FIT visual abstract

Guest Plain English summary: Worried about symptoms of bowel cancer? A simple stool test may help.

Kai Sheng Saw, Chen Liu, William Xu, Chris Varghese, Susan Parry, Ian Bissett

Have you ever worried if you or a loved one has bowel cancer? Bleeding from the rectum, changing bowel habits, unexplained weight loss, abdominal pain and bloating are symptoms associated with bowel cancer, warranting a visit to the doctors. However, studies have demonstrated that presence of these symptoms are poor predictors of colorectal cancer diagnosis.(1)

Currently, when these symptoms are raised with your doctor, it is very likely that the next step would be a colonoscopy or colonography. This involves clearing your bowel with bowel preparation laxatives for the test, and the discomfort of having a medical instrument inserted into one’s back passage. These colonic investigations also carry small but significant procedural risks.

The faecal immunochemical test, or FIT, is a simple and non-invasive test for patients who present to their doctors with symptoms concerning for bowel cancer. It is stool test that can reliably detect minute amounts of human blood in faeces that is not always visible to the naked eye. Most bowel cancers bleed to varying degrees into the colon and mix with faeces. FIT has been widely used in bowel cancer screening programmes but surprisingly it is only with COVID constraining access to healthcare that interest to expand its clinical use for patients with bowel cancer symptoms has taken hold.

We hypothesised that the FIT test could measure the amount of blood in faeces of patients presenting with concerning symptoms and categorise them into different colorectal cancer risk groups to help doctors determine the need for and urgency of recommending further invasive colonic investigation.

At the end of August 2021, we looked at over 9600 relevant academic publications on this topic, selected 15 high quality studies that were best designed to answer the question and combined their results for further analysis.

Our analysis showed that at the lowest possible detectable faecal blood by FIT (≥2 microgram Hb/g faeces), a positive FIT test would detect approximately 96 out of 100 colorectal cancers. In two of the largest studies conducted in the UK (2, 3), up to 63% of patients who under current standards would undergo an invasive colonic investigation because of reported symptoms, would be able to avoid one. 

When settings are adjusted to be in line with current National Institute for Health and Care Excellence (NICE) recommendations (≥10 microgram Hb/g faeces), a positive FIT test would pick up approximately 88 out of 100 colorectal cancers. If one has a negative FIT test at this setting, it is estimated that approximately only 1 in 243 patients undergoing invasive colonic investigation would have a cancer detected, meaning by contemporary practices, 242 patients would undertake the risk of a colonoscopy despite not having bowel cancer. (2,3)

Conversely, if FIT detects higher levels of blood in faeces (such as at ≥100 or ≥150 microgram Hb/g faeces), approximately 1 in 3 patients will have bowel cancer diagnosed. 

For patients with symptoms, these results indicate that when very low levels of blood are detected in stool by FIT, the chances of having bowel cancer are adequately low, hence invasive investigation may be avoided. Conversely, if relatively higher levels of blood are indicated by FIT, the probability of an existing bowel cancer is very high and urgent colonic investigation would be ideal to detect and treat the cancer as soon as possible.

No test is perfect. The currently accepted gold standard, colonoscopy, is estimated to miss 5 in 100 cancers.(4) With the correct settings, our analysis suggests that FIT approximates this diagnostic accuracy while being non-invasive, accessible and cheap.  While colonic imaging tests have an irreplaceable role in the diagnosis of bowel cancer, it may be more optimal for patients, clinicians, and health care systems to rationalise the use of colonoscopy and colonography to avoid delays in diagnosis and treatment for those who are deemed to be at highest risk of bowel cancer.

There are more intricacies related to this question and areas requiring further research, hence, for more information, we invite you to read our Open Access article that was recently published in BJS

References

1.         Vega P, Valentin F, Cubiella J. Colorectal cancer diagnosis: Pitfalls and opportunities. World J Gastrointest Oncol. 2015;7(12):422-433.

2.         D’Souza N, Georgiou Delisle T, Chen M, Benton S, Abulafi M, Group NFS. Faecal immunochemical test is superior to symptoms in predicting pathology in patients with suspected colorectal cancer symptoms referred on a 2WW pathway: a diagnostic accuracy study. Gut. 2021;70(6):1130-1138.

3.         Turvill JL, Turnock D, Cottingham D, Haritakis M, Jeffery L, Girdwood A, et al. The Fast Track FIT study: Diagnostic accuracy of faecal immunochemical test for haemoglobin in patients with suspected colorectal cancer. British Journal of General Practice. 2021;71(709):E643-E651.4.         Pickhardt PJ, Hassan C, Halligan S, Marmo R. Colorectal cancer: CT colonography and colonoscopy for detection–systematic review and meta-analysis. Radiology. 2011;259(2):393-405.

doctor and patient

Guest blog: An investigation of sample size calculations in surgical trials

by Chloe Jacklin, Jeremy N Rodrigues, Joanna Collins, Jonathan Cook, Conrad J Harrison
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

We can all recognise the importance of the number of participants in a randomised controlled trial (RCT). Too few participants risks statistical errors, and too many will be overly expensive, and worryingly, unnecessarily expose participants to the risks of research1. To calculate the appropriate number of study participants, trialists must decide a target difference between the two intervention groups that would be considered meaningful. This decision becomes even more challenging when using a patient reported outcome measure (PROM) because, without context, PROM scores are challenging to interpret.

PROMs are defined as “a measurement of any aspect of a patient’s health that comes directly from the patient, without interpretation of the patient’s response by a physician or anyone else”2. Their use has gained popularity and credibility3, not least because it promotes patient-centred care but also because it has gained recognition from governing and advisory bodies2,4. This is further relevant to surgery where new initiatives to foster patient-centred research have been instigated to tackle criticisms of low quality evidence5,6. It is therefore important researchers, clinicians, and funding bodies are aware of the principles of measurement science underlying PROMs and their use in sample size calculations.

