-
JAMA Oncology Jul 2020Minimally invasive techniques are increasingly common in cancer surgery. A recent randomized clinical trial has brought into question the safety of minimally invasive... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Minimally invasive techniques are increasingly common in cancer surgery. A recent randomized clinical trial has brought into question the safety of minimally invasive radical hysterectomy for cervical cancer.
OBJECTIVE
To quantify the risk of recurrence and death associated with minimally invasive vs open radical hysterectomy for early-stage cervical cancer reported in observational studies optimized to control for confounding.
DATA SOURCES
Ovid MEDLINE, Ovid Embase, PubMed, Scopus, and Web of Science (inception to March 26, 2020) performed in an academic medical setting.
STUDY SELECTION
In this systematic review and meta-analysis, observational studies were abstracted that used survival analyses to compare outcomes after minimally invasive (laparoscopic or robot-assisted) and open radical hysterectomy in patients with early-stage (International Federation of Gynecology and Obstetrics 2009 stage IA1-IIA) cervical cancer. Study quality was assessed with the Newcastle-Ottawa Scale and included studies with scores of at least 7 points that controlled for confounding by tumor size or stage.
DATA EXTRACTION AND SYNTHESIS
The Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist was used to abstract data independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between surgical approach and oncologic outcomes.
MAIN OUTCOMES AND MEASURES
Risk of recurrence or death and risk of all-cause mortality.
RESULTS
Forty-nine studies were identified, of which 15 were included in the meta-analysis. Of 9499 patients who underwent radical hysterectomy, 49% (n = 4684) received minimally invasive surgery; of these, 57% (n = 2675) received robot-assisted laparoscopy. There were 530 recurrences and 451 deaths reported. The pooled hazard of recurrence or death was 71% higher among patients who underwent minimally invasive radical hysterectomy compared with those who underwent open surgery (hazard ratio [HR], 1.71; 95% CI, 1.36-2.15; P < .001), and the hazard of death was 56% higher (HR, 1.56; 95% CI, 1.16-2.11; P = .004). Heterogeneity of associations was low to moderate. No association was found between the prevalence of robot-assisted surgery and the magnitude of association between minimally invasive radical hysterectomy and hazard of recurrence or death (2.0% increase in the HR for each 10-percentage point increase in prevalence of robot-assisted surgery [95% CI, -3.4% to 7.7%]) or all-cause mortality (3.7% increase in the HR for each 10-percentage point increase in prevalence of robot-assisted surgery [95% CI, -4.5% to 12.6%]).
CONCLUSIONS AND RELEVANCE
This systematic review and meta-analysis of observational studies found that among patients undergoing radical hysterectomy for early-stage cervical cancer, minimally invasive radical hysterectomy was associated with an elevated risk of recurrence and death compared with open surgery.
Topics: Female; Humans; Hysterectomy; Minimally Invasive Surgical Procedures; Observational Studies as Topic; Survival Analysis; Uterine Cervical Neoplasms
PubMed: 32525511
DOI: 10.1001/jamaoncol.2020.1694 -
BMC Cancer May 2018Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for...
BACKGROUND
Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials.
METHODS
We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC.
RESULTS
Three thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports.
CONCLUSION
NECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cervix Uteri; Chemoradiotherapy, Adjuvant; Clinical Trials as Topic; Female; Humans; Hysterectomy; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Survival Rate; Treatment Outcome; Uterine Cervical Neoplasms
PubMed: 29728073
DOI: 10.1186/s12885-018-4447-x -
The Lancet. Oncology Aug 2022The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear.... (Meta-Analysis)
Meta-Analysis
Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis.
BACKGROUND
The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques.
METHODS
In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508.
FINDINGS
7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44-0·79] and CKC: 0·63 [0·50-0·81]) and increased for laser ablation (1·69 [1·27-2·24]) and cryotherapy (1·84 [1·33-2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68-1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70-3·02]; laser conisation: 1·77 [1·29-2·43]; and LLETZ: 1·37 [1·16-1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78-1·41]; cryotherapy: 1·01 [0·35-2·92]; and cold coagulation: 0·67 [0·02-29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low.
INTERPRETATION
More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning.
FUNDING
National Institute for Health and Care Research: Research for Patient Benefit.
