Multidisciplinary Management of Adult Patients with Chylothorax: A Consensus Statement.

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and 4 specialties (Pulmonary, Interventional Radiology, Thoracic Surgery & Nutrition) with experience and expertise in managing adult patients with chylothorax. We performed a literature and internet search for reports addressing 7 clinically relevant questions pertaining to the management of adult patients with chylothorax. This consensus statement, consisting of best practice statements based on expert consensus addressing these 7 PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience. Panel members participated in the development of the final best practice statements using the modified Delphi technique. Our consensus statement aims to offer guidance in clinical decision making when managing patients with chylothorax while also identifying gaps in knowledge and inform future research.

Leveraging the pleural space for anticancer therapies in pleural mesothelioma.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

Joint ERS/EACTS/ESTS clinical practice guidelines on adults with spontaneous pneumothorax.

OBJECTIVES: The optimal management for spontaneous pneumothorax (SP) remains contentious, with various proposed approaches. This joint clinical practice guideline from the ERS, EACTS and ESTS societies provides evidence-based recommendations for the management of SP. METHODS: This multidisciplinary Task Force addressed 12 key clinical questions on the management of pneumothorax, using ERS methodology for guideline development. Systematic searches were performed in MEDLINE and Embase. Evidence was synthesised by conducting meta-analyses, if possible, or narratively. Certainty of evidence was rated with GRADE (Grading, Recommendation, Assessment, Development and Evaluation). The Evidence to Decision framework was used to decide on the direction and strength of the recommendations. RESULTS: The panel makes a conditional recommendation for conservative care of minimally symptomatic patients with primary spontaneous pneumothorax (PSP) who are clinically stable. We make a strong recommendation for needle aspiration over chest tube drain for initial PSP treatment. We make a conditional recommendation for ambulatory management for initial PSP treatment. We make a conditional recommendation for early surgical intervention for the initial treatment of PSP in patients who prioritise recurrence prevention. The panel makes a conditional recommendation for autologous blood patch in secondary SP patients with persistent air leak (PAL). The panel could not make recommendations for other interventions, including bronchial valves, suction, pleurodesis in addition to surgical resection or type of surgical pleurodesis. CONCLUSIONS: With this international guideline, the ERS, EACTS and ESTS societies provide clinical practice recommendations for SP management. We highlight evidence gaps for the management of PAL and recurrence prevention, with research recommendations made. SHAREABLE ABSTRACT: This update of an ERS Task Force statement from 2015 provides a concise comprehensive update of the literature base. 24 evidence-based recommendations were made for management of pneumothorax, balancing clinical priorities and patient views.https://bit.ly/3TKGp9e.

Australasian Malignant PLeural Effusion (AMPLE)-4 trial: study protocol for a multi-centre randomised trial of topical antibiotics prophylaxis for infections of indwelling pleural catheters.

BACKGROUND: Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis (vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC. METHODS: A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants. DISCUSSION: Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections. ETHICS AND DISSEMINATION: Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.

Topical antibiotics prophylaxis for infections of indwelling pleural/peritoneal catheters (TAP-IPC): A pilot study.

BACKGROUND AND OBJECTIVE: Indwelling pleural catheter (IPC) and indwelling peritoneal catheter (IPeC) have established roles in the management of malignant pleural and peritoneal effusions but catheter-related infections remain a major concern. Topical mupirocin prophylaxis has been shown to reduce peritoneal dialysis catheter infections. This study aimed to assess the (i) compatibility of IPC with mupirocin and (ii) feasibility, tolerability and compliance of topical mupirocin prophylaxis in patients with an IPC or IPeC. METHODS: (i) Three preparations of mupirocin were applied onto segments of IPC thrice weekly and examined with scanning electron microscope (SEM) at different time intervals. (ii) Consecutive patients fitted with IPC or IPeC were given topical mupirocin prophylaxis to apply to the catheter exit-site following every drainage/dressing change (at least twice weekly) and followed up for 6 months. RESULTS: (i) No detectable structural catheter damage was found with mupirocin applied for up to 6 months. (ii) Fifty indwelling catheters were inserted in 48 patients for malignant pleural (n = 41) and peritoneal (n = 9) effusions. Median follow-up was 121 [median, IQR 19-181] days. All patients tolerated mupirocin well; one patient reported short-term local tenderness. Compliance was excellent with 95.8% of the 989 scheduled doses delivered. Six patients developed catheter-related pleural (n = 3), concurrent peritoneal/local (n = 1) and skin/tract (n = 2) infections from Streptococcus mitis (with Bacillus species or anaerobes), Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa. CONCLUSION: This first study of long-term prevention of IPC- or IPeC-related infections found topical mupirocin prophylaxis feasible and well tolerated. Its efficacy warrants future randomized studies.