The Difference ELicitation in TriAls (DELTA2) guidelines outline the required reporting items for sample size calculations and provide guidance on rigorous target difference determination1. The target difference should be the PROM’s minimal important difference (MID). A popular definition of MID is “the smallest difference in score in the domain of interest which patients perceived as beneficial and which would mandate, in the absence of troublesome side-effects and excessive cost, a change in the patient’s management”7. There are several methods to estimate MIDs which vary in methodological rigour. It is important to be aware that some methods are rather arbitrary and not patient-centred such as using half of the standard deviation (also known as Cohen’s D), and some are superior such as anchoring the PROM to a global change score. The optimal method is to triangulate several good estimates of the MID8–10. Furthermore, the context-specific nature of MIDs must be appreciated because they balance the benefits and disadvantages of an intervention for a given population, treatment, and follow-up duration9. Therefore, an out-of-context MID may compromise a trial’s results.

We used DELTA2 to appraise the sample size calculations in RCTs where the intervention and/or comparator was a surgical intervention, and a PROM was used in the sample size calculation. We looked at trials published in high impact journals from the last 6 years because these are the most cited in their fields and have large international readerships of clinicians, academics and policy makers. A total of 57 were eligible, of which 51 were superiority design.

We found that sample size calculations in high profile surgical RCTs that used a PROM as their primary outcome were suboptimal compared to the contemporary DELTA2 standards. This included missing reporting items, using relatively arbitrary methods to determine the target difference; unclear justification for the target difference; and the application of MIDs calculated in different contexts. Of note, our sample included trials supported by £28 million of UK public research funding that had poor target difference justification.

Our results may reflect the demands for prompt and pragmatic answers to clinical research questions with convenient but suboptimal MIDs, and desire for cost-effective trials by opting for larger target differences.

While we acknowledge the difficult balance between delivering timely answers to clinical questions versus investment in measurement science, there are potential solutions. Recent advances in trial methodology may lead to improvements in target difference setting11–13. For example, adaptive trial designs allow trialists to dynamically refine trial-specific MIDs and adjust sample sizes accordingly. Funding bodies, research ethics committees and journals act as the gateway to research, and could drive improvements in RCT measurement quality by actively promoting alternative trial designs and enforcing careful target difference determination. Rigid budgets and risk aversion of commissioners and funding applicants present potential obstacles; however, this needs to be balanced against the risk to participants and excess cost caused by poor sample size calculations.

References

  1. Cook JA, Julious SA, Sones W, et al. DELTA 2 guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial. BMJ. 2018. doi:10.1136/bmj.k3750
  2. Services H. Guidance for industry: Patient-reported outcome measures: Use in medical product development to support labeling claims: Draft guidance. Health Qual Life Outcomes. 2006;4:1-20. doi:10.1186/1477-7525-4-79
  3. Black N. Patient reported outcome measures could help transform healthcare. BMJ. 2013;346(7896):1-5. doi:10.1136/bmj.f167
  4. Bottomley A, Jones D, Claassens L. Patient-reported outcomes: Assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency. Eur J Cancer. 2009;45(3):347-353. doi:10.1016/j.ejca.2008.09.032
  5. McCall B. UK implements national programme for surgical trials. Lancet. 2013;382(9898):1083-1084. doi:10.1016/S0140-6736(13)62009-7
  6. England RC of S. Surgical Trials Initiative — Royal College of Surgeons. https://www.rcseng.ac.uk/standards-and-research/research/surgical-trials-initiative/. Accessed October 15, 2021.
  7. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10(4):407-415. doi:10.1016/0197-2456(89)90005-6
  8. Rodrigues JN, Mabvuure NT, Nikkhah D, Shariff Z, Davis TRC. Minimal important changes and differences in elective hand surgery. J Hand Surg Eur Vol. 2015. doi:10.1177/1753193414553908
  9. Rodrigues JN. Different terminologies that help the interpretation of outcomes. J Hand Surg Eur Vol. 2020;45(1):97-99. doi:10.1177/1753193419870100
  10. Chan KBY, Man-Son-Hing M, Molnar FJ, Laupacis A. How well is the clinical importance of study results reported? An assessment of randomized controlled trials. CMAJ. 2001.
  11. Dimairo M, Pallmann P, Wason J, et al. The Adaptive designs CONSORT Extension (ACE) statement: A checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020. doi:10.1136/bmj.m115
  12. Thorlund K, Haggstrom J, Park JJ, Mills EJ. Key design considerations for adaptive clinical trials: A primer for clinicians. BMJ. 2018. doi:10.1136/bmj.k698
  13. Park JJH, Thorlund K, Mills EJ. Critical concepts in adaptive clinical trials. Clin Epidemiol. 2018. doi:10.2147/CLEP.S156708

Image source: Enlivity 2021 Creative Commons

Apple and Orange

Guest blog: Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic: how to compare apples and oranges?

Authors: Kenneth A McLean, Sivesh K Kamarajah, James C Glasbey

Early in the pandemic, it was recognised that patients had a higher rate of death associated with pulmonary complications if they become infected with SARS-CoV-2 in the perioperative period 1. However, the key question is why? Was this solely down to SARS-CoV-2 infections, was this due to differences in who was prioritised for surgery, or due to some other reason? These are difficult questions to answer, especially without comparable data from the pre-pandemic period. 

To address this, our paper published in the BJS pools together two large-scale, prospective and multi-specialty international cohorts 2: one from the pre-pandemic period from the STARSurg Collaborative 3 and another from during the pandemic from the COVIDSurg collaborative 4. Since these projects both included elective abdominal cancer surgery patients, and collected similar data on them and their postoperative outcomes, we were able to make a fair comparison between these cohorts. 

Overall, there was only a minority of patients with a perioperative SARS-COV-2 infection (4.3%), which is reassuring that most patientsundergoing surgery during this period were safeguarded. Interestingly, when postoperative outcomes were compared between the periods, the pulmonary complication rate observed was relatively similar (7.1% [before] vs 6.3% [during], p=0.158) but the 30-day mortality was much higher (0.7% [before] versus 2.0% [during], p<0.001). This was perhaps due to more “severe” pulmonary complications during the pandemic, e.g. a higher proportion of patients with acute respiratory distress syndrome. 

