic databases: PubMed, EMbase, the Cochrane Library, Web of Science, and China Biology Medicine disc (CBM), were searched from inception through August 9, 2021. No limits were applied to race, sex, or language, except for human subjects. The details of search strategies for electronic database were showed in Study inclusion was assessed by two pairs of independent reviewers . Disagreements were discussed and resolved by consensus and, when needed, a third reviewer acted as an adjudicator (LH) until a consensus was reached.Type of study design: Randomized controlled trials (RCTs) that have been published in peer-review journals and had at least one 24-weeks follow-up.Type of patients: Patients (≥18 years old) with SpA including axial SpA and peripheral SpA confirmed by physician/specialist according to the 1984 modified New York criteria and ASAS classification criteria for SpA.Type of intervention and comparator: Studies comparing any biologics  against non-biologics .Outcomes: Reporting at least one outcome of malignancy or tuberculosis.Two reviewers (SM and XJ) independently individual trial data, and two additional reviewers (LW and YW) cross-checked the extracted results. Disagreements were discussed and solved through consensus, and a third reviewer acted as an adjudicator (LH) if necessary. From each selected trial, we collected general information , study population , and intervention characteristics . Primary outcome data was number and type of malignancies and tuberculosis.All included trials were assessed for risk of bias by two reviewers (SM and XJ) with version 2 of the Cochrane Risk of Bias Assessment tool. The following domains of individual trials were assessed: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases . We assessed the risk of bias using the categories of yes (low risk of bias), no (high risk of bias), and unclear .We identified the number of patients with at least one malignancy or tuberculosis, based on the analysis of adverse event in individual trial. The number of patients with SpA receiving at least one dose of study drug represented the denominator of our outcome measurement.Our study protocol required the use of a fixed-effect model for meta-analysis due to its superior performance while pooling the clinical trials with few or rare events, comparing to random-effect model, and the results were expressed as Peto odds ratio (OR) and associated 95%CI. Peto OR is preferred for few or rare events, and it is not necessary to have corrections for zero cell counts in a single group. We stratified by biologics classes to explore how different biologics classes affect the risk of malignancy and tuberculosis infection. Since there were fewer cases of malignancy and tuberculosis, we could not compare the dose or frequency of administration. Therefore, for the clinical trials that investigated different doses and frequencies of the same biologics class, we pooled cases of malignancy or tuberculosis across the different doses and frequencies for analysis. The I  statistip-value < 0.05 was considered as statistically significant in all tests.Meta-analysis was conducted using “meta” package on R 3.6.2 software. A total of 13,103 unique citations were identified through electronic bibliographic databases and hand-searching. There were 8,925 records that were potentially relevant to our topic in our first selection round, of which 166 were deemed eligible for full review. Finally, a total of 63 trials met inclusion criteria for our systematic review and meta-analysis. All the included studies were reported in Chinese or English. The details of study selection process were showed in The 63 RCTs containing 19,291 patients with SpA, were published between 2003 and 2021. Among these RCTs, 27 investigated axSpA and 36 investigated peripheral SpA. A majority of RCTs were two-arms clinical trials, with follow-up periods ranging from 12 to 144 weeks .All studies provided sufficient details of randomization. Although most of the clinical trials declared that they were double-blind, more than half of the trials indicated inadequate in the method of allocation concealment. In all studies, the co-interventions and baseline characteristics were similar between the biologics group and control group, and control groups (placebo and) were grouped together. In some patients who previously received placebo or csDMARDs, switching from place to active medication might introduce a potential risk of bias. In some trials (28/58), the method of imputation of no response, with “advancement penalty”, was used to address this potential risk of bias. The risk of bias graph of assessment for all the included RCTs was demonstrated in Published data in 63 retrieved RCTs reported 69 malignancies in 11,281 patients receiving at least one dose of biologics (0.6%) and 14 malignancies in 7,913 control patients (0.2%). Of the 83 malignancies, 55 were solid tumors , 17 were skin cancer , 4 were lymphomas, and 7 were not specified. Mean durations of placebo exposure and active treatment exposure were 21 ± 9 weeks and 37 ± 22 weeks. Malignancies occurred in 12, 29, 27, and 7 patients with durations of active treatment exposure more than 52 weeks, 24–52 weeks, less than 24 weeks and less than 12 weeks, respectively.p = 0.85), which indicated that there was no statistical heterogeneity in these trials. Overall, there was an increased risk of malignancies in individuals with SpA using biological and targeted drugs vs. placebo patients  was 0% p = 0.023; I2 = 0%, and p = 0.889) without evidence of publication bias  without evidence of publication bias  without evidence of publication bias , while anti-TNFα antibody was not   .p = 0.403; I2 = 0%, and p = 0.676), IL-17 inhibitors in patients with axial SpA  without evidence of publication bias  without evidence of publication bias , and the other two in Germany. Two cases of tuberculosis occurred in the patients treated with adalimumab, two in patients treated with infliximab, one in patients treated with golimumab, and one in patients treated with tofacitinib.p = 1.00). Comparing to placebo, the risk of tuberculosis infection in patients treated with biologics or targeted drugs was increased  without evidence of publication bias  anion bias . No tubeion bias . In addiion bias .p > 0.05 in all pooled Peto ORs, except for IL-17 inhibitors and small molecular targeted drugs in peripheral SpA, compared to placebo. In addition, we only find an elevated risk of tuberculosis infection in individuals with axial SpA receiving TNF-ɑ inhibitors therapy.There has been concern regarding a putative increasing risk of malignancies and tuberculosis with either biologics and small molecular targeted drugs treatment because of the impacts of these therapies on the immune system. Our work shows that there is an elevated risk of malignancies and tuberculosis in patients with SpA receiving biologics or small molecular targeted drugs therapy, compared to placebo. While investigating the risk of malignancies in the treatment with biologics by different types of biological agents in each SpA type, we find a wide 95%CI and Malignancies in single RCTs of biological and targeted drugs treatment in patients with SpA were rare, and the observed differences were not statistically significant in their occurrence between groups. We investigated the risk of malignancies in treatment with biologics and small molecular targeted drugs in SpA including axial SpA and peripheral SpA by meta-analysis, overall as well as by biological agents’ classes in each SpA type.The comparison of IL-17 inhibitors to placebo was the only one biologic that achieved significant difference in patients with peripheral SpA rather than axial SpA. Nevertheless, all seven included RCTs investigated exclusively individuals with psoriatic arthritis . Interestingly, a comprehensive clinical trial safety dataset consisting of twenty-three RCTs of secukinumab in ankylosing spondylitis, psoriatic arthritis, and psoriasis indications indicated that the exposure-adjusted incident rates per 100 patient-years for malignancies in treatment with secukinumab were 0.8, 1.1, and 0.5 in the psoriasis, psoriatic arthritis, and ankylosing spondylitis studies, respectively . BecauseThe comparison of TNF-α inhibitors to placebo in SpA including peripheral SpA and axial SpA did not achieve statistical significance. A collaborative study from the ARTIS and DANBIO registers showed that treatment with TNF-α inhibitors in patients (n = 8703) with SpA was not associated with increased risks of cancer, neither overall nor for the most cancer types, such as prostate cancer, lung cancer, colorectal cancer, lymphoma, breast cancer, and malignant melanoma . A subgrAdditionally, in our study, there was a statistically significant increase in the risk of malignancies accompanying small molecule targeted drugs use, relative to placebo. In our study, two clinical trials on