The impact of outpatient versus inpatient management on health-related quality of life outcomes for patients with malignant pleural effusion: the OPTIMUM randomised clinical trial.

BACKGROUND: The principal aim of malignant pleural effusion (MPE) management is to improve health-related quality of life (HRQoL) and symptoms. METHODS: In this open-label randomised controlled trial, patients with symptomatic MPE were randomly assigned to either indwelling pleural catheter (IPC) insertion with the option of talc pleurodesis or chest drain and talc pleurodesis. The primary end-point was global health status, measured with the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) at 30 days post-intervention. 142 participants were enrolled from July 2015 to December 2019. RESULTS: Of participants randomly assigned to the IPC (n=70) and chest drain (n=72) groups, primary outcome data were available in 58 and 56 patients, respectively. Global health status improved in both groups at day 30 compared with baseline: IPC (mean difference 13.11; p=0.001) and chest drain (mean difference 10.11; p=0.001). However, there was no significant between-group difference at day 30 (mean intergroup difference in baseline-adjusted global health status 2.06, 95% CI -5.86-9.99; p=0.61), day 60 or day 90. No significant differences were identified between groups in breathlessness and chest pain scores. All chest drain arm patients were admitted (median length of stay 4 days); seven patients in the IPC arm required intervention-related hospitalisation. CONCLUSIONS: While HRQoL significantly improved in both groups, there were no differences in patient-reported global health status at 30 days. The outpatient pathway using an IPC was not superior to inpatient treatment with a chest drain.

Intrapleural therapy for pleural infection from bronchopleural fistula in an adult with hyper-IgE syndrome.

We presented the case of an adult patient with hyper-IgE syndrome (HIES) who was admitted acutely with a large hydropneumothorax from lung consolidation, a bronchopleural fistula and pleural infection. He has had recurrent pulmonary and skin infections since childhood and longstanding pneumatoceles. He was treated with systemic antibiotics and chest tube drainage. Administration of two doses of low-dose intrapleural therapy (1 mg tissue plasminogen activator and 5 mg deoxyribonuclease) allowed complete evacuation of his residual loculated pleural fluid, aided resolution of his infection without provoking a significant air leak and avoided the need for surgery.

Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma.

Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples. Invasive pleural tumours were characterised by a transcriptomic signature enriched for genes associated with MEF2C and MYOCD signaling, muscle differentiation and myogenesis. Further analysis using the CMap and LINCS databases identified geldanamycin as a potential antagonist of this signature, so we evaluated its potential in vitro and in vivo. Nanomolar concentrations of geldanamycin significantly reduced cell growth, invasion, and migration in vitro. However, administration of geldanamycin in vivo did not result in significant anti-cancer activity. Our findings show that myogenesis and muscle differentiation pathways are upregulated in pleural mesothelioma which may be related to the invasive behaviour. However, geldanamycin as a single agent does not appear to be a viable treatment for mesothelioma.

Indwelling Pleural Catheter: Management of Complications.

Multiple randomized clinical trials have established the advantages of indwelling pleural catheter (IPC) in the management of malignant pleural effusions, resulting in its widespread adoption in clinical practice. Complications can occur with IPC use and must be recognized and managed effectively. This review provides a comprehensive overview of IPC complications and their best care. Pain postinsertion or during drainage of IPC is easily manageable and must be distinguished from tumor-related chest wall pain. IPC-related infections require systemic antibiotics and often intrapleural fibrinolytic/deoxyribonuclease therapy. The removal of IPC for infection is usually unnecessary. Symptomatic loculation usually responds to fibrinolytics but may recur. Catheter tract metastases are common in mesothelioma patients and usually respond to radiotherapy without inducing damages to the IPC. Less common complications include dislodgement, irreversible blockage, and fractures (upon removal) of the catheter. Recommendations on the management of IPC complications by recent consensus statement/guideline are discussed. Expert opinions on management approaches are included in areas where evidence is lacking to guide care.

A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.

Antibiotic administration via indwelling peritoneal catheter to treat infected malignant ascites.

Indwelling pleural catheter is an established management for malignant pleural effusions. Extending its use to patients with malignant ascites by insertion of a catheter intraperitoneally enables regular outpatient drainage and improves quality-of-life. However, indwelling pleural/peritoneal catheter (IPC/IPeC) is associated with catheter-related infections, traditionally managed with systemic antibiotics and occasionally requires catheter removal. Direct administration of antibiotics intra-abdominally via peritoneal dialysis (PD) catheters is a well-established, efficacious practice in PD-related peritonitis and minimizes systemic adverse effects. We applied the same principles to a patient with peritoneal mesothelioma who developed peritonitis 3 weeks after insertion of IPeC. Intraperitoneal vancomycin was administered via, and compatible with, the IPeC. The patient tolerated the treatment without adverse effects and made a full recovery without requiring catheter removal.