Overall, we estimated the number of deaths related to pulmonary complications (the “population attributable fraction”) increased from 37.0% (95% CI: 14.6% – 64.1%) pre-pandemic to 66.0% (95% CI: 48.6% – 79.3%) during the pandemic. This is (perhaps unsurprisingly) difficult to tease out the exact role of SARS-COV-2 infection in this – not least because SARS-COV-2 infections didn’t exist in the pre-pandemic group. We also found some major differences in patient selection and surgical practice during the pandemic. For example, while patients operated during the pandemic tended to have an overall lower baseline risk of pulmonary complications, they still had higher rate of open operations (this may be at least in part due to uncertainty at the time whether or not laparoscopic surgery was high-risk for COVID-19 transmission 5). To allow us to account for these differences in the cohorts, we used a technique called “mediation analysis”, which allows us to estimate exactly how much SARS-COV-2 infection contributed to (“mediated”) 30-day postoperative mortality during the pandemic.  

Figure 1: Multivariable natural effects model of postoperative death associated with time period, mediated by SARS-COV-2 infection.

We found that even after adjustment, there was still an almost 3-times higher likelihood of death when being operated on during the pandemic, compared to pre-pandemic (OR: 2.72, 95% CI: 1.58 to 4.67, p<0.001). However, we estimated that over half of excess deaths (54.8%) during the pandemic were explained by the presence of a SARS-CoV-2 infection. If in a parallel universe these patients were operated on pre-pandemic (e.g. with no risk of SARS-CoV-2 infection) there would still have likely been a higher rate of death than expected (perhaps due to a collateral impact on other hospital services from the pandemic that reduced capacity to rescue). However, overall, there would have been no significant difference in postoperative mortality during the pandemic (OR:1.57, 95% CI: 0.91 to 2.73, p=0.108), compared to pre-pandemic. 

In the first pandemic wave, despite attempts by care providers to continue safe elective surgery by operating on lower-risk patients, a significantly higher risk-adjusted mortality was observed. Whilst over 50% of excess deaths were explained by SARS-CoV-2 infection, the remainder may indicate a collateral impact on other hospital services that reduced capacity to rescue. The COVID-19 pandemic isn’t over yet, and upscaling elective surgery safely to meet the backlog is one of the major challenges facing health systems going forward. This study highlights the ongoing need for governments to ensure hospitals have Covid secure pathways 6 and to take appropriate and timely measures to ensure hospitals services aren’t overwhelmed. Several million patients have had their cancer surgeries delayed or cancelled 7, and there are serious concerns that despite best efforts to prioritise care this may lead to reductions in cancer survival in the long-term 8. It is likely to be several years until universal vaccination is available, and so until then strategies to mitigate risk of SARS-COV-2 infection must be implemented to continue surgery safely. 

References:

1.         Cai M, Wang G, Zhang L, Gao J, Xia Z, Zhang P, et al. Performing abdominal surgery during the COVID-19 epidemic in Wuhan, China: a single-centred, retrospective, observational study. Br J Surg. 2020;107(7):e183-e5.

2.         STARSurg Collaborative and COVIDSurg Collaborative. Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic: a comparative analysis of two prospective international cohort studies. BJS. 2021;[in press].

3.         STARSurg Collaborative. REspiratory COmplications after abdomiNal surgery (RECON): study protocol for a multi-centre, observational, prospective, international audit of postoperative pulmonary complications after major abdominal surgery. British Journal of Anaesthesia. 2020;124(1):e13-e6.

4.         COVIDSurg Collaborative. Outcomes of Elective Cancer Surgery During the COVID-19 Pandemic Crisis. 2020 [updated 12/05/20. Available from: https://clinicaltrials.gov/ct2/show/NCT04384926.

5.         Spinelli A, Pellino G. COVID-19 pandemic: perspectives on an unfolding crisis. British Journal of Surgery. 2020;107(7):785-7.

6.         Glasbey JC, Nepogodiev D, Simoes JFF, Omar O, Li E, Venn ML, et al. Elective Cancer Surgery in COVID-19–Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study. Journal of Clinical Oncology. 2020:JCO.20.01933.

7.         COVIDSurg Collaborative. Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans. The British journal of surgery. 2020;107(11):1440-9.

8.         COVIDSurg Collaborative. Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries: an international, prospective, cohort study. The Lancet Oncology. 2021.

Perioperative lactate dynamics and value for prediction of clinically relevant post-hepatectomy liver failure (grade B or C) in the exploration cohort (509 patients) a Median lactate values (with interquartile range) before surgery (baseline), maximum value within 24 h (Max) and on the morning of postoperative day 1 (POD1; *all P 

Video: Early postoperative arterial lactate concentrations to stratify risk of post-hepatectomy liver failure

Post-hepatectomy liver failure (PHLF) represents the major determinant for death after liver resection. Early recognition is essential. Early postoperative lactate values are powerful, readily available markers for clinically relevant PHLF and associated complications after hepatectomy with potential for guiding postoperative care. This video explains the recent study published in BJS.

Cumulative incidence of retained common bile duct stones on postoperative endoscopic retrograde cholangiopancreatography Active intervention versus surveillance per common bile duct (CBD) stone size. IOC, intraoperative cholangiography; ECRP, endoscopic retrograde cholangiopancreatography.

Video: Intervention versus surveillance in patients with common bile duct stones detected by intraoperative cholangiography

Each year 13 000 patients undergo cholecystectomy in Sweden, and routine intraoperative cholangiography (IOC) is recommended to minimize bile duct injuries. IOC plus an intervention to remove CBD stones identified during cholecystectomy was associated with reduced risk for retained stones and unplanned ERCP, even for the smallest asymptomatic CBD stones in this BJS study.

Hernias in children

Guest blog in plain English: Hernias in children

Nathalie Auger, Francesca del Giorgio, Annie Le-Nguyen, Marianne Bilodeau-Bertrand, Nelson Piché

University of Montreal Hospital Research Centre, Montreal, Quebec, Canada

Are women who have inguinal hernias more likely to have a child with an inguinal hernia? Have you ever wondered why a child may develop an inguinal hernia? Inguinal hernias affect about 4% of children1,2, but the reasons why are very unclear. An inguinal hernia occurs when intestinal tissues push through a weak spot in the abdominal wall. Most children with inguinal hernias are thought to have developed this disorder while still in their mother’s womb1,3. Yet there has been little attention to the possibility that the characteristics of mothers could predict which children will develop inguinal hernias while growing up.