tofacitinib reported the occurrence of malignancy, one of which showed no tumorigenesis, and the other showed four patients with malignancy in the tofacitinib group. Besides, there were 8 patients with malignancy in the apremilast group, while only 2 patients with malignancy in placebo group. Due to the limitations of the shorter observation period in RCTs and the fact that these small molecule targeted drugs are newly used to treat SpA, our findings accentuate the necessity for long-term observational studies.In our study, the main finding was that anti-TNFα antibody significantly increased the risk of tuberculosis infection in individuals with axial SpA. The increasing risk of tuberculosis is a main safety issue for anti-TNF-α therapy. Three widely used anti-TNF-α drugs with long-term safety profiles-infliximab and adalimumab-have been indicated to increase the risk of developing tuberculosis, which is similar to our finding. Anti-TNF-α therapies are well known to have a significant effect on immune cells, deactivating T cells and macrophages, and induction of apoptosis in key immune cells . Moreovein situ malignancies, in some countries, screening may be mandatory or highly recommended. However, in all the included studies, malignancies were only reported as an adverse event, and the details of the screening for in situ malignancies were not disclosed. It should also be noted that malignancies that occur within the short period of RCTs may not be new onset. It is necessary to perform in-depth screening while recruiting patients, due to the contraindications of biologics. Fifth, the doses of frequency of a biologic varied greatly among the included studies. It is difficult to performed a sensitivity analysis by dose. Therefore, this may be a bias for safety evaluation. Sixth, region of study performance and standard of care may differ by region on top of the local incidence of tuberculosis. However, it is difficult to compare the difference between studies conducted in regions where the background risk of tuberculosis may vary, as only six cases of tuberculosis were reported in the included studies. Seventh, screening and care for tuberculosis may change a lot over time (2003–2020). However, screening for tuberculosis were reported in only 11 of the 58 clinical trials, and were mostly based on PPD, chest radiographs, IGRA, or a combination, and the detailed information of screening, diagnosis and standard of care for tuberculosis were unavailable to us. This may result in a difference in the number of reported tuberculosis cases. Eighth, we only included these RCTs that have been published in peer-review journals since the results of these studies is more reliable. However, this may also lead to the potential publication bias. We have discussed them in the Limitation.There are several study limitations to consider. First, the short period of exposure in the included RCTs is a major solid limitation. Therefore, our results can only represent short- or medium-term risk assessment of malignancy and TB using biologics. Second, definitions of malignancies and TB may differ by individual studies, and many studies did not strictly follow the standard definition of tuberculosis and malignancies within the Medical Dictionary for Regulatory Activities (MeDRA) dictionary. These cases were collected based on the original publication case description only with relevant differences between studies. These may result in a bias in collecting these cases. Third, there may be a bias for safety evaluation due to the patients previously exposed to biologics. Of the included studies, 24 studies explicitly excluded the patients previously treated with any biologics, 19 studies allowed the patients prior to biologics efficacy failures, but this was generally limited to ≤30% of enrolled patients, and the other studies did not report this information. Since the detailed information on individuals previously exposed to biologics were not reported, it is difficult to perform further subgroup analysis. Fourth, for Above all, this systematic review and meta-analysis showed an increased risk of malignancies in individuals with peripheral SpA receiving biologics therapy, particularly for IL-17 inhibitors, and small molecule targeted drugs, a slightly increased risk of malignancy in TNF receptor-Fc fusion protein in axial SpA, and increased risk of tuberculosis in individuals with axial SpA treated with anti-TNFα antibody. Our findings may have direct implications in the management of a large number of patients treated currently with biologics and small molecule targeted drugs. In addition, due to limitations of very small number of events of malignancy and tuberculosis, our findings need to be validated by studies with larger population and longer follow-up.


Given the global public health burden of mental illness, there is a critical need for culturally validated psychopathology assessment tools that perform well in diverse societies. This study examines the psychometric properties of the Adult Self-Report (ASR) and Adult Behavioral Checklist (ABCL) from the Achenbach System of Empirically Based Assessments in adults in China. Chinese adults (N = 1276) and their spouses completed the ASR and ABCL, respectively. We conducted confirmatory factor analysis on 99 ASR items and 93 ABCL items. Estimators of model fit confirmed that both measures demonstrated excellent fit . Syndrome loadings on both measures were satisfactory but generally higher on the ASR. Neither gender nor education had significant effects, but there were informant x gender effects on most problem scales. Cross-informant agreement correlations between the ASR and ABCL were medium to large. Findings from this novel sample of Chinese adults are consistent with previous validation studies supporting the dimensionality, syndrome structure, gender differences, and inter-informant agreement of the ASR and ABCL. Our findings contribute to the cross-cultural understanding of mental health assessment and offer a psychometrically sound approach to measuring adult psychopathology in Chinese populations. The comprehensive measurement of adult psychopathology is an inherently important aspect of preventing or mitigating negative long-term individual and societal outcomes associated with the trajectory of mental illness. Negative outcomes of mental disorders include long-term effects on occupational functioning and reductions in earning potential and the labor force; healthcare and behavioral healthcare resource utilization and spending; and involvement in the criminal justice system ,2,3. As One such instrument is the Achenbach System of Empirically Based Assessment (ASEBA), one of the most widely used and rigorously validated measures to assess behavioral, emotional, and social problems and adaptive functioning in individuals of all ages ,5,6,7. TThough the ASR and ABCL have been validated and performed consistently in thousands of adults, cross-cultural differences in phenotypic expressions of psychopathology in these instruments have garnered little attention in the literature. Potential differences in economic, social, and cultural factors as well as the expression of specific psychopathology among disparate cultures/ethnic groups suggest that quantitative assessment methods may not necessarily measure theoretical constructs in the same way in different societies  . This hiResearch into the cross-cultural generalizability of the ASR/ABCL, though limited, has yielded informative findings. Individual society studies include Mahr et al.  and CorfAfter excluding those Ivanova samples that were demographically limited, Rescorla et al. ,15 analyIn order to better understand how ethnic and cultural factors influence the development and expression of psychopathological traits, more research is needed examining the cross-cultural generalizability of commonly used adult psychopathology measures. To that end, we examined Chinese versions of the ASR and ABCL with respect to their syndrome structure, effects of gender, education, and informant on scale scores, and cross-informant agreement. Furthermore, we compared our ASR scores with ASR scores from the 17 societies in the Rescorla et al.  internatThe participants in the current study were the parents of children from a larger population-based Jintan Cohort Project, which was established in 2004 in Jintan, Jiangsu province, located in the southeastern region of Mainland China ,19,20. TThe Adult Self-Report (ASR) and Adult Behavior Checklist (ABCL) serve two informants to assess adult behavior. The Adult Self-Report is designed to ask participants to provide information about him/herself. The parallel ABCL is designed to ask collateral informants  to answer similar questions to describe the ASR target. More specifically, in the current study, spouses of the ASR subject were chosen as informants to fill in the ABCL questionnaire to further assess the