Australasian Malignant PLeural Effusion (AMPLE)-3 trial: study protocol for a multi-centre randomised study comparing indwelling pleural catheter (±talc pleurodesis) versus video-assisted thoracoscopic surgery for management of malignant pleural effusion.

INTRODUCTION: Malignant pleural effusions (MPEs) are common. MPE causes significant breathlessness and impairs quality of life. Indwelling pleural catheters (IPC) allow ambulatory drainage and reduce hospital days and re-intervention rates when compared to standard talc slurry pleurodesis. Daily drainage accelerates pleurodesis, and talc instillation via the IPC has been proven feasible and safe. Surgical pleurodesis via video-assisted thoracoscopic surgery (VATS) is considered a one-off intervention for MPE and is often recommended to patients who are fit for surgery. The AMPLE-3 trial is the first randomised trial to compare IPC (±talc pleurodesis) and VATS pleurodesis in those who are fit for surgery. METHODS AND ANALYSIS: A multi-centre, open-labelled randomised trial of patients with symptomatic MPE, expected survival of ≥ 6 months and good performance status randomised 1:1 to either IPC or VATS pleurodesis. Participant randomisation will be minimised for (i) cancer type (mesothelioma vs non-mesothelioma); (ii) previous pleurodesis (vs not); and (iii) trapped lung, if known (vs not). Primary outcome is the need for further ipsilateral pleural interventions over 12 months or until death, if sooner. Secondary outcomes include days in hospital, quality of life (QoL) measures, physical activity levels, safety profile, health economics, adverse events, and survival. The trial will recruit 158 participants who will be followed up for 12 months. ETHICS AND DISSEMINATION: Sir Charles Gairdner and Osborne Park Health Care Group (HREC) has approved the study (reference: RGS356). Results will be published in peer-reviewed journals and presented at scientific meetings. DISCUSSION: Both IPC and VATS are commonly used procedures for MPE. The AMPLE-3 trial will provide data to help define the merits and shortcomings of these procedures and inform future clinical care algorithms. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12618001013257 . Registered on 18 June 2018. PROTOCOL VERSION: Version 3.00/4.02.19.

Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials. METHODS: We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study. This was combined with RNA-seq analysis to characterize the tumour immune environment. RESULTS: The comprehensive genome analysis identified 12 driver genes, including new candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed SBS5/40 were dominant in 93% of samples, and defects in homologous recombination repair were infrequent in our cohort. The tumour immune environment contained high M2 macrophage infiltrate linked with MMP2, MMP14, TGFB1 and CCL2 expression, representing an immune suppressive environment. The expression of TGFB1 was associated with overall survival. A small subset of samples (less than 10%) had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a 'hot' immune environment independent of the somatic mutations. CONCLUSIONS: We propose accounting for genomic and immune microenvironment status may influence therapeutic planning in the future.

GCIG-Consensus guideline for Long-term survivorship in gynecologic Cancer: A position paper from the gynecologic cancer Intergroup (GCIG) symptom benefit committee.

INTRODUCTION: Long-term survivors of gynecological cancers may be cured but still have ongoing health concerns and long-term side effects following cancer treatment. The aim of this brainstorming meeting was to develop recommendations for long-term follow-up for survivors from gynecologic cancer. METHODS: International experts, representing each member group within the Gynecologic Cancer InterGroup (GCIG), met to define long-term survival, propose guidelines for long term follow-up and propose ways to implement long term survivorship follow-up in clinical trials involving gynecological cancers. RESULTS: Long-term survival with/from gynecological cancers was defined as survival of at least five years from diagnosis, irrespective of disease recurrences. Review of the literature showed that more than 50% of cancer survivors with gynecological cancer still experienced health concerns/long-term side effects. Main side effects included neurologic symptoms, sleep disturbance, fatigue, sexual dysfunction, bowel and urinary problems and lymphedema. In this article, long-term side effects are discussed in detail and treatment options are proposed. Screening for second primary cancers and lifestyle counselling (nutrition, physical activity, mental health) may improve quality of life and overall health status, as well as prevent cardiovascular events. Clinical trials should address cancer survivorship and report patient reported outcome measures (PROMs) for cancer survivors. CONCLUSION: Long-term survivors after gynecological cancer have unique longer term challenges that need to be addressed systematically by care givers. Follow-up after completing treatment for primary gynecological cancer should be offered lifelong. Survivorship care plans may help to summarize cancer history, long-term side effects and to give information on health promotion and prevention.