We studied whether women who were previously diagnosed or treated for an inguinal hernia were more likely to have a child with an inguinal hernia. To test our research question, we analyzed the health status of 795,590 children from the province of Quebec, Canada4. We collected information from their mothers including her age, pregnancy complications, diseases she may have had in the past, and whether she was ever treated for an inguinal hernia. We closely followed her child over time to find out if the child was ever hospitalized for an inguinal hernia between birth and 13 years of age. We used regression methods to determine how characteristics of the mothers were associated with the chance of having an inguinal hernia in the child, and made sure that we controlled for confounders that could lead to incorrect measurements.

Our findings were very enlightening. We confirmed that mothers with a history of inguinal hernia were more likely to have a child who develops an inguinal hernia. But we found that the risk was higher for daughters than sons. Girls whose mothers had an inguinal hernia were 5 times more likely to themselves have an inguinal hernia. Additionally, mothers with connective tissue disorders such as rheumatoid arthritis or lupus were more likely to have sons with inguinal hernias. The figure illustrates just how strong some of the associations were.

These results suggest that the characteristics of a mother may affect a child’s chance of having an inguinal hernia. The likelihood of having an inguinal hernia also depends on if the child is a girl or a boy. Some of this difference may be because the development of inguinal hernias in boys is not the same as in girls. But it is also possible that there is a genetically sex-linked component. Finally, the relationship between maternal connective tissue diseases and the risk of inguinal hernia in boys suggests that connective tissue architecture may be involved as well.

Although more research is needed to confirm these findings, doctors and patients should be aware that children with abdominal symptoms who have a mother with a history of an inguinal hernia or connective tissue disorder may themselves be more likely to have an inguinal hernia. For more information, we invite you to read our study that was recently published in British Journal of Surgery4.

References

1          Azarow K, Cusick R. Pediatric Surgery [Internet]. The Surgical clinics of North America, Vol. 92. 2012. Available from: http://www.sciencedirect.com/science/article/pii/S0039 610912000680 [accessed 11 February 2021]

2          Lao OB, Fitzgibbons RJ, Cusick RA. Pediatric inguinal hernias, hydroceles, and undescended testicles. Surgical Clinics of North America 2012; 92: 487–504.

3          Kapur P, Caty MG, Glick PL. Pediatric hernias and hydroceles. Pediatric Clinics of North America 1998; 45: 773–789.

4          Auger P, Del Giorgio F, Le-Nguyen A, Bilodeau-Bertrand M, Piché N. Pediatric hernias and hydroceles. British Journal of Surgery 2021.

Guest blog: Venous resection during pancreatoduodenectomy – there is still much to gain

J.V. Groen, Department of Surgery, Leiden University Medical Centre, Leiden, J.V.Groen@lumc.nl 

N. Michiels, Department of Surgery, Leiden University Medical Centre, Leiden, N.Michiels@lumc.nl        

J.S.D. Mieog, Department of Surgery, Leiden University Medical Centre, Leiden, J.S.D.Mieog@lumc.nl 

IMPORTANCE

The use of venous resection (portal or superior mesenteric vein [PV-SMV]) during pancreatoduodenectomy is increasing.1-4 In a recent international survey, we found that most pancreatic surgeons prefer a segmental resection with primary anastomosis over a partial wedge resection, because of a lower perceived risk of complications.5 The impact of the type of venous resection (wedge or segmental) on postoperative morbidity and survival is poorly understood in current literature.

QUESTION

Does type of venous resection during pancreatoduodenectomy for pancreatic cancer impact postoperative morbidity and overall survival?

FINDINGS

We performed a nationwide retrospective analysis of 1311 patients who underwent pancreatoduodenectomy for pancreatic cancer within the Dutch Pancreatic Cancer Group (2013-2017). A venous resection was performed in 27% patients (65% wedge resection; 35% segmental resection). Patients with segmental resection had more Clavien-Dindo ≥III complications (adjusted odds ratio 1.90, 95% confidence interval 1.22-2.98) and worse survival (adjusted hazard ratio 1.40, 95% confidence interval 1.10-1.78) compared to no venous resection. Patients with segmental resection had a higher rate of PV-SMV thrombosis (18%) as compared to patients with wedge resection (5%) and without venous resection (1%). Vascular complications (PV-SMV thrombosis or haemorrhage) were the indication for relaparotomy in 18 out of 23 (78%) patients with segmental resection. Tumour invasion in the resected PV-SMV did not differ between patients with segmental (67%) or wedge resection (69%).

In patients treated with neoadjuvant therapy, survival was comparable between types of venous resection, although patients with segmental resection had more Clavien-Dindo ≥III complications (52%) compared to venous wedge (19%) and without venous resection (21%).

MEANING

In contrast with the found preference for a segmental resection in the international survey, most patients underwent a wedge resection. Little is known what exactly drives the surgeon’s preference regarding choice of type of venous reconstruction.5 The results of this study implicate that an upfront segment resection is associated with both poor postoperative morbidity and poor survival. These findings are in line with a recent large international cohort study6 and contribute to the growing evidence that neoadjuvant chemotherapy should be considered in borderline resectable disease and suspected venous involvement. 

FUTURE

This study, and other studies from our group5,7, on venous resection during pancreatoduodenectomy demonstrated that there is much to gain with regards to patient selection (~30% of patients with venous resection do not have tumour invasion in the resected PV-SMV), surgical technique (variation in clamping techniques, heparinization, types of reconstruction and use of grafts and flow measurements), postoperative management (e.g. vascular complications as PV-SMV thrombosis, haemorrhages and portal hypertension) and pathological assessment (lack of internationally accepted grossing techniques of venous resections). We believe this is especially relevant for the future since venous resection will be even more common with the increasing use of neoadjuvant therapy. 

