Systemic review of the robustness of randomized controlled trials for the treatment of cholangiocarcinoma in three domains: survival-inferred fragility index, restricted mean survival time, and the spin effect

Background:The vast majority of patients with cholangiocarcinoma(CC)have advanced disease at diagnosis and are candidates for palliative treatment only.The robustness of the randomized controlled trials regarding the treatment of CC are assessed.Methods:A systematic review of all randomized control trials(RCT)of treatments for both intra-and extrahepatic CC between 2010 and 2020 was performed.The survival-inferred fragility index(SIFI;the minimum number of reassignments of the best survivors between arms that would overturn the statistical outcomes)was calculated.In addition,the gain,or loss,in survival in RCTs was evaluated by the restricted mean survival time(RMST)difference.Finally,the level of spin i.e.,misrepresentation of study outcomes,was measured in inconclusive studies to assess distorted reporting strategies.Results:Out of 6,167 studies retrieved,11 could be retained for full text revision(7 with both intra-and extrahepatic CC,3 with peri-hilar CC,and 1 with peri-hilar or distal CC).Only 3 studies included resected patients(2 with both intra-and extrahepatic CC and 1 with peri-hilar or distal CC).Nine studies investigated systemic chemotherapy(including 3 after surgical resection),one study evaluated photodynamic therapy,and another investigated the use of an endoscopically inserted stent in the biliary tract.The median SIFI was−2[interquartile range(IQR):−6.25,−0.25]across all studies.Overall,the median RMST difference was 0.56 months(IQR:0.10,0.95).Finally,for inconclusive studies,the level of spin was high,moderate,and low in respectively 12.5%,25%,and 62.5% of the studies.Conclusions:RCTs of CC showed a low degree of robustness with a frequent proportion of associated spin.

Is there utility for fluorine-18-fluorodeoxyglucose positron-emission tomography scan before surgery in breast cancer? A 15-year overall survival analysis

BACKGROUND The prognostic value of preoperative fluorine-18-fluorodeoxyglucose positronemission tomography(18 F-FDG PET)scan for determining overall survival(OS)in breast cancer(BC)patients is controversial.AIM To evaluate the OS predictive value of preoperative PET positivity after 15 years.METHODS We performed a retrospective search of the Universitair Ziekenhuis Brussel patient database for nonmetastatic patients who underwent preoperative PET between 2002-2008.PET positivity was determined by anatomical region of interest(AROI)findings for breast and axillary,sternal,and distant sites.The prognostic role of PET was examined as a qualitative binary factor(positive vs negative status)and as a continuous variable[maximum standard uptake value(SUVmax)]in multivariate survival analyses using Cox proportional hazards models.Among the 104 identified patients who received PET,36 were further analyzed for the SUVmax in the AROI.RESULTS Poor OS within the 15-year study period was predicted by PET-positive status for axillary(P=0.033),sternal(P=0.033),and combined PET-axillary/sternal(P=0.008)nodes.Poor disease-free survival was associated with PET-positive axillary status(P=0.040)and combined axillary/sternal status(P=0.023).Cox models confirmed the long-term prognostic value of combined PETaxillary/sternal status[hazard ratio(HR):3.08,95%confidence interval:1.42-6.69].SUVmax of ipsilateral breast and axilla as continuous covariates were significant predictors of long-term OS with HRs of 1.25(P=0.048)and 1.54(P=0.029),corresponding to relative increase in the risk of death of 25%and 54%per SUVmax unit,respectively.In addition,the ratio of the ipsilateral axillary SUVmax over the contralateral axillary SUVmax was the most significant OS predictor(P=0.027),with 1.94 HR,indicating a two-fold relative increase of mortality risk.CONCLUSION Preoperative PET is valuable for prediction of long-term survival.Ipsilateral axillary SUVmax ratio over the uninvolved side represents a new prognostic finding that warrants further investigation.

5-Amino-4-oxopentanoic acid photodynamic diagnosis guided microsurgery and photodynamic therapy on VX2 brain tumour implanted in a rabbit model

Background Complete tumour resection is important for improving the prognosis of brain tumour patients. However, extensive resection remains controversial because the tumour margin is difficult to be distinguished from surrounding brain tissue. It has been established that 5-amino-4-0xopentanoic acid （5-aminolevulinic acid, ALA） can be used as a photodynamic diagnostic marker and a photosensitizer for photodynamic therapy in surgical treatment of brain tumours. We investigated the efficacy of ALA photodynamically guided microsurgery and photodynamic therapy on VX2 brain tumour implanted in a rabbit model. Methods Eighty New Zealand rabbits implanted with VX2 brain tumours were randomly assigned to five groups： control, conventional white light microsurgery, a photodynamic therapy group, a photodynamically guided microsurgery group and a group in which guided microsurgery was followed by photodynamic therapy. The VX2 tumour was resected under a surgical microscope. The tumour resection was confirmed with histological analysis. All animals were examined with MRI for presence of any residual tumour tissue. The survival time of each rabbit was recorded. Results All treatment groups showed a significantly extended survival time compared with the control group. Photodynamically guided microsurgery combined with photodynamic therapy significantly prolonged survival time, compared with guided microsurgery alone. MRI and the autopsy results confirmed removal of most of the tumours. Conclusions Our results suggest that photodynamically guided surgery and photodynamic therapy significantly reduce or delay local recurrence, increase the effectiveness of radical resection and prolong the survival time of tumour bearing rabbits. Their combination has the potential to be used as a rapid and highly effective treatment of metastatic brain tumours.