individual who completed the ASR.not true, 1 = somewhat or sometimes true, and 2 = very true or often true based on the preceding 6 months. The ABCL obtains ratings from collaterals for 118 problem items, 115 of which are also on the ASR. As detailed by Achenbach and Rescorla [rural, urban, and suburban), and education .The ASR contains 120 problem items written at a fifth-grade reading level that respondents rate as 0 = Rescorla , ABCL anU.S. normative data for the ASR and the ABCL were collected in a national household survey , with ABAchenbach and colleagues, who were the original developers of the ASR and ABCL , authoriVery True or Often True) and 1 (Somewhat or Sometimes True) were recoded as 1 = present in order to obtain a dichotomous scale. We used the WLSMV estimator, with the root mean square error of approximation (RMSEA), the comparative fit index (CFI), and the Tucker–Lewis index (TLI) as our measures of model fit. Good fit was set at RMSEA ≤ 0.06, CFI ≥ 0.95, TLI ≥ 0.95, based on Hooper et al. [2 and characterized using Cohen’s [p < 0.001 and report ESs rather than F and p values. Finally, we used independent sample t-tests to compare mean ASR syndrome scores for our Chinese sample with ASR scores from the 17 societies in the Rescorla et al. [Following Ivanova et al. ,13, we cr et al. . Similarr et al. . Next, f Cohen’s  criteriaa et al.  internata et al.  14-socieDemographic characteristics of the ASR and ABCL samples appear in Our ASR CFA yielded RMSEA = 0.016, CFI = 0.989, and TLI = 0.988, all indicating excellent model fit. For collateral-reports, we found that RMSEA = 0.018, CFI = 0.996 and TLI = 0.996, also indicating excellent model fit. Therefore, we found that the Jintan data showed excellent fit to the 8-syndrome model for both the ASR and the ABCL.Syndrome loadings for both the self-report and collateral-report showed satisfactory results , but ABC2) were small (<6%), six were medium (6–13.9%), and two were large (≥14%). There were no significant effects for gender or education. Of the 51 interactions, 37 were not significant, while the remaining 14 were significant at p < 0.001.As shown in A notable finding in DSM-oriented scales do not show this pattern, as informant ESs only ranged from 2% to 7% across the six scales.This same pattern was found for the syndromes comprising the Internalizing and Externalizing composites. Informant ESs ranged from 8% to 12% for the three Internalizing syndromes  but only from 1% to 4% for the three Externalizing syndromes . Interestingly, the Although the main effects for gender were not significant, there were small (ESs = 1–2%) but significant informant × gender interactions for 14 of the 17 problem scales, as seen in There was a very large informant effect for the Personal Strength scale (ES = 19%), with ASR scores higher than ABCL scores. Education was also significant (ES = 3%), as higher Personal Strengths scores were associated with more education while the main effects for education were not significant in all other scales. Gender was not significant, but there was a significant informant x gender interaction (ES = 1%), such that the ASR > ABCL differences were smaller for men than for women, with husbands rating their wives’ Personal Strengths the lowest of the four mean scores. No effects were significant for the Friends scale. On the Spouse/Partner scale, the only significant effect was education level, with higher (more favorable) Spouse/Partner scores in dyads where the target adult had more education.p < 0.01) medium-to-large cross-informant correlations between ASR and ABCL syndrome scales , DSM-Oriented scales , the Personal Strength scale (0.58), the Friends scale (0.55), and the Spouse/Partner scale (0.46).Our results indicated significant  and are also shorter, so an argument could be made that DSM-oriented scales inherently capture less variance. Second, DSM-oriented scales appear to assess more observable problems than empirically derived scales , which could have driven cross informant agreement up and lowered the informant effect for DSM-oriented scales. Finally, this difference could also be due to sampling fluctuations, i.e., unique features of our sample.The ASR yielded more self-reported internalizing conditions than the ABCL, while self-reports of externalizing conditions were similar on the two measures. That scores of Externalizing but not Internalizing were highly similar on the ASR and ABCL could reflect collaterals’ lack of awareness of their spouses’ experiences of internal distress and depression. As is commonly discussed in the literature on psychopathology assessment in children, externalizing behaviors typically are more observable than internalizing behaviors and thus would be expected to yield greater informant agreement . This woAlthough the main effects for gender were not significant, the significant informant × gender interactions on the majority of problem scales suggest that women in the sample were less likely to disclose their depression, anxiety, and somatic problems to their husbands than vice versa. Perhaps the cultural practice of emotional restraint is exhibited to a greater degree in Chinese women than men; however, it is also possible that there was general underreporting by women in the current sample. Further, the sizable informant effect for the Personal Strengths scale indicates that adults rated their own Personal Strengths higher than did their collaterals. These significant findings seem somewhat inconsistent with the high Spouse/Partner scale scores found on both the ASR and the ABCL for the Chinese sample.DSM-oriented scales. This underreporting of mental illness by Chinese populations is consistent with previous findings, which demonstrate that the parent-reported prevalence of childhood behavior problems and the adult self-reported prevalence of behavior problems in Chinese samples are lower than those of many other countries [Our comparisons between the Chinese sample and 14-society  sample revealed that the Chinese sample reported overall lower scores on the ASR-broad-band, ASR-syndromes, and ASR ountries ,17,32. Aountries . AnotherThe adults in the Chinese sample appeared to “underreport” most kinds of problems on the ASR and ABCL, but they may have “overreported” on the Spouse/Partner scale, where higher scores are more favorable. Their mean scores were more than double those of the multicultural samples. It is possible that the traditional Chinese emphasis on the resiliency and harmony of the family unit  led our The Rule-Breaking Behavior scale yielded five items with loadings less than 0.3 on the ASR. The concept of “saving face,” prominent in Chinese culture, may have contributed to the issues with this scale. In collectivist cultures, individuals tend to attribute losing face to internal attributes versus individualist cultures in which factors external to one’s ability are stressed . PerhapsOur findings support the utility of the ASR and ABCL in Chinese populations and are generally consistent with previous research validating their utility in multinational societies ,13,14,15Findings should be interpreted in light of this study’s limitations. Notably, the taxonomy of problem behaviors studied in the current sample is not comprehensive and cannot be generalized to all forms of adult psychopathology in Chinese populations. It is possible that there are behaviors and traits specific to Chinese culture not reflected in these measures, which were originally developed based on data from Western samples. Similarly, Jintan is located in the Southeastern part of China and cannot be fully representative of the broader Chinese population who practice subcultures. Furthermore, our Jintan sample had a narrow age range because all the adults were parents of teenage children, unlike the Rescorla et al. ,15 interIn conclusion, although ASEBA’s ASR and ABCL English versions are widely used, we are the first to report findings of the Chinese version of the ASR and ABCL. This analysis represents an important contribution to the cross-cultural understanding of mental health assessment as it offers a psychometrically sound approach to measuring adult psychopathology in Chinese populations. More research should examine the ASR and ACBL in wider samples of Western and non-Western individuals to further improve the generalizability of the findings reported here.Furthermore, we would also like to emphasize the importance of the clinical implications of these instruments outside of research, as they may serve as initial routine screening tools in various health settings to improve quality of care for adults in multiple dimensions of health outcomes, including behavioral, social, emotional, and thought problems. Particularly, in the area of early prevention, they provide clinicians with a useful, yet cost-effective, baseline assessment off of which to make decisions regarding type and level of care.