Several imaging tools are being investigated which can help selecting the right patients who need a venous resection to achieve a radical resection. Intraoperative ultrasound provides real-time imaging and feedback about the tumour, vascular involvement and resectability in patients with pancreatic cancer.8,9 We are currently analysing the data of our ULTRAPANC study which assesses the added value of intraoperative ultrasound in patients with pancreatic cancer and vascular involvement (https://www.trialregister.nl/trial/7621). A recent study showed the utility of computed tomography coupled with 3-dimensional image reconstruction in the assessment of superior mesenteric artery involvement after neoadjuvant therapy, the authors distinguish a “halo sign” (not involved) from a  “string sign” (involved).10 An interesting topic would be if these ‘’halo and string signs’’,  are also useful in the assessment of venous involvement with intraoperative ultrasound (or analogous ‘’signs’’, as the venous wall does not have an tunica adventitia). 

Recently defined benchmark outcomes for pancreatoduodenectomy with venous resection can be used to assess outcomes and identify areas for improvement on a hospital, regional or national level.11 The PREOPANC-4 trial (protocol in preparation) within the Dutch Pancreatic Cancer Group will investigate the implementation of a best-practice algorithm for patients with locally advanced pancreatic cancer. This study has the potential to improve surgical technique and management of patients undergoing arterial/venous resection during pancreatoduodenectomy in the Netherlands. 

In the present study, no data were available on the diagnosis, treatment and outcome of patients with PV-SMV thrombosis. We are currently collecting data for a successive study in which we will provide an overview of the current clinical practice in the Netherlands regarding the prevention, diagnosis, treatment and outcome of PV-SMV thrombosis following venous resection during pancreatoduodenectomy. A group from Japan recently performed an impressive study among 40 centres which showed that venous resection during pancreatoduodenectomy with splenic vein division frequently causes variceal formation, bleeding, and thrombocytopenia.12

Within the Dutch Pancreatic Cancer Group, pathological assessment of venous involvement have recently been standardized. The location of deepest invasion in the resected PV-SMV is assessed and all edges of the resected PV-SMV are assessed for radicality. A prospective study with this standardized pathological assessment is needed in to investigate the true prognostic value of (depth of) tumour invasion in the resected PV-SMV.

REFERENCES

  1. Kantor O, Talamonti MS, Wang CH, Roggin KK, Bentrem DJ, Winchester DJ, Prinz RA, Baker MS. The extent of vascular resection is associated with perioperative outcome in patients undergoing pancreaticoduodenectomy. HPB (Oxford) 2018;20(2): 140-146.
  2. Kleive D, Sahakyan MA, Berstad AE, Verbeke CS, Gladhaug IP, Edwin B, Fosby B, Line PD, Labori KJ. Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy. Br J Surg 2017;104(11): 1558-1567.
  3. van Roessel S, Mackay TM, Tol J, van Delden OM, van Lienden KP, Nio CY, Phoa S, Fockens P, van Hooft JE, Verheij J, Wilmink JW, van Gulik TM, Gouma DJ, Busch OR, Besselink MG. Impact of expanding indications on surgical and oncological outcome in 1434 consecutive pancreatoduodenectomies. HPB (Oxford) 2019;21(7): 865-875.
  4. Worni M, Castleberry AW, Clary BM, Gloor B, Carvalho E, Jacobs DO, Pietrobon R, Scarborough JE, White RR. Concomitant vascular reconstruction during pancreatectomy for malignant disease: a propensity score-adjusted, population-based trend analysis involving 10,206 patients. JAMA Surg 2013;148(4): 331-338.
  5. Groen JV, Stommel MWJ, Sarasqueta AF, Besselink MG, Brosens LAA, van Eijck CHJ, Molenaar IQ, Verheij J, de Vos-Geelen J, Wasser MN, Bonsing BA, Mieog JSD, Dutch Pancreatic Cancer G. Surgical management and pathological assessment of pancreatoduodenectomy with venous resection: an international survey among surgeons and pathologists. HPB (Oxford) 2021;23(1): 80-89.
  6. Machairas N, Raptis DA, Velázquez PS, Sauvanet A, de Leon AR, Oba A, Koerkamp BG, Lovasik B, Chan C, Yeo C, Bassi C, Ferrone CR, Kooby D, Moskal D, Tamburrino D, Yoon DS, Barroso E, de Santibañes E, Kauffmann EF, Vigia E, Robin F, Casciani F, Burdío F, Belfiori G, Malleo G, Lavu H, Hartog H, Hwang HK, Han HS, Marques HP, Poves I, Rosado ID, Park JS, Lillemoe KD, Roberts K, Sulpice L, Besselink MG, Abuawwad M, Del Chiaro M, de Santibañes M, Falconi M, D’Silva M, Silva M, Hilal MA, Qadan M, Sell NM, Beghdadi N, Napoli N, Busch OR, Mazza O, Muiesan P, Müller PC, Ravikumar R, Schulick R, Powell-Brett S, Abbas SH, Mackay TM, Stoop TF, Gallagher TK, Boggi U, van Eijck C, Clavien PA, Conlon KCP, Fusai GK. The Impact of Neoadjuvant Treatment on Survival in Patients Undergoing Pancreatoduodenectomy with Concomitant Portomesenteric Venous Resection: An International Multicenter Analysis. Ann Surg 2021.
  7. Groen, Jesse V. MD∗; van Manen, Labrinus MD∗; van Roessel, Stijn MD, PhD†; van Dam, Jacob L. MD‡; Bonsing, Bert A. MD, PhD∗; Doukas, Michael MD, PhD§; van Eijck, Casper H.J. MD, PhD‡; Farina Sarasqueta, Arantza MD, PhD∥; Putter, Hein MD, PhD¶; Vahrmeijer, Alexander L. MD, PhD∗; Verheij, Joanne MD, PhD∥; Besselink, Marc G. MD, PhD†; Groot Koerkamp, Bas MD, PhD‡; Mieog, J. Sven D. MD, PhD∗ Resection of the Portal-Superior Mesenteric Vein in Pancreatic Cancer, Pancreas: September 2021 – Volume 50 – Issue 8 – p 1218-1229 doi: 10.1097/MPA.0000000000001897
  8. Sibinga Mulder BG, Feshtali S, Farina Sarasqueta A, Vahrmeijer AL, Swijnenburg RJ, Bonsing BA, Mieog JSD. A Prospective Clinical Trial to Determine the Effect of Intraoperative Ultrasound on Surgical Strategy and Resection Outcome in Patients with Pancreatic Cancer. Ultrasound Med Biol 2019;45(8): 2019-2026.
  9. van Veldhuisen E, Walma MS, van Rijssen LB, Busch OR, Bruijnen RCG, van Delden OM, Mohammad NH, de Hingh IH, Yo LS, van Laarhoven HW, van Leeuwen MS, Nio CY, van Santvoort HC, de Vries J, Wessels FJ, Wilmink JW, Molenaar IQ, Besselink MG, van Lienden KP, Dutch Pancreatic Cancer G. Added value of intra-operative ultrasound to determine the resectability of locally advanced pancreatic cancer following FOLFIRINOX chemotherapy (IMAGE): a prospective multicenter study. HPB (Oxford) 2019.
  10. Habib JR, Kinny-Köster B, van Oosten F, Javed AA, Cameron JL, Lafaro KJ, Burkhart RA, Burns WR, He J, Thompson ED, Fishman EK, Wolfgang CL. Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: Surgical planning with the “halo sign” and “string sign”. Surgery 2020.
  11. Raptis DA, Sánchez-Velázquez P, Machairas N, Sauvanet A, Rueda de Leon A, Oba A, Groot Koerkamp B, Lovasik B, Chan C, Yeo CJ, Bassi C, Ferrone CR, Kooby D, Moskal D, Tamburrino D, Yoon DS, Barroso E, de Santibañes E, Kauffmann EF, Vigia E, Robin F, Casciani F, Burdío F, Belfiori G, Malleo G, Lavu H, Hartog H, Hwang HK, Han HS, Poves I, Rosado ID, Park JS, Lillemoe KD, Roberts KJ, Sulpice L, Besselink MG, Abuawwad M, Del Chiaro M, de Santibañes M, Falconi M, D’Silva M, Silva M, Abu Hilal M, Qadan M, Sell NM, Beghdadi N, Napoli N, Busch ORC, Mazza O, Muiesan P, Müller PC, Ravikumar R, Schulick R, Powell-Brett S, Abbas SH, Mackay TM, Stoop TF, Gallagher TK, Boggi U, van Eijck C, Clavien PA, Conlon KCP, Fusai GK. Defining Benchmark Outcomes for Pancreatoduodenectomy With Portomesenteric Venous Resection. Ann Surg 2020;272(5): 731-737.
  12. Mizuno S, Kato H, Yamaue H, Fujii T, Satoi S, Saiura A, Murakami Y, Sho M, Yamamoto M, Isaji S. Left-sided Portal Hypertension After Pancreaticoduodenectomy With Resection of the Portal Vein/Superior Mesenteric Vein Confluence in Patients With Pancreatic Cancer: A Project Study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Ann Surg 2021;274(1): e36-e44.
Cerebral microbleed

