Systematic review and simulation study of ignoring clustered data in surgical trials.

BACKGROUND: Multiple surgical procedures in a single patient are relatively common and lead to dependent (clustered) data. This dependency needs to be accounted for in study design and data analysis. A systematic review was performed to assess how clustered data were handled in inguinal hernia trials. The impact of ignoring clustered data was estimated using simulations. METHODS: PubMed, Embase and the Cochrane Library were reviewed systematically for RCTs published between 2004 and 2013, including patients undergoing unilateral or bilateral inguinal hernia repair. Study characteristics determining the appropriateness of handling clustered data were extracted. Using simulations, various statistical methods accounting for clustered data were compared with an analysis ignoring clustering by assuming 100 hernias, with a varying percentage of patients having bilateral hernias. RESULTS: Of the 50 eligible trials including patients with bilateral hernias, 20 (40 per cent) did not provide information on how they dealt with clustered data and 18 (36 per cent) avoided clustering by assessing the outcome by patient and not by hernia. None of the remaining 12 trials (24 per cent) considered clustering in the design or analysis. In the simulations, ignoring clustering led to an increased type I error rate of up to 12 per cent and to a loss in power of up to 15 per cent, depending on whether the patient or the hernia was the randomization unit. CONCLUSION: Clustering was rarely considered in inguinal hernia trials. The simulations underline the importance of considering clustering as part of the statistical analysis to avoid false-positive and false-negative results, and hence inappropriate study conclusions.

Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer.

BACKGROUND: The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated. OBJECTIVE: To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells. METHODS: IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments. RESULTS: IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival. CONCLUSIONS: Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.

Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer.

Recent studies in multiple epithelial cancers have shown that the inhibitory receptor programmed cell death 1 (PD-1) is expressed on tumor-infiltrating lymphocytes and/or programmed death ligand 1 (PD-L1) is expressed on tumor cells, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway. In addition, phase 1 clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 have shown promising results in several human cancers. The purpose of this study was to investigate the impact of PD-L1 expression in human breast cancer specimens. We conducted an immunohistochemistry study using a tissue microarray encompassing 650 evaluable formalin-fixed breast cancer cases with detailed clinical annotation and outcomes data. PD-L1 was expressed in 152 (23.4 %) of the 650 breast cancer specimens. Expression was significantly associated with age, tumor size, AJCC primary tumor classification, tumor grade, lymph node status, absence of ER expression, and high Ki-67 expression. In univariate analysis, PD-L1 expression was associated with a significantly worse OS. In multivariate analysis, PD-L1 expression remained an independent negative prognostic factor for OS. In subset analyses, expression of PD-L1 was associated with significantly worse OS in the luminal B HER2(-) subtype, the luminal B HER2(+) subtype, the HER2 subtype, and the basal-like subtype. This is the first study to demonstrate that PD-L1 expression is an independent negative prognostic factor in human breast cancer. This finding has important implications for the application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.

Octreotide prophylaxis is not beneficial for biochemical activity and clinical severity of postoperative pancreatic fistula after pancreatic surgery.

BACKGROUND: Prospective randomized trials indicate that prophylactic octreotide treatment does not decrease the incidence of postoperative pancreatic fistula (POPF). The aim of this study was to analyze if octreotide prophylaxis could decrease the severity grade of POPFs after pancreatic surgery. METHOD: Seventy-eight of 684 patients undergoing pancreatic resection with POPF were included in the study. Prophylactic octreotide treatment was started immediately after surgery and was performed in 22 patients, whereas 56 patients had no octreotide treatment and served as controls. Lipase activity was measured in the abdominal drainage on postoperative days (POD) 3, 5 and 7. Primary endpoints of the study were clinical severity of the POPF and lipase activity in the drainage. RESULTS: There was no significant difference concerning length of postoperative hospital stay. Lipase activity in the abdominal drainage was not influenced by octreotide prophylaxis at POD 5 or 7 compared to POD 3. Multivariate analysis showed that the risk to develop a type B or C fistula in the octreotide group was independent of the kind of operation and the consistency of the pancreas (RR = 3.4; CI = 1.0-11.7; p = 0.050 and RR = 6.3; CI = 1.4-29.6; p = 0.019). CONCLUSION: Octreotide prophylaxis after pancreatic surgery has no beneficial effect on clinical severity of POPF.