Stroke is a common cerebrovascular disease among the middle-aged and elderly, which can lead to a series of neurological disorders. Acupuncture is an important part of traditional Chinese medicine, with great value in improving the neurological deficits of stroke patients. In addition, rehabilitation therapy is also of great significance for alleviating the neurological deficits of patients and improving their activities of daily living.  To explore the effect of acupuncture and moxibustion combined with rehabilitation therapy on the recovery of neurological function and prognosis of stroke patients. n = 52) treated with acupuncture combined with rehabilitation therapy and a control group (n = 48) treated with rehabilitation therapy alone. The two groups were compared in terms of the following items: therapeutic efficacy, plasma levels of cortisol (Cor) and neuropeptide Y (NPY), nerve function, motor function, balance ability, self-care ability, swallowing function, negative emotions, and quality of life.  The case data of 100 stroke patients treated in the Wuhan Hospital of Traditional Chinese Medicine from January 2019 to July 2021 were analyzed retrospectively. According to the treatment plan patients received, they were divided into the following two groups: an observation group (P < 0.05). The levels of Cor and NPY, as well as the neurological function, motor function, balance ability, self-care ability, swallowing function, and negative emotions, were not significantly different between the two groups before treatment (P > 0.05). While after intervention, all the above indexes improved in both groups, with better improvements in the observation group compared with the control group (P < 0.05). And the various dimensions concerning the quality of life of patients were also significantly better in the observation group when compared with the control group.  The therapeutic effect of the observation group was significantly higher than that of the control group ( Acupuncture of traditional Chinese medicine combined with rehabilitation therapy has outstanding effects in stroke treatment and can effectively improve the neurological function, prognosis, and quality of life of patients, which is worthy of clinical promotion. Stroke, a cerebrovascular disease that occurs frequently in middle-aged and elderly people, is a sudden attack of disturbance of cerebral blood circulation, with the characteristics of fast onset, rapid development, and many complications , 2. ReleWestern medicine, the main clinical treatment for stroke, can improve clinical symptoms and inhibit disease progression to a certain extent. However, due to the high disability rate of patients with neurological impairment, the overall effect of western medicine treatment in long-term clinical practice is not ideal, and the prognosis of patients is poor, which seriously affects the life quality of patients . As an iGiven that there are currently few studies on the effects of acupuncture combined with rehabilitation therapy on the neurological function of stroke patients, this study conducted a detailed discussion on it, aiming to provide more references for the treatment of stroke patients.The case data of 100 stroke patients who came to the Wuhan Hospital of Traditional Chinese Medicine from January 2019 to July 2021 were analyzed retrospectively. According to different treatment plans, 52 patients treated by acupuncture combined with rehabilitation therapy were included in the observation group, and 48 patients who received rehabilitation therapy alone were included in the control group. Inclusion criteria were as follows: patients who were diagnosed with stroke by MRI or cranial CT and met the diagnostic criteria for stroke , patientBoth groups received conventional treatments, which mainly included protecting brain cells, improving brain microcirculation, relieving cerebral edema, lowering blood pressure, and preventing infection and symptomatic treatment such as lowering intracranial pressure for those with excessive intracranial pressure. Limb function training was started 48 hours after the patient had clear consciousness, stable vital signs, and no progression or deterioration of neurological-related symptoms. The training started with the simplest movements and progressed to more complex ones, the amount of exercise increased gradually, and the training mode shifted from passive to active. Repetitive exercises were performed on the affected side with lying position and supine position, respectively. Functional training of the affected side limbs was enhanced to increase muscle tension, then repeated exercises were continued, and the range of activities was gradually expanded according to the situation. Specific training was as follows: (1) placement of nonaffected limbs: patients were asked to place the limbs in a normal functional position, with the affected side's shoulder joint rotated outwardly, the elbow joint kept in a stretched position, the hip joint properly adducted, the ankle joint in the dorsal flexion position, and the knee joint properly flexed. (2) Joint function training: patients were instructed to drive the affected joint with the uninhibited limb and perform active joint exercises and passive joint exercises appropriately. (3) Posture transfer: patients were asked to lie down, then sit, and then maintain a standing position, following the principle of systematization. (4) Balance training: patients were instructed to perform training such as trunk scoliosis and rotation and then gradually guided to carry out walking and stair climbing training. (5) Swallowing function training: patients were instructed to perform mouth-opening, mouth-closing, tongue-out, puffing, and swallowing exercises in order to improve their swallowing function. Limb function training was performed once a day for 30 minutes for 1 month.Patients in the observation group were treated with acupuncture and moxibustion on the basis of the above treatment. According to the principle of treatment and acupuncture based on syndrome differentiation, the acupuncture points such as Jianyu, Hegu, Huantiao, Shousanli, Yanglingquan, Zusanli, Taichong, Shenshu, Dazhui, Twelve Jing, Weizhong, and Waiguan were selected for patients with hemiplegia; for those with speech dysfunction, acupoints such as Yamen, Lianquan, and Tongli were selected; for patients with crooked mouth, acupuncture points such as Cheekche, Taichong, Renzhong, Hegu, and Dilun were selected. The specific methods of acupuncture and moxibustion were as follows: routine disinfection of the skin at the puncture site was performed on patients in the sitting-supine position. It was worth noting that the Neiguan acupoint adopted the reduction method, Sanyinjiao acupoint adopted the replenishing method, Shuigou acupoint adopted the cough method, and Weizhong and Chize acupoints adopted the straight needling method. The lifting-thrusting method was adopted to make patients feel twitching and swelling on the limbs. The rest of the acupoints was operated according to the method of invigorating and reducing deficiency, and bilateral acupoints were selected for treatment, focusing on the acupoints on the affected side, with a depth of 0.5 to 1.0 cun. After acupuncture, the needle was left for 25 to 30 minutes. The treatment was performed once a day with a total of 4 courses of treatment (7 days as a course of treatment).(1) We evaluated and compared the therapeutic effects of two groups of patients and divided them into markedly effective: the patient's neurological deficit score was ≥81% after treatment; effective: the patient's neurological deficit score was between 36% and 80% after treatment; ineffective: the neurological deficit score of the patient was ≤35% after treatment. (2) The National Institutes of Health Stroke Scale (NIHSS)  was usedt-test was used for comparisons before and after treatment and independent samples t-test for intergroup comparisons. P < 0.05 indicated that the difference was of statistical significance.SPSS 19.0 statistical software (IBM) was used for statistical analysis of the data, and GraphPad 7 was used for image rendering. Count data were recorded in the form of number of cases and percentages (%), and the chi-square test was used for analysis. For measurement data, paired P > 0.05), suggesting comparability  between the two groups (rability .P < 0.05)  of 96.15%. while the number of patients in the control group was 22, 16, and 10, respectively, with an ORR of 79.17%. The results showed that the observation group had a higher effective rate than the control group ( < 0.05) .P > 0.05); while after treatment, the NIHSS score of both groups was reduced, and the score in the observation group (11.24 ± 1.12) was lower than that in the control group (17.19 ± 1.23) (P < 0.05) (No significant difference was observed in the NIHSS scores between the two groups before treatment ( < 0.05) .P < 0.05) (The plasma levels of Cor and NPY decreased in both groups after treatment and were lower in the observation group compared with the control group ( < 0.05) .P > 0.05). While after treatment, the FAM score (46.28 ± 4.06) and Barthel score (85.67 ± 4.96) increased significantly in the observation group compared with the control group (P < 0.05)  .P > 0.05). While the BBS score increased significantly in both groups after treatment, the score in the observation group was higher than that in the control group (P < 0.05) (No significant difference was observed in the BBS score between the two groups before treatment ( < 0.05) .P > 0.05). However, after intervention, the MDADI score increased significantly in both groups (P < 0.05) and was higher in the observation group compared with the control group (P < 0.05) (There was no significant difference in the MDADI score between the two groups before treatment ( < 0.05) .P > 0.05). While after treatment, the two scores decreased significantly in both groups (P < 0.05) and were lower in the observation group compared with the control group (P < 0.05) (The SDS and SAS scores were not significantly different between the two groups before treatment ( < 0.05) .P < 0.05)  .Stroke is a common clinical cerebrovascular disease characterized by sudden attack of blood circulation disorders in the brain. Cerebral vascular blockage, rupture, and ischemia caused by internal carotid artery, vertebral artery atherosclerosis, arterial intimal hyperplasia, hypertrophy, and carotid artery trauma are the pathological basis of stroke . Stroke First, we compared the neurological deficits of patients between the two groups, and the results showed that the neurological recovery of the observation group was better than that of the control group. The efficacy evaluation results also showed that the observation group had a significantly higher ORR than the control group, suggesting that acupuncture combined with rehabilitation therapy could further alleviate neurological deficits. Then, plasma Cor and NPY levels were also compared before and after treatment. Elevated NPY levels can cause strong cerebral vasoconstriction, resulting in reduced local blood flow in the brain and aggravating the severity of the disease . In addiSubsequently, we compared the motor function, self-care ability, balance ability, and swallowing function between the two groups. The swallowing function was significantly improved in both groups after treatment, especially in the observation group. Cerebral infarction can lead to brain damage and nerve function damage, and blood flow to the affected area or nervous system damage will cause a series of complications such as limb dysfunction, cognitive dysfunction, and swallowing dysfunction, while acupuncture can stimulate specific acupoints to regulate qi and blood and warm the meridians, thereby more effectively relieving the patient's dysfunction . BesidesIn summary, acupuncture and moxibustion of traditional Chinese medicine combined with rehabilitation therapy have outstanding effects in the treatment of stroke and can effectually improve the neurological function, prognosis, and life quality of patients, which is worthy of clinical promotion. However, this study also has certain shortcomings. First, due to the small sample size, the research results need to be further verified with a large sample size. In the future, multicenter and large-sample research will be carried out to obtain more accurate research results. Second, this study failed to compare the efficacy of acupuncture at different acupoints. Therefore, the efficacy of acupuncture treatment, as well as the curative effect of acupuncture combined with different targeted rehabilitation treatment modes, needs to be further explored.