Guest blog: Cerebral microbleeds following thoracic endovascular aortic repair

W. Eilenberg a,b**, M. Bechstein d**, P. Charbonneauc, F. Rohlffs a, A. Eleshra a, G. Panuccio a, J. Bhangu b, J. Fiehler d, R. Greenhalgh e, S. Haulon c, T. Kölbel a*

German Aortic Center, Department of Vascular Medicine, University Heart & Vascular Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Department of General Surgery, Division of Vascular Surgery, Medical University of Vienna, Vienna, Austria

Centre de l’Aorte, Hôpital Marie Lannelongue, Groupe hospitalier Paris Saint Joseph, Université Paris Saclay, France

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Vascular Surgical Research Group, Imperial College, London, UK.

** both authors contributed equally

E-mail: wolf.eilenberg@meduniwien.ac.at

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. 

Stroke and cerebral damage are frequent findings after thoracic endovascular aortic repair (TEVAR) with a postoperative clinical stroke rate of 3-4% and silent brain infarcts (SBI) in about 80%.(1-4) However, the mechanism of stroke and subclinical cerebral damage in TEVAR is under-investigated. Current clinical research-efforts such as the STEP-registry (strokes from thoracic endovascular procedures) aim to better understand incidence of, and risk factors for stroke and cerebral damage after TEVAR, and to develop strategies for prevention.(5, 6) More than 60% of patients undergoing arch-TEVAR were reported to have SBIs on diffusion weighted magnetic resonance imaging (DW-MRI) despite protective efforts such as carbon dioxide (CO2) flushing of the endografts.(5, 6) The aim of the current study is to examine the occurrence of CMBs in patients after TEVAR within the STEP-registry and to evaluate their association with patient- and procedural factors.

Ninety-one patients treated with TEVAR in proximal landing zone (PLZ) 0-3 from September 2018 to January 2020 at the German Aortic Center (Hamburg, Germany) and Marie Lannelongue Hospital (Paris, France) were included in the study.(5) The location and number of CMBs were identified and analyzed with regards to procedural aspects, clinical outcome and Fazekas-score as indicator of preexisting vascular leukoencephalopathy.

Indication for TEVAR was type B dissection, degenerative aneurysm or other aortic disease in 44/91 (48.4%), 34/91 (37.3%) and 13/91 (14.3%) patients, respectively. Anatomical details have been described in detail previously.(5)

PLZ were 0, 1, 2 and 3 in 23/91 (25.3%), 10/91 (11.0%), 47/91 (51.6%) and 11/91 (12.1%) patients, respectively. Seventy-one/91 (78.0%) patients were treated in an elective setting. 23 (25%) patients received branched-TEVAR (B-TEVAR), 15 (17%) patients fenestrated-TEVAR (F-TEVAR) of which 4 (4%) patients had in-situ laser fenestrations. Fifty-three/91 (58%) patients received tubular endografts. The median proximal diameter of the aortic endoprosthesis was 38 (34-46) mm and 37/91 (40.7%) patients received a proximal bare stent. Technical success was reported in all cases. Intraoperative complications, such as prolonged hypotension, iatrogenic dissection of the left subclavian artery, aortic rupture during deployment of a stent-graft and proximal common iliac rupture, were reported in 4/91 (4.4%) patients. No periprocedural ischemic stroke or death occurred within 30 postoperative days (POD). 