Nuclear expression of snail is an independent negative prognostic factor in human breast cancer.

BACKGROUND: Snail is a key regulator of epithelial-mesenchymal transition of tumor cells. Several studies have shown nuclear Snail expression to be a negative prognostic factor in human cancer, where it is generally associated with more aggressive tumor behavior and worse survival. OBJECTIVES AND METHODS: To further explore the role of Snail expression in breast cancer, we conducted a study on a tissue microarray, encompassing 1043 breast cancer cases. RESULTS: A total of 265 (25.4%) breast cancers were positive for Snail. Snail expression was significantly associated with greater tumor size, higher tumor stage and grade, positive lymph node status, and hormone receptor negative status and was differently expressed in the intrinsic subtypes of breast cancer, being the highest in the basal-like subtype and the lowest in the luminal A subtype. In multivariate analysis, Snail proved to be an independent negative prognostic factor for OS. In the intrinsic subtypes, Snail expression was a negative prognostic factor for OS in the luminal B HER2(-), the luminal B HER2(+), and the basal-like subtype. CONCLUSIONS: This is the first study demonstrating that nuclear Snail expression is an independent negative predictor of prognosis in breast cancer, thus suggesting that it may represent a potential therapeutic target.

Volume-controlled vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery: a meta-analysis.

It is unknown whether there are any clinically relevant differences between volume-controlled (<30-50 ml/24h across trials) vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery on outcomes such as seroma formation, wound infection or length of hospital stay. Randomised controlled trials comparing volume-controlled drainage vs no or short-term drainage after axillary lymph node dissection in breast cancer surgery were identified systematically using Pubmed, EMBASE and The Cochrane library. Trial data were reviewed and extracted independently by two reviewers in a standardised unblinded manner. Six randomised controlled trials which included a total of 561 patients fulfilled our inclusion criteria. Patients randomised to volume-controlled drainage were less likely to develop clinically relevant seromas compared to patients randomised to no/short-term drainage. There was, however, no difference in wound infections between patients treated with volume-controlled drainage and patients with no or short-term drainage. Patients randomised to volume-controlled drainage stayed significantly longer in hospital than patients randomised to no/short-term drainage. Based on available evidence, clinically relevant seromas occur more frequently in patients treated with no/short-term drainage. However, no/short-term drainage after axillary lymph node dissection does not lead to an increase in wound infections and is associated with shorter hospital stay.

A less invasive anterior intrapelvic approach for the treatment of acetabular fractures and pelvic ring injuries.

BACKGROUND: The ilioinguinal approach by Letournel has fundamentally contributed to the successful treatment of acetabular fractures. Since most of the present complications arise from soft tissue structures in the inguinal part, it would be desirable to avoid the surgical dissection of this region. We have therefore developed a less invasive anterior intrapelvic approach consisting of a suprapubic access combined with the lateral window of the ilioinguinal approach. METHODS: Between January 2000 and October 2002, 14 patients with acetabular fractures and 6 patients with pelvic ring injuries were consecutively operated using our technique. The patients were prospectively followed up clinically and by standard X-rays for 1 year. RESULTS: In 19 patients the technique was successful and only one patient was converted to an ilioinguinal approach due to difficulties in reducing the fracture. Our access allowed good visibility but reduction manoeuvres were sometimes difficult and the development of a new reduction forceps became necessary. Anatomical and satisfactory reduction was achieved in 13 acetabular fractures and 4 pelvic ring injuries. One cutaneous femoris neurapraxy and one superficial infection occurred related to the approach and both resolved with conservative treatment. Clinical outcome at one year was good to excellent in 17 patients (modified Merle d'Aubigné/Postel score). In 3 patients the result was fair to poor for reasons unrelated to the approach. CONCLUSIONS: Our approach permits visualisation of the entire anterior column and pelvic ring without the necessity to dissect the inguinal neurovascular structures. Our preliminary results demonstrate that safe reduction and stable fixation of selected acetabular- and pelvic ring fractures are possible.