Musculoskeletal pain is commonly experienced in patients with Parkinson's disease (PD). Few studies have investigated the clinical characteristics and risk factors associated with musculoskeletal pain.To investigate the distribution, clinical characteristics, and factors associated with musculoskeletal pain in a large sample of patients with PD.We enrolled 452 patients from two clinics and used a standardized questionnaire to collect demographic and clinical information. Musculoskeletal pain was diagnosed based on the Ford Classification System, and pain severity was assessed with the numeric rating scale (NRS). Multivariate regression models explored the association between clinical features of PD and quality of life and pain.p = 0.017), motor symptoms (p < 0.001), and depression (p < 0.001) were significantly associated with quality of life.Two hundred and six patients (45.58%) reported musculoskeletal pain, typically in their lower limbs and backs. Levodopa resulted in a ≥30% reduction in pain intensity scores in 170 subjects. Female sex  and Levodopa-equivalent daily doses  were associated with an increased risk for musculoskeletal pain. Pain duration (The lower limbs and back are common sites of musculoskeletal pain in patients with PD, and up to 82.52% of patients were responsive to Levodopa. Female sex and LEDDs are associated with musculoskeletal pain, suggesting that dopamine deficiencies, and not the motor and non-motor impairment, might be the most critical baseline risk factor of musculoskeletal pain. Pain is an important non-motor symptom of Parkinson's disease (PD), with an estimated prevalence of 40–83% . Pain caMusculoskeletal pain is the cause of pain in 40–90% of patients with PD , 5. HoweIt is well-known that Levodopa is the most effective treatment for the motor symptoms of PD and can also alleviate MSP . HoweverThis study investigates the clinical characteristics and associated factors of MSP to better understand the etiology of MSP in a large sample of patients with PD in China.All the study procedures were performed following the principles of the Declaration of Helsinki and the institutional review boards of the Xuanwu Hospital  and the First Affiliated Hospital of the Anhui University of Traditional Chinese Medicine . Each participant provided written informed consent.Consecutive outpatients with idiopathic PD who visited the movement disorders clinic of Xuanwu Hospital of Capital Medical University and the Neurology Department of the First Affiliated Hospital of the Anhui University of Traditional Chinese Medicine between July 2017 and January 2020 were enrolled. The inclusion criteria were (a) idiopathic PD diagnosed according to the 2015 Movement Disorder Society (MDS) clinical diagnostic criteria ; (b) ageMusculoskeletal pain was diagnosed by the Ford Classification System  for painAll patients were asked to indicate the distribution of pain sites, duration of pain, and rate average pain intensity over the past 3 months on an 11-point numeric rating scale (NRS) , with 0 We used the MDS-Unified PD Rating Scale (MDS-UPDRS) to measure motor symptoms in the ON and OFF states. The Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), PD Sleep Scale (PDSS), and PD Questionnaire (PDQ-39) were used to assess the severity of depression, anxiety, sleep quality, and QoL, respectively. The type and dose of PD medications at the time of assessment were recorded. Levodopa-equivalent daily doses (LEDDs) were calculated using the formulae described by Tomlinson et al. . The usep < 0.05. Clinical and demographic data were represented as mean ± SD, median with 25–75% interquartile range (IQR), or number (%). The Shapiro–Wilk test showed that our data for NRS scores (ON/OFF state) are not normally distributed. We used the non-parametric Wilcoxon signed-rank test to compare the NRS scores reported in the ON state with those reported in the OFF state. We calculated the proportion of pain in the ON/OFF state for every pain severity category in the MSP group.Statistical analyses were performed with SPSS version 23 . Statistical significance was defined as t-test for continuous variables and the χ2-test for categorical variables to compare the patients who reported MSP and those who did not. The Box-Tidwell method was used to evaluate the linear relationships between continuous independent variables and the logit transformed dependent variable. The variables that exhibited significant between-group differences in these univariate analyses were entered into a multivariable binary logistic regression model with stepwise (forward) to calculate odds ratios (ORs) and 95% CIs to identify predictors of MSP.Each patient was assigned 1 point if MSP was present or 0 if absent. The cut-off scores of HAMA, HAMD, and PDSS are 7 points for anxiety, 8 for depression, and 105 for sleep disorders, respectively. We used a To investigate the PDQ-39 domains associated with MSP, we first conducted a Pearson correlation analysis to determine candidate factors among the continuous variables. Then, we used multiple linear regression analysis to identify the genuinely relevant variables, and the regression analyses were corrected for the potential confounders.p = 0.046), had a higher proportion of females , a longer disease duration , higher MDS-UPDRS part I scores , and higher doses of LEDDs . There were no significant differences in the MDS-UPDRS part III, MDS-UPDRS part IV, HAMD, HAMA, PDSS, PDQ scores, and the Hoehn and Yahr scale between groups.A total of 452 patients were included in the analyses. The demographics and clinical characteristics of the study population are described in n = 160; 77.67%), upper and lower back , upper limbs , hands and wrists , shoulders , ankles and feet , neck , whole-body , pelvic region and thighs , and head   . Patientp < 0.001).All patients received antiparkinsonian drugs. Of the 206 patients with MSP, 170 (82.52%) reported that MSP was responsive to Levodopa, as indicated by reducing pain with at least 30% improvement over a short period, whereas 36 patients (17.48%) showed no response. Of the non-responsive patients, one reported that MSP was worsened by Levodopa and alleviated when the Levodopa dose was reduced. In general, the NRS scores recorded in the ON state after Levodopa treatment  were lower than those recorded in the OFF state before Levodopa treatment  and LEDDs . PD duration, MDS-UPDRS part III score in the OFF state and MDS-UPDRS part IV, PDSS (≥105 or <105), HAMD (≥8 or <8), and HAMA (≥7 or <7) scores were not significantly associated with MSP.p < 0.001), HAMD scores , and MSP durations  were significantly positively related to PDQ-39 scores. The MDS-UPDRS part IV, HAMA, PDSS, and NRS scores and ages were not related to PDQ-39 scores.In the present study, we found that 45.58% of patients with PD experienced MSP. The distribution of MSP was variable and associated with various sensations. MSP was responsive to Levodopa therapy, and female sex and higher LEDDs were identified as risk factors for MSP. There was a significant association between longer MSP durations and reduced QoL.We found that lower limbs and back pain were the most common sites. Similar results were reported in a previous study, demonstrating that MSP prevalence in specific body parts ranged from 20 to 60%. Among them, MSP in the back and lower limbs have the highest prevalence . Other sConsistent with previous reports , LevodopAs noted, female sex was a risk factor for MSP in our study; this observation is consistent with those of previous studies showing that women are more likely to have MSP across all age groups than men , 20. A sIn addition to the female sex, LEDD was also a risk factor for MSP in our logistic regression analysis. A previous study reported LEDD as a related factor associated with higher pain scores but not a risk factor . In thisFurthermore, our analyses identified no relationship between MDS-UPDRS part III scores and MSP presence, and other studies also reported similar findings , 29. Somr = 0.11), depression (r = 0.16), or anxiety (r = 0.2) reported in that study was weak. Furthermore, the previous study did not include additional analyses, such as logistic regression, which could be influenced by various confounding factors that affected the presence of MSP. This may explain the discrepancy between our results and those of the previous study. The lack of a relationship between motor symptoms and MSP is consistent with the observations reported for other pain conditions. For example, in complex regional pain syndrome, which can occur in various movement disorders, motor disorders are not associated with abnormal sensory plasticity   . ThirdlyIn conclusion, our study shows that MSP commonly occurs in patients with PD, affecting multiple body parts with various sensations. The most common MSP sites are the lower limbs and back. Levodopa therapy can alleviate MSP with an 82.52% response rate. Women and higher LEDDs are more likely associated with a higher risk of MSP than PD-related motor symptoms, which has substantially changed our understanding of PD with MSP. The observation that pain duration is an important determinant of QoL reinforces the need for future strategies aimed at improving MSP.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JL designed the study, interpreted the results, and wrote the manuscript. B-FZ designed the study, collected the data, and analyzed the data. S-SM, S-ZJ, and H-ZC collected the data. S-YL and CH advised the methodology and interpreted the results. Z-QG and HZ revised the manuscript. PC supervised the study, revised the manuscript, and is the study guarantor. All authors contributed to the article and approved the submitted version.This work was supported by the National Key R&D Program of China , Anhui University Science Research Project (Grant No. KJ2021A058), and the Outstanding Young Talents Project of Universities in Anhui Province Study Abroad (Grant No. gxgwfx2021028).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