Topics: Conization; Female; Humans; Infant, Newborn; Network Meta-Analysis; Premature Birth; Uterine Cervical Neoplasms; Uterine Cervical Dysplasia
PubMed: 35835138
DOI: 10.1016/S1470-2045(22)00334-5 -
Cellular Physiology and Biochemistry :... 2016Radical hysterectomy (RH) for the treatment of cervical cancer frequently caused pelvic organ dysfunctions. This study aimed to compare the results of pelvic organ... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND/AIMS
Radical hysterectomy (RH) for the treatment of cervical cancer frequently caused pelvic organ dysfunctions. This study aimed to compare the results of pelvic organ function and recurrence rate after Nerve sparing radical hysterectomy (NSRH) and RH treatment through systematic review and meta-analysis.
METHODS
PubMed, Web of Science and China Knowledge Resource Integrated Database were searched from inception to 25 February 2015. Studies of cervical cancer which reported radical hysterectomy or nerve sparing radical hysterectomy were included. The quality of included studies was evaluated using the guidelines of Cochrane Handbook for Systematic Reviews of Interventions. Statistical analysis was performed using Review Manager 5.3 software (Cochrane Collaboration).
RESULTS
A total of 20 studies were finally included. Meta-analysis demonstrated that NSRH was associated with less bladder and anorectal dysfunction than RH. The time to bladder and anorectal function recovery after NSRH was shorter than RH. Patients undergoing NSRH also scored higher than patients undergoing RH at Female Sexual Function Index (FSFI). On the other hand, the local recurrence and overall recurrence rate were similar between NSRH and RH.
CONCLUSION
NSRH may be an effective technique for lowering pelvic organ dysfunction and improving the function recovery without increasing the recurrence rate of cervical cancer.
Topics: Databases, Factual; Female; Humans; Hysterectomy; Neoplasm Recurrence, Local; Odds Ratio; Sexual Dysfunction, Physiological; Urinary Bladder; Uterine Cervical Neoplasms
PubMed: 27160267
DOI: 10.1159/000443122 -
European Journal of Surgical Oncology :... Apr 2024This systematic review (SR) and meta-analysis aims to compare the surgery-related results and oncological outcomes between SH and RH in patients with early-stage... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This systematic review (SR) and meta-analysis aims to compare the surgery-related results and oncological outcomes between SH and RH in patients with early-stage cervical cancer.
METHOD
We systematically searched databases including PubMed, Embase and Cochrane to collect studies that compared oncological and surgery-related outcomes between SH and RH groups in patients with stage IA2 and IB1 cervical cancer. A random-effect model calculated the weighted average difference of each primary outcome via Review Manager V.5.4.
RESULT
Seven studies comprising 6977 patients were included into our study. For oncological outcomes, we found no statistical difference in recurrence rate [OR = 0.88; 95% CI (0.50, 1.57); P = 0.68] and Overall Survival (OS) [OR = 1.23; 95% CI (0.69, 2.19), P = 0.48]. No difference was detected in the prevalence of positive LVSI and lymph nodes metastasis between the two groups. Concerning surgery-related outcomes, the comprehensive effects revealed that the bladder injury [OR = 0.28; 95% CI (0.08, 0.94), P = 0.04] and bladder disfunction [OR = 0.10; 95% CI (0.02, 0.53), P = 0.007] of the RH group were higher compared to the SH group.
CONCLUSION
This meta-analysis suggested there are no significant differences in terms of both recurrence rate and overall survival among patients with stage IA2-IB1 cervical cancer undergoing SH or RH, while the SH group has better surgery-related outcomes. These data confirm the need to narrow the indication for RH in early-stage cervical cancer.
Topics: Female; Humans; Disease-Free Survival; Uterine Cervical Neoplasms; Neoplasm Staging; Hysterectomy; Neoplasm Recurrence, Local; Retrospective Studies
PubMed: 38471373
DOI: 10.1016/j.ejso.2024.108252 -
BMJ Clinical Evidence Jul 2011Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme, to the current... (Review)
Review
INTRODUCTION
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme, to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5-15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent cervical cancer? What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: human papillomavirus (HPV) vaccine for preventing cervical cancer; conisation of the cervix for microinvasive carcinoma (stage Ia1), conisation of the cervix plus lymphadenectomy (stage Ia2 and low-volume, good prognostic factor stage Ib), radical trachelectomy for low-volume stage Ib disease, neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of hysterectomy versus each other for treating early-stage and bulky early-stage cervical cancer.
Topics: Acute Disease; Chemoradiotherapy; Disease-Free Survival; Humans; Hysterectomy; Incidence; Papillomavirus Vaccines; Uterine Cervical Neoplasms
PubMed: 21791123
DOI: No ID Found -
Archives of Gynecology and Obstetrics Sep 2021Radical hysterectomy with pelvic lymphadenectomy presents the standard treatment for early cervical cancer. Recently, studies have shown a superior oncological outcome... (Meta-Analysis)
Meta-Analysis Review
Protective operative techniques in radical hysterectomy in early cervical carcinoma and their influence on disease-free and overall survival: a systematic review and meta-analysis of risk groups.