On MRI performed within 7 POD (Median 4 (2-7)), a total of 1531 CMBs were detected in 58 (63.7%) patients by two neuroradiological experts; bilateral CMBs were identified in 46/58 (79.3%) patients (P=0.078). CMBs were present unilaterally in the right or left hemisphere in 9/58 (15.5%) and 3/58 (5.2%) patients (P=0.0001) respectively. 

More CMBs were found in the middle cerebral territory vs. the posterior territory and the anterior territory ((3.35 (5.56 SD) vs. 2.26 (4.05 SD) vs. 0.966 CMBs (2.87 SD) (P=0.045)),  Procedural factors associated with the presence of CMBs were deployment in zone 0/1 vs. 2/3 (P=0.001), placement of a branched or fenestrated endograft (P=0.025) and longer procedure time (≥120 min) (P=0.019). Proximal diameter of the endoprosthesis ≥40mm (P=0.016), reoperations linked to primary operation (P=0.017) and atheroma grade 4 and 5 (P=0.048) were significantly associated with CMB in a multivariate logistic binary regression model, whereas compliant balloon (P=0.053) use showed only a tendency.  

Multiple linear regression with Firth regression showed more CMBs in TEVAR with proximal diameter ≥40mm OR 6.8 (95% CI 1.65-41.59; P=0.007) and higher DWM Fazekas-score in postoperative MRI OR 2.6 (95% CI 1.06-7.92; P=0.037, indicator of pre-existing vascular leukoencephalopathy). There was no significant correlation between CMBs and SBIs (P=0.376). 

Since there is no pre-operative MRI data to compare to, a causal association between CMBs and TEVAR cannot be proven by the study design. Nevertheless, the observed rate of CMBs after TEVAR (63,7%) was increased compared to rates reported in the literature among a general population of similar mean age (28%).(7) Although the rate among elderly patients with preexisting cardiovascular diseases may generally be higher, a causal linkage between TEVAR and CMBs can therefore also not be ruled by our findings. With the multi-territorial pattern, an embolic and secondary hemorrhagic origin caused by TEVAR may be hypothesized. The middle cerebral artery territory was most frequently affected due to its higher volume and share of blood.(8), (9) CMBs may be of various origin. As SW-MRI is sensitive to para-, dia- and ferromagnetic compounds, the susceptible MRI lesions referred to as “CMBs” may in this postoperative state also result from embolic micromaterial originating from endovascular devices or dispersed microcalcifications from the aortic arch.

We could not identify a significant correlation between SBI and CMBs (P=0.376). In contrast to SBI, which were found predominantly in the left hemisphere, CMBs were detected bilaterally in the vast majority of patients (79.3 %) and unilateral occurrence was more frequent in the right hemisphere (P=0.0001). While cerebral microbleeds are known to occur predominantly in deep or infratentorial regions in the presence of cardiovascular risk factors, and in the temporal lobe in patients with cerebral amyloid angiopathy, a spatial predilection for the right hemisphere in case of unilateral occurrence has so far not been described.(10, 11)

We found an association of CMBs with the PLZ and atheroma grade of the aortic arch matching previously described associations of stroke, SBI and high-intensity transient signals on transcranial doppler with atheroma grade and PLZ. (12, 13)

Although the occurrence of CMBs after TEVAR did not lead to clinically apparent stroke, a potential long-term effect on cognitive function cannot be ruled out. 

The limitations of this study include its retrospective nature and the non-consecutive patient cohort. Pre-operative MRI weren´t available to safely differentiate between procedure-related and preexisting CMBs.  Multivariable and subgroup analysis are limited by low patient numbers and third error in multivariable analysis. Results should be interpreted with caution and only be used to generate hypotheses for future studies. 

CMBs are present bi-hemispherical in the majority of patients after endovascular arch TEVAR and associated with morphological and procedural factors. The clinical importance of this finding needs to be further examined.

References

1.         Kahlert P, Eggebrecht H, Jánosi RA, Hildebrandt HA, Plicht B, Tsagakis K, et al. Silent cerebral ischemia after thoracic endovascular aortic repair: a neuroimaging study.  Ann Thorac Surg. 98. Netherlands: © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc; 2014. p. 53-8.

2.         Perera AH, Rudarakanchana N, Monzon L, Bicknell CD, Modarai B, Kirmi O, et al. Cerebral embolization, silent cerebral infarction and neurocognitive decline after thoracic endovascular aortic repair. Br J Surg. 2018;105(4):366-78.

3.         Ullery BW, McGarvey M, Cheung AT, Fairman RM, Jackson BM, Woo EY, et al. Vascular distribution of stroke and its relationship to perioperative mortality and neurologic outcome after thoracic endovascular aortic repair.  J Vasc Surg. 56. United States: © 2012 Society for Vascular Surgery. Published by Mosby, Inc; 2012. p. 1510-7.

4.         Varkevisser RRB, Swerdlow NJ, de Guerre L, Dansey K, Li C, Liang P, et al. Thoracic Endovascular Aortic Repair With Left Subclavian Artery Coverage Is Associated With a High 30-Day Stroke Incidence With or Without Concomitant Revascularization. J Endovasc Ther. 2020;27(5):769-76.

5.         Charbonneau P, Kölbel T, Rohlffs F, Eilenberg W, Planche O, Bechstein M, et al. Silent Brain Infarction After Endovascular Arch Procedures: Preliminary Results from the STEP Registry.  Eur J Vasc Endovasc Surg. England: © 2020 European Society for Vascular Surgery. Published by Elsevier B.V; 2020.

6.         Rohlffs F, Haulon S, Kolbel T, Greenhalgh R, Collaborators S. Stroke From Thoracic Endovascular Procedures (STEP) Collaboration. Eur J Vasc Endovasc Surg. 2020;60(1):5-6.