More than 80% of global cervical cancer cases and deaths occur in Low-to-Middle-Income Countries. Improving the efficacy of treatments without increasing the costs in these regions is therefore imperative. The aim of our Phase III Randomised Controlled Trial was to investigate the effects of the addition of a mild heating technology, modulated electro-hyperthermia, to chemoradiotherapy protocols for the management of locally advanced cervical cancer patients in a resource-constrained setting. We previously reported on the positive outcomes on local disease control, quality of life, and early toxicity. Our recent results showed a significant improvement in two and three year disease free survival, without any significant changes to the toxicity profile, and with an improvement in quality of life, alongside a cost saving over three years. The effect was most significant in patients with Stage III disease, and a significant systemic effect was observed in patients with distant nodal metastases.p = 0.017; and HR: 0.70, 95%CI: 0.51–0.98, p = 0.035; respectively). There were no significant differences in late toxicity between the groups, and QoL was significantly improved in the mEHT group. In the CEA, mEHT + CRT dominated the model over CRT alone. (4) Conclusions: CRT combined with mEHT improves QoL and DFS rates, and lowers treatment costs, without increasing toxicity in LACC patients, even in resource-constrained settings.(1) Background: Modulated electro-hyperthermia (mEHT) is a mild to moderate, capacitive-coupled heating technology that uses amplitude modulation to enhance the cell-killing effects of the treatment. We present three year survival results and a cost effectiveness analysis from an ongoing randomised controlled Phase III trial involving 210 participants evaluating chemoradiotherapy (CRT) with/without mEHT, for the management of locally advanced cervical cancer (LACC) in a resource constrained setting . (2) Methods: We report hazard ratios (HR); odds ratio (OR), and 95% confidence intervals (CI) for overall survival and disease free survival (DFS) at two and three years in the ongoing study. Late toxicity, quality of life (QoL), and a cost effectiveness analysis (CEA) using a Markov model are also reported. (3) Results: Disease recurrence at two and three years was significantly reduced by mEHT (HR: 0.67, 95%CI: 0.48–0.93,  Around 602,127 new cases of cervical cancer and an estimated 341,831 deaths from cervical cancer were reported globally in 2020. More than 80% of these cases and deaths occurred in Low-to-Middle-Income-Countries (LMICs) , and hasThere is emerging evidence that radiofrequency (RF) electromagnetic fields associated with some HT techniques have additional effects during the treatments . ModulatThis technique proposes a dosing paradigm based on energy deposition and absorption, with thermal effects being an outcome of the treatment, and not the goal of the treatment. The biophysics of the technology are described in detail elsewhere in the literature ,24. The p = 0.006) and 0.36 , respectively, in favour of the administration of mEHT  and 43 [42%] participants in the mEHT Group and Control Group, respectively, were alive at the last follow-up. The frequency of participants achieving two year OS in the group with LDC at six months post-treatment (42/59 [71.2%]) was significantly higher than those who did not achieve LDC . Local Disease Control is a significant predictor of two year OS . The risk of death was 30% lower in the mEHT group   a.p = 0.047; 95%CI: 0.37–0.99). Age was also a significant predictor of two year OS in the group of participants with Stage III disease   .p = 0.001, 95%CI: 0.93–0.98), but not in the Control Group . We subsequently analysed participants according to their age group at the time of randomization . As there were only three participants younger than 30 years, we combined them with the group of participants between 30 and 50 years. Considering the participants younger than 50 years, and 50 years and older separately, the addition of mEHT had the most significant effect on two year OS in the age group 50 years and above .When analysing the sample by treatment arm, age was a significant predictor of two year OS in the mEHT Group , with participants treated with mEHT having 33% less risk of developing a recurrence during the first two years than the Control Group participants   compared to Control Group participants. When evaluated by disease stage, mEHT was not significantly predictive of two year DFS in participants with Stage II disease but remained significant for participants with Stage III disease (Two year DFS was seen significantly more frequently in the mEHT Group (36/99 [36.4%]) than in the Control Group  b. Partic disease .p = 0.74; adjusted for age, disease stage and HIV status)  (Three year OS was achieved by 33.7% (34/101) and 44% (44/100) of participants from the Control and mEHT Groups, respectively. The risk of death in the first three years was 28% lower for the participants who received mEHT, although this was not significant  a, and wh status) .p < 0.0001) with an odds ratio of 3.4 of achieving DFS in favour of the mEHT Group  and a hazard ratio of 0.70   b. When e status) .There was no significant difference in frequencies of reported late toxicity (grouped according to grades I/II and grades III/IV), between the two treatment groups or between the HIV-positive and HIV–negative participants at 9 months, 12 months, 18 months, and 24 months post-treatment. Multivariate Cox proportionate hazards models, including arm, HIV status and cisplatin doses, did not show any significant predictors of grades I/II or grades III/IV late toxicity.p = 0.0368), cognitive function was significantly improved in the mEHT group (p = 0.0044), and participants in the Control Group reported a reduction in role functioning while the mEHT Group participants reported an improvement in role functioning with a significant difference between the two groups (p = 0.0172). When assessing the change from baseline to 12 months within each group, there was an improvement in all scales except for role functioning in the mEHT Group, with significant improvements in Global Health Scale, Pain, Fatigue, and Emotional functioning. In the Control Group, there were significant improvements in the Visual Analogue Scale, Global Health Scale, Nausea and Vomiting, and Emotional Functioning, while Physical Functioning, Role Functioning and Cognitive Functioning decreased in the Control Group  less costly and more effective, from the perspective of both government and private healthcare funders. This result is driven by the difference in DFS and is due to the high costs of recurrent and progressive disease. This model did not use a societal costing perspective, which incorporates productivity-loss costs as well as dying costs, especially before retirement age. The incremental cost-effectiveness ratio (ICER) plane shows that CRT + mEHT produces more health effects at a lower cost over three years, in the government and private healthcare model, per disease free cycle  . The proF-FDG PET/CT scans, examinations, and fine needle aspiration if indicated. Local disease control was considered a failure if any disease was confirmed in the pelvis [The results from this study show a significant improvement in two and three year DFS with the addition of mEHT to CRT protocols for LACC, without any significant changes in late toxicity. This follows our previous paper describing the improvement in LDC with the addition of mEHT to CRT. The strict criteria for LDC evaluation is one of the strengths of the study. Evaluation of LDC was based on pre- and post-treatment 18e pelvis . We prevOur sample included HIV-positive participants, who are expected to have worse outcomes ,37,38, aWe initially estimated a reduction in two year mortality of 50% in order to achieve a power of 90% based on our sample size. While two year OS rates were not significantly improved, the reduction in disease recurrence at two years in the mEHT group was significant and was more than 50% (36.4% DFS in the mEHT Group and only 13.7% DFS in the Control Group), giving a statistical power of >90% for the DFS assessment. The effect of mEHT on outcomes was seen more significantly in the two year and three year DFS analyses than in the OS analyses, and the significance remained in both the HIV-positive and -negative participants and when considering participants based on age category. However, the significance was lost when considering only the participants with Stage II disease. In the OS analyses, the significance of the effects of mEHT on outcomes was less consistent. This may be a result of the inclusion of non-cancer related deaths in the OS analysis, which likely masked the effects of mEHT in the OS analyses. In our sample, the majority of the HIV-positive participants were younger than 50 years, and this may contribute to the improved OS outcomes seen in participants over the age of 50 years, compared to those younger than 50 years. This suggests that, while mEHT still improves the OS of HIV-positive participants, the effect is higher in HIV-negative participants as seen in the older group containing mostly HIV-negative women. In the group of participants who were 50 years and older, mEHT was a consistently significant predictor of DFS, regardless of HIV-status.18F-FDG PET/CT scans. Delays were most frequently attributed to technical problems, machine down-time, and source supply problems (in the case of the 18F-FDG PET/CT scans), as previously reported [18F-FDG PET/CT scans pre-treatment and six months post-treatment to assess clinical response to treatment. The 18F-FDG PET/CT scans were therefore not used