PURPOSE
Radical hysterectomy with pelvic lymphadenectomy presents the standard treatment for early cervical cancer. Recently, studies have shown a superior oncological outcome for open versus minimal invasive surgery, however, the reasons remain to be speculated. This meta-analysis evaluates the outcomes of robotic and laparoscopic hysterectomy compared to open hysterectomy. Risk groups including the use of uterine manipulators or colpotomy were created.
METHODS
Ovid-Medline and Embase databases were systematically searched in June 2020. No limitation in date of publication or country was made. Subgroup analyses were performed regarding the surgical approach and the endpoints OS and DFS.
RESULTS
30 studies fulfilled the inclusion criteria. Five prospective, randomized-control trials were included. Patients were analyzed concerning the surgical approach [open surgery (AH), laparoscopic surgery (LH), robotic surgery (RH)]. Additionally, three subgroups were created from the LH group: the LH high-risk group (manipulator), intermediate-risk group (no manipulator, intracorporal colpotomy) and LH low-risk group (no manipulator, vaginal colpotomy). Regarding OS, the meta-analysis showed inferiority of LH in total over AH (0.97 [0.96; 0.98]). The OS was significantly higher in LH low risk (0.96 [0.94; 0.98) compared to LH intermediate risk (0.93 [0.91; 0.94]). OS rates were comparable in AH and LH Low-risk group. DFS was higher in the AH group compared to the LH group in general (0.92 [95%-CI 0.88; 0.95] vs. 0.87 [0.82; 0.91]), whereas the application of protective measures (no uterine manipulator in combination with vaginal colpotomy) was associated with increased DFS in laparoscopy (0.91 [0.91; 0.95]).
CONCLUSION
DFS and OS in laparoscopy appear to be depending on surgical technique. Protective operating techniques in laparoscopy result in improved minimal invasive survival.
Topics: Carcinoma, Squamous Cell; Colpotomy; Early Detection of Cancer; Female; Humans; Hysterectomy; Laparoscopy; Minimally Invasive Surgical Procedures; Pregnancy; Uterine Cervical Neoplasms
PubMed: 34021804
DOI: 10.1007/s00404-021-06082-y -
Archives of Gynecology and Obstetrics Aug 2022Radical hysterectomy and pelvic lymphadenectomy is the standard treatment for early cervical cancer. Studies have shown superior oncological outcome for open versus... (Meta-Analysis)
Meta-Analysis Review
Perioperative morbidity of different operative approaches in early cervical carcinoma: a systematic review and meta-analysis comparing minimally invasive versus open radical hysterectomy.
PURPOSE
Radical hysterectomy and pelvic lymphadenectomy is the standard treatment for early cervical cancer. Studies have shown superior oncological outcome for open versus minimal invasive surgery, but peri- and postoperative complication rates were shown vice versa. This meta-analysis evaluates the peri- and postoperative morbidities and complications of robotic and laparoscopic radical hysterectomy compared to open surgery.
METHODS
Embase and Ovid-Medline databases were systematically searched in June 2020 for studies comparing robotic, laparoscopic and open radical hysterectomy. There was no limitation in publication year. Inclusion criteria were set analogue to the LACC trial. Subgroup analyses were performed regarding the operative technique, the study design and the date of publication for the endpoints intra- and postoperative morbidity, estimated blood loss, hospital stay and operation time.
RESULTS
27 studies fulfilled the inclusion criteria. Five prospective, randomized-control trials were included. Meta-analysis showed no significant difference between robotic radical hysterectomy (RH) and laparoscopic hysterectomy (LH) concerning intra- and perioperative complications. Operation time was longer in both RH (mean difference 44.79 min [95% CI 38.16; 51.42]), and LH (mean difference 20.96 min; [95% CI - 1.30; 43.22]) than in open hysterectomy (AH) but did not lead to a rise of intra- and postoperative complications. Intraoperative morbidity was lower in LH than in AH (RR 0.90 [0.80; 1.02]) as well as in RH compared to AH (0.54 [0.33; 0.88]). Intraoperative morbidity showed no difference between LH and RH (RR 1.29 [0.23; 7.29]). Postoperative morbidity was not different in any approach. Estimated blood loss was lower in both LH (mean difference - 114.34 [- 122.97; - 105.71]) and RH (mean difference - 287.14 [- 392.99; - 181.28]) compared to AH, respectively. Duration of hospital stay was shorter for LH (mean difference - 3.06 [- 3.28; - 2.83]) and RH (mean difference - 3.77 [- 5.10; - 2.44]) compared to AH.