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy. METHODS: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234). RESULTS: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01). CONCLUSIONS: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.

Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) Study-2: Use of 2.5 mg alteplase as a starting intrapleural dose.

BACKGROUND AND OBJECTIVE: Intrapleural tissue plasminogen activator/deoxyribonuclease (tPA/DNase) therapy is increasingly used in pleural infection. Bleeding risks and costs associated with tPA remain the clinical concerns. Our dose de-escalation series aims to establish the lowest effective dosing regimen for tPA/DNase. This study assesses the intrapleural use of 2.5 mg tPA/5 mg DNase for pleural infection. METHODS: Consecutive patients with pleural infection treated with a starting regime of 2.5 mg tPA/5 mg DNase were included from two centres in Australia and UK. Escalation of tPA dose was permitted if clinical response was inadequate. RESULTS: Sixty-nine patients (mean age 61.0 years) received intrapleural 2.5 mg tPA/5 mg DNase. Most (88.4%) were treated successfully and discharged from hospital without surgery by 90 days. Patients received a median of 5 [interquartile range [IQR] = 3-6] doses of tPA/DNase. Total amount of tPA used per patient was 12.5 mg [median, IQR = 7.5-15.0]. Seventeen patients required dose escalation of tPA; most (n = 12) for attempted drainage of distant non-communicating locule(s). Treatment success was corroborated by clearance of pleural opacities on radiographs (from median 27.0% [IQR = 17.1-44.5] to 11.0% [IQR = 6.4-23.3] of hemithorax, p < 0.0001), increased pleural fluid drainage (1.98 L [median, IQR = 1.38-2.68] over 72 h following commencement of tPA/DNase) and reduction of serum C-reactive protein level (by 45.0% [IQR = 39.3-77.0] from baseline at day 5, p < 0.0001). Two patients required surgery. Six patients with significant comorbidities (e.g., advanced cancer) had ongoing infection when palliated and died. Two patients experienced self-limiting pleural bleeding and received blood transfusion. CONCLUSION: A starting intrapleural regime of 2.5 mg tPA/5 mg DNase, with up-titration if needed, can be effective and deserves further exploration.

Living with mesothelioma: A systematic review of patient and caregiver psychosocial support needs.

OBJECTIVE: Practice guidelines emphasize the importance of investigating psychosocial distress in mesothelioma patients and family caregivers. We aimed to synthesize research on the psychosocial support needs of mesothelioma patients and their family caregivers. METHODS: We conducted a systematic review with a narrative synthesis and quality assessment. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: MEDLINE, EMBASE, Scopus, PsychArticles, and PsycINFO were searched until December 2020 and 37 studies in English met inclusion criteria. Most (n = 24) included mesothelioma patients as a very small proportion of their cancer samples. A narrative synthesis was conducted on the 13 studies including only mesothelioma patients (n = 297) and/or caregivers (n = 82). Patients and caregivers want improvements in the diagnosis delivery and access to palliative care. Patients want emotional support, patient-centered treatment, improved information about illness progression and death, and to meet others with mesothelioma. Caregivers want one-on-one practical and emotional support. Study quality varied. CONCLUSIONS: Few studies focus on the psychosocial support needs relevant to mesothelioma. Mesothelioma patients and family caregivers highlight targeted psychosocial care as an unmet need. PRACTICE IMPLICATIONS: Efforts are required to design and test psychosocial interventions for this vulnerable and overlooked group. PROTOCOL REGISTRATION: PROSPERO (registration number CRD42020167852).

Risk assessment of malignant transformation of oral leukoplakia in patients with previous oral squamous cell carcinoma.

The aim of this study was to identify the risk factors associated with developing oral squamous cell carcinoma (OSCC) from surgically excised oral leukoplakia (OL) in patients with previous oral cavity cancer. Clinicopathological data of 84 patients who were treated for OL between July 2002 and July 2020 and who had previously received treatment for OSCC were reviewed retrospectively. The follow-up time ranged from 0.69 to 17.99 years (mean 6.78 ± 4.25 years). The overall cumulative malignant transformation rate was 25% and the annual transformation rate was 5.73%. Kaplan-Meier survival analysis and the log-rank test showed that Candida infection (P = 0.010) was a risk factor associated with malignant transformation. In the multivariate Cox regression analysis, tongue and floor of the mouth as the location of the leukoplakia (P = 0.039), multifocal lesions of OL (P = 0.047), and Candida infection (P = 0.018) were the three independent prognostic factors related to the development of OSCC from the treated OL. A cautious approach to OL of the tongue with Candida infection or multifocal disease in this group of patients would be appropriate.