for staging purposes in our study; however, participants with visceral and bone metastases and bilateral hydronephrosis on the 18F-FDG PET/CT scans were still excluded as they required a change in the treatment protocol. The pre-treatment 18F-FDG PET/CT scans indicated that more than half of the patients were in stage IVB disease, as seen by the high number of patients with extra-pelvic nodal involvement and local invasion of the bladder and rectum that was not detected during the routine clinical staging procedures. In a sub-group analysis of these participants, it was noted that there was complete metabolic resolution of all diseases, local and distant, in around a quarter of those who received mEHT. This suggests that mEHT may potentiate the abscopal effect induced by ionising radiation. This also provided an opportunity to assess the systemic effects of mEHT. The previously reported abscopal results [A limitation of the study is the substandard RT and BT administered as a result of a lack of sophisticated imaging and planning techniques in our setting, compared to developed settings. Due to resource constraints, the standard of care weekly cisplatin schedule was also not prescribed. Other limiting factors related to resource constraints include time to start EBRT, time to complete RT, and time between treatment completion and reported . Anotherreported . Funding results , combine results ,46,47, cp = 0.073) [Only one Phase III study has investigated CRT with/without classical HT (using capacitive HT), for the management LACC, and they reported an improvement in five year DFS from 60.6%  to 70.8% , although the difference was not significant  . While r= 0.073) , and the= 0.073) , while m= 0.073) , with a The substantial improvements in quality of life are an important result to consider as prolonged life is not always associated with quality of life in cancer patients. The adverse effects from oncology treatments can negatively impact the quality of life even in patients who are disease free, while persistent and recurrent disease are often considered to be poor predators of quality of life. An increase in life expectancy, together with a decreased quality of life and increased costs of treatment for adverse effects and persistent/recurrent disease, can place additional burden on the healthcare system. The CEA performed confirms that the improvement in quality of life, and improvement in DFS, not only benefits the patients and the community, but also has the potential to reduce the economic burden of the disease in both private and public healthcare settings.While it is unclear how much of an effect mEHT as a radiosensitiser would have when added to optimal RT and BT delivery for cervical cancer, it is encouraging to see such a large improvement in two and three year DFS with the addition of mEHT, even in sub-optimal conditions and in our high-risk population. There is still room for improvement in five year OS rates in cervical cancer patients with stage III and IV disease globally, even with sophisticated RT techniques, and a safe and effective radiosensitiser, such as mEHT, may still be a beneficial adjunct to RT in optimal settings. The continued monitoring of participants in the reported study will provide more insight into the effects of mEHT on five year survival. Modulated electro-hyperthermia is a feasible addition to LACC treatment protocols to improve outcomes, especially in settings in which sophisticated imaging and RT technologies are not accessible.Modulated electro-hyperthermia enhances outcomes of LACC patients when added to CRT, without increasing the toxicity profile of treatments. The associated improvement in quality of life along with the reduction in healthcare costs makes this intervention a feasible and effective adjunct to CRT for the management of LACC. The addition of mEHT improved LDC and DFS in our sample, without additional toxicity, and with improved role functioning of the patients, benefiting both the patients, the community, and the already-strained healthcare system. Modulated electro-hyperthermia could therefore be considered as an adjunct to CRT, especially in resource-constrained settings and for cervical cancer patients with advanced disease. The five year follow-up results and detailed CEA will provide further insight into the long term benefits of mEHT as an adjunct to CRT. Further investigations into the immunological effects of mEHT could assist in the long-term goal of shifting RT from a local treatment, to a systemic treatment when combined with mEHT, offering additional options for patients with metastatic disease. Studies on the systemic effects of mEHT, as well as studies with the aim of better understanding the thermal and non-thermal effects of mEHT, are likely to shed more light on the mechanisms of action and further improve the application and recommendations for the use of mEHT in a clinical setting.


Up to 1–4% of OLP patients could develop oral cancer, and identifying factors that could help in early detection could be extremely useful. The aim of our cohort study was to assess the clinical characteristics of one of the biggest populations ever reported with a histologically confirmed diagnosis of OLP. We identified that OLP patients who developed oral cancer usually underwent less frequent periodical follow-up visits, and older age increased the risk of death. As a significant number of OLP patients have a risk of malignant transformation, there is a critical need to review these patients preferentially, by trained clinicians, at least once a year, possibly for a lifetime.Background: Oral lichen planus (OLP) is considered an oral potentially malignant disorder. The aim of our study was to estimate the risk for oral cancer in patients diagnosed with OLP. Methods: A population-based cohort study between January 1988 and December 2020 at one hospital in Northern Italy was performed. The primary endpoint of the study was that of the histopathological diagnosis of oral cancer during the follow-up period. Results: The study population comprised 3173 patients. During the follow-up period, 32 men and 50 women developed an oral squamous cell carcinoma (2.58%), with a mean time of 103.61 months after the initial diagnosis of OLP, and 21 patients died because of oral cancer. Almost half of the deceased patients had the last follow-up visit before cancer diagnosis in a period of more than 12 months. Older age, having a red form of OLP and fewer sites of involvement, increased the risk of having cancer, while age and no treatment increased the risk of death. Conclusion: This is the largest group of OLP patients with such a long follow up ever reported. Due to the increased risk of having a malignant transformation, especially in elderly subjects, OLP patients should be regularly followed up, particularly in the Northern Italian population. Oral lichen planus (OLP) is a potentially malignant, chronic inflammatory disease, affecting nearly 2% of the population and causing a variety of oral lesions ,2,3. ItsAs said, the most severe complication of OLP is the development of an oral squamous cell carcinoma (OSCC), although this is still a very controversial matter. A recent systematic review reported a combined malignant transformation rate of 1.14% for OLP (95% CI = 0.84–1.49), also stating that these data could be underestimated due to essentially too restrictive diagnostic criteria, inadequate follow-up periods, and/or low quality of studies .At the end of the 1980s, our group started to collect data to estimate the potential risk of malignant transformation in a Northern Italian cohort of OLP patients, and we published the first results in late 2004 [We conducted a population-based cohort study examining patients with OLP diagnosed between January 1988 and December 2020 at one hospital in Northern Italy. At baseline, we collected demographic information, including smoking (current or former smoker vs. nonsmoker), alcohol consumption (current or former drinker vs. nondrinker), clinical aspect of the lesions, sites of involvement, and HCV status. Subjects had to be residents in the Piedmont region, Northwest Italy. We decided to study the risk of oral cancer development, considering also commonly cited confounding factors. The work was approved by the ethical review board of the CIR-Dental School, University of Turin (CIR-PO-pga2020/09), which did not necessitate specific informed consent because of the nature of the study. The study was also registered on the ISRCTN registry (#ISRCTN47966874).The individual data and outcome events were collected from a standardized computerized database  to a digA.Clinical features: the presence of characteristic bilateral papular and/or reticular lesions (Wickham striae), alone or in association with atrophic or erosive lesions; lesions in close contact to oral amalgam restorations  were excluded from the analysis; unilateral lesions in patients under new medication in the previous 6 months  were also excluded.B.Histopathological features: hyperkeratosis, either ortho- or parakeratosis; well-defined “band-like” zone of lymphocytic infiltration in the upper layer of the stroma: evidence of “liquefaction degeneration” of the lower layer of the epithelium, and absence of epithelial dysplasia .All adult patients examined during the inclusion period were enrolled. A final diagnosis of OLP was based on the following criteria:The clinical forms of OLP were divided into: (a) “white form”, which included the papular, reticular, and plaque forms; (b) “red form”, which included all the atrophic or erosive lesions, irrespective of a simultaneous presence of a white form. For symptomatic patients, corticosteroids therapy, in association with antimycotics, was given as previously published . If subjThe primary endpoint of the study was that of the histopathological diagnosis