CONCLUSION
Minimally invasive radical hysterectomy appears to be associated with reduced intraoperative morbidity and blood loss and improved reconvalescence after surgery. Besides oncological and surgical factors these results should be considered when counseling patients for radical hysterectomy and underscore the need for new randomized trials.
Topics: Female; Humans; Hysterectomy; Laparoscopy; Morbidity; Postoperative Complications; Prospective Studies; Robotic Surgical Procedures; Uterine Cervical Neoplasms
PubMed: 34625835
DOI: 10.1007/s00404-021-06248-8 -
PloS One 2014Nerve-sparing radical hysterectomy (NSRH) may be associated with lower postoperative morbidity than radical hysterectomy (RH). We aimed to compare the clinical efficacy... (Meta-Analysis)
Meta-Analysis Review
BACKGROUD AND OBJECTIVE
Nerve-sparing radical hysterectomy (NSRH) may be associated with lower postoperative morbidity than radical hysterectomy (RH). We aimed to compare the clinical efficacy and safety of abdominal or laparoscopic NSRH and RH for treating cervical cancer through systematic review and meta-analysis.
METHODS
PubMed, EMBASE, The Cochrane Library and the Chinese National Knowledge Infrastructure databases were systematically searched for all relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to compare intra- and postoperative outcomes for the two techniques.
RESULTS
A total of 17 clinical trials were identified. Meta-analysis showed that although operating time was significantly longer for abdominal or laparoscopic NSRH than for RH, NSRH based on laparotomy or laparoscopy proved more effective for postoperative recovery of bladder function. NSRH was also associated with lower bladder dysfunction morbidity and fewer postoperative complications. Two abdominal trials and one laparoscopic study further suggested that NSRH was associated with shorter time to recovery of anal/rectal function. In contrast, RH and NSRH based on laparotomy or laparoscopy were similar in terms of extent of resection, recurrence rate, survival rate, blood loss and frequency of intraoperative complications. The meta-analysis showed that abdominal NSRH was not significantly different from RH in length of hospital stay, while one trial suggested that length of hospital stay was shorter after laparoscopic NSRH than after the corresponding RH.
CONCLUSION
NSRH may be a reliable technique for treating early cervical cancer. Available evidence suggests that it is better than RH for postoperative recovery of pelvic organ function and postoperative morbidity, while the two techniques involve similar clinical safety and extent of resection. These results should be considered preliminary since they are based on a relatively small number of controlled trials, most of which were non-randomized. The findings should be verified in larger, well-designed studies.
Topics: Female; Humans; Hysterectomy; Nervous System; Organ Sparing Treatments; Safety; Uterine Cervical Neoplasms
PubMed: 24748015
DOI: 10.1371/journal.pone.0094116 -
Frontiers in Oncology 2022To compare cervical cancer recurrence and patient survival after radical hysterectomy followed by either adjuvant chemotherapy (AC) or adjuvant radiotherapy with or...
Cervical Cancer Recurrence and Patient Survival After Radical Hysterectomy Followed by Either Adjuvant Chemotherapy or Adjuvant Radiotherapy With Optional Concurrent Chemotherapy: A Systematic Review and Meta-Analysis.
OBJECTIVE
To compare cervical cancer recurrence and patient survival after radical hysterectomy followed by either adjuvant chemotherapy (AC) or adjuvant radiotherapy with or without concurrent chemotherapy (AR/CCRT).
METHODS
We systematically searched PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov to identify studies reporting recurrence or survival of cervical cancer patients who received AC or AR/CCRT after radical hysterectomy. Data were meta-analyzed using a random-effects model, and heterogeneity was evaluated using the test. Subgroup and sensitivity analyses were performed to identify potential sources of heterogeneity.
RESULTS
The meta-analysis included 14 non-randomized studies and two randomized controlled trials, altogether involving 5,052 cervical cancer patients. AC and AR/CCRT groups did not differ significantly in rates of total or local recurrence or mortality. Nevertheless, AC was associated with significantly lower risk of distant recurrence [odds ratio (OR) 0.67, 95% confidence interval (CI) 0.55-0.81] and higher rates of overall survival [hazard ratio (HR) 0.69, 95%CI 0.54-0.85] and disease-free survival rate (HR 0.77, 95%CI 0.62-0.92).
CONCLUSIONS
AC may be an effective alternative to AR/CCRT for cervical cancer patients after radical hysterectomy, especially younger women who wish to preserve their ovaries and protect them from radiation damage.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021252518).
PubMed: 35311123
DOI: 10.3389/fonc.2022.823064