of oral cancer. A latency time of at least 6 months between the diagnosis of OLP, and the diagnosis of the oral carcinoma was considered to exclude concurrent presentations; accordingly, the follow up began 6 months after the OLP diagnosis. Secondary outcome measures were considered as follows: tumor site of involvement, T classification, neck nodes association, treatment modalities, outcome, and survival rate.The start of the study period was defined as the day of the histopathological confirmation diagnosis of clinical OLP. The cohort was followed up to 31 December, 2020; if earlier, the end of the study period was defined as the first of the following events: death, diagnosis of an oral squamous cell carcinoma, or the impossibility to reattend the clinical visit due to personal reason. In the subgroup of oral cancer patients, we also collected data after the oncological diagnosis. Periodical visits for all patients were carried out with a frequency usually based on the clinical feature and the need for therapy; in general, patients were seen at least once a year. Whenever a malignant evolution was suspected, an incisional biopsy was performed.The risk of bias due to patient selection was restricted by the consecutive patient inclusion and lack of auto-selection. The aim of the study was to study all our patients to delineate the increase in risk for cancer development as precisely as possible; the sample size was not limited to the number of subjects needed to detect a substantial increase.T-test or Wilcoxon–Mann–Whitney or Chi-squared or Fisher’s exact tests) were applied to compare patients who developed oral cancer during the follow up with those who did not develop it and to compare cancers features between dead and survived cancer patients. Then, a multivariate Cox proportional-hazards (PH) model was performed for investigating the association between time-to-onset of cancer and the following factors of interest: gender, age at lichen diagnosis, type of lichen, number of sites involved, smoking habits, HCV, and corticosteroid therapy. In the subgroup of cancer patients, cumulative hazards and survival to 60 and 120 months after cancer diagnosis were computed. Furthermore, a multivariate Cox PH model was carried out for investigating the association between survival time and cancer-related variables . All statistical analyses were carried out considering a first-type error α = 0.05 and using R software (version 4.0.5).Demographic and clinical characteristics were described by mean and standard deviation, median and interquartile range, or frequency and percentage, according to variable distributions. Additionally, appropriate statistical tests . The mean age at presentation was 59 years (SD = 12.65). Follow up ranged from 12 to 384 months (median follow up of 48 months). The clinical features of total subjects are reported in During the follow-up period, 32 men and 50 women developed an oral squamous cell carcinoma (2.58%), with a median time of 96 months after the initial diagnosis of OLP .p < 0.001). Most of the OLP patients were nonsmokers (86.1%), with an even bigger percentage in cancer patients (91.5%) but not statistically significant. Regarding HCV status, 193 patients were infected: this positive status was statistically more prominent in the cancer group (p = 0.031). According to the OLP clinical OLP form, 1893 patients (59.7%) had white lichen and 1280 the red form (40.3%); a higher percentage of red lichen has been described in cancer cases but without statistical significance. Although most patients had multiple oral sites of involvement, cancer patients developed OLP lesions in a statistically smaller number of sites (p = 0.018). The buccal mucosa was the most common location in each form (88.8%), followed by the tongue (59%) and gingiva (41.6%). The gingiva involvement was less reported in oncological patients (p = 0.012). Cancer patients underwent previously medical treatment similarly to others.The mean age of these patients was 60.78 years (SD = 10.31). Patients who underwent a malignant transformation have been followed up for a longer period (p = 0.010), and they had a more frequent, but not statistically significant, form of red lichen. Moreover, in terms of gender, smoke exposure, and HCV status, the two groups were similar. Deceased patients also statistically showed bigger tumors and more diffuse node involvement . In general, on the biopsy specimen, 40 patients were identified as well differentiated, 32 as moderately differentiated, and 6 as poorly differentiated. Four patients were identified as carcinoma in situ. Deceased patients had bigger oncological lesions (p = 0.013) and showed more neck involvement (p = 0.019). The tongue was the site most affected (39%), followed by the buccal mucosae (30.5%) and the gingiva (20.7%). Surgery was the primary modality of treatment, performed in 76 patients; postoperative radiation therapy was provided to 19 patients (after surgery) and to 3 patients as elective; only 3 patients did not undergo any therapy. The interval (in months) from the last follow-up visit before the histopathological cancer diagnosis was also recorded, and we reported a statistical difference between deceased and alive patients (p = 0.016), the last ones usually seen in the first 6 months after the last regular visit.n > 1, it was 36 months, with a statistically significant difference (p = 0.018).Almost half of the deceased patients had the last follow-up visit before cancer diagnosis in a period of more than 12 months. The median time for patients with a diagnosis of a tumor T1 or T2 and N1 was 6 months, while for patients with T3 or T4 and The multivariate Cox PH model, for investigating the association between time-to-onset of cancer and all the factors of interest , revealep = 0.02 and p = 0.04, respectively). More than 6 months since the last visit of follow up increased the risk of death, but not statistically (p = 0.73), such as a bigger size of lesions, neck involvement, and worse histopathological grading.Differently, the multivariate Cox PH model for investigating the association between survival time and cancer-related variables among cancer  showed tFinally, the reported survival rate was 82% at 60 months and 68% at 120 months  .OLP is currently considered an oral potentially malignant disorder (OPMD), although its malignant transformation rate is controversial, largely because of the lack of specific, worldwide agreed, diagnostic criteria . In the Very recently, a systematic review of systematic reviews recorded a 0.44% to 2.28% rate of malignant transformation of OLP , similarn = 7) who developed an oncological event. However, as tobacco and excessive alcohol consumption are the main risk factors for OSCC, it is always important, at least, to discuss the issue with OLP patients when it is relevant.As reported previously, most patients in our OLP cohort showed no increased prevalence of cigarette smoking . HoweverThe percentage of OLP patients who were HCV positive and developed an OSCC was higher than in HCV negative ones, and this status increased the risk of cancer even if not statistically. However, the proportion of OLP with chronic HCV infection in our cohort has shown a steady decrease in the last 2 decades , suggestOur study showed that white OLP could also progress to oral cancer, although it has recently been published  that purOur evaluation did not find a statistical difference between OLP and OSCC cases for the site of lesions and for the atrophic-erosive form (red lichen), as compared to the white form, even if the multivariate analysis showed that the red form put the patients at greater risk of malignant transformation. Risk factors for malignant transformations were reported in the literature to be the location of OLP lesions (margins of the tongue) and clinical features of lesions  ,18. MoreThe use of immunosuppressants has been regarded as a possible risk factor of malignant transformation, but it is unclear if this could be related to the suppression of the immune response or because of the decreasing local inflammatory reaction ,21,22. MWhen performing research about OLP, as said, rigorously diagnostic criteria guided by both pathological and clinical characteristics should be sustained to differentiate studied disease from other similar disorders, hence warranting that selection biases should be prevented. This is particularly important when studying its malignant transformation pattern because other OPMDs, such as proliferative verrucous leukoplakia (PVL) above all, or oral lupus erythematosus and oral lichenoid lesions. In particular, PVL, which carries a higher malignant transformation rate, may share some clinical and histologic characteristics with OLP but express dissimilar clinical comportment ,26,27,28Finally, we decided to make a comparison of survival with data previously reported by our group, but in patients without signs of OLP . CompariThis is the largest group of OLP patients with such a long follow up ever reported. The risk of malignant transformation was found to be increased for elderly patients with a red form and fewer sites of involvement, regardless of gender, smoking status, HCV status, and previous therapies. The risk of death was higher in elderly patients with more aggressive forms who did not undergo any treatment. The reported survival rate, however, was slightly better if compared to those of a similar population without signs of OLP. As Northern Italian OLP patients have an increased risk of malignant transformation, there is a need to review all these patients by trained clinicians, at least once a year, possibly for a lifetime. It would also be advisable to instruct patients to anticipate the visit if they were to show changes in shape, volume, or associated pain that do not respond to normal topical therapy for more than 15 days.