7.         Poels MM, Ikram MA, van der Lugt A, Hofman A, Krestin GP, Breteler MM, et al. Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. Stroke. 2011;42(3):656-61.

8.         Naylor AR. Translating Evidence into Practice: Surveillance after Carotid Interventions. Eur J Vasc Endovasc Surg. 2018;56(2):298-9.

9.         Kim DE, Park JH, Schellingerhout D, Ryu WS, Lee SK, Jang MU, et al. Mapping the Supratentorial Cerebral Arterial Territories Using 1160 Large Artery Infarcts. JAMA Neurol. 2019;76(1):72-80.

10.       Mesker DJ, Poels MM, Ikram MA, Vernooij MW, Hofman A, Vrooman HA, et al. Lobar distribution of cerebral microbleeds: the Rotterdam Scan Study.  Arch Neurol. 68. United States2011. p. 656-9.

11.       Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study.  Neurology. 70. United States2008. p. 1208-14.

12.       Feezor RJ, Martin TD, Hess PJ, Klodell CT, Beaver TM, Huber TS, et al. Risk factors for perioperative stroke during thoracic endovascular aortic repairs (TEVAR). J Endovasc Ther. 2007;14(4):568-73.

13.       Morita Y, Kato T, Okano M, Suu K, Kimura M, Minamino-Muta E, et al. Incidence and Predictors of Catheterization-Related Cerebral Infarction on Diffusion-Weighted Magnetic Resonance Imaging. Biomed Res Int. 2016;2016:6052125.

St Gallen

Guest blog: Invasive lobular cancer of the breast remains a surgical challenge

U Narbe, P -O Bendahl, M Fernö, C Ingvar, L Dihge, L Rydén

Invasive lobular breast cancer is the second most common histological subtype and constitutes around 10-15% of all breast cancer. It is recognized by a peculiar diffuse growth pattern and disseminated spread of cancer cells contributing to diagnostic delay and difficulties in detecting the primary tumors by mammography and nodal metastasis by axillary ultrasound. Consequently, although invasive lobular breast cancer mainly displays a favorable luminal A molecular subtype, it is often diagnosed at a higher stage than invasive cancer of no special type. Despite these characteristics, histopathological subtype is not accounted for in Clinical Guidelines, in contrast to the molecular subtypes. In the BJS publication “The St. Gallen 2019 Guidelines understage the Axilla in Lobular Breast Cancer: a Population-Based Study” by Ulrik Narbe and co-authors, we have elaborated on the consequences for patients with invasive lobular cancers if completion axillary clearance would be omitted in patients with 1-2 nodal metastases.

For the breast surgeon, lobular cancer poses a challenge to surgery of the breast and to the axilla. Large tumor size and diffuse infiltrating margins are associated with an increased risk of positive margins after breast conserving surgery and in breast centers where MRI is available, complementary imaging is recommended ahead of primary surgery. Still a larger proportion of patients (66%) with lobular cancer undergo a mastectomy compared to other histological subtypes (43%) according to our registry study, supporting previous publications. So the dogma of de-escalating breast surgery from mastectomy to partial mastectomy in lobular cancer is challenging, keeping in mind that positive resection margins is a mandatory quality criteria in most centers pushing the choice of initial surgery towards upfront mastectomy.

Axillary surgery is moving towards de-escalation of surgical interventions for patients with 1-2 sentinel node metastases after the results of the Z0011 trial have been implemented worldwide and clearly supports that omission of completion axillary dissection is non-inferior provided the inclusion criteria for the trial is fulfilled. The Z0011 criteria for omission of completion axillary dissection is restricted to patients undergoing breast-conserving surgery, and is thus not applicable for lobular cancers operated by mastectomy. The St. Gallen 2019 guidelines extended the indication for abstaining completion axillary dissection to all patients of any tumor size irrespective of type of breast surgery. In addition, the guidelines recommended that the decision on adjuvant chemotherapy for luminal A-like tumors should include nodal staging and patients with 4 or more nodal metastasis (nodal stage II) were recommended adjuvant chemotherapy. For these patients there is hitherto no data on the role of genomic tests for risk stratification until the results of OPTIMA trial are presented. In this paper, we present data from the National Swedish Quality Registry with prospectively collected data retrieved from the period when a completion axillary clearance for patients with sentinel node metastases was recommended. We found a strong association between invasive lobular breast cancer and nodal stage II disease independent of other determinants such as tumour size.

Moreover, we validated the predominance of luminal A-like subtype in lobular cancer and among those the risk of nodal stage II disease was higher than for the corresponding group of invasive cancers of no specific type (19% compared with 3%). Importantly, patients with lobular cancer retained a predominance (60%) for luminal A-like subtype in the nodal stage II subgroup. In contrast, patients with nodal stage II disease and non-lobular cancers had a lower fraction of luminal A-like tumors (23%) compared with patients with a lower nodal status implicating that for most patients with nodal stage II and non-lobular cancers, the molecular subtype would guide adjuvant treatment decisions rather than nodal stage.

The biological mechanism behind the prevalence of a higher nodal burden in lobular cancer is today speculative. Hormone responsive tumors (ER positive) of all histological subtypes are characterized by a slightly increased risk of nodal metastasis, probably linked to a lower immunologic reaction in the primary tumor facilitating lymphatic spread. Moreover, the cornerstone of lobular cancers – loss of E-cadherin – facilitates detachment of cancer cells which might be of importance for metastatic spread. In the present study, we clearly present data on the independent association of lobular cancer with nodal spread underscoring that this association is not solely explained by a hormone responsive phenotype or a larger tumor size. 

This study highlights that lobular cancer is associated with a higher nodal burden than non-lobular cancer and omission of completion axillary clearance in sentinel node positive patients could thus understage the axilla. The consequence of this is that some 19% of all patients with invasive lobular cancer and luminal A-like subtype would be dismissed from recommendation of adjuvant chemotherapy. Today, the updated St. Gallen 2021 guidelines states that completion axillary clearance is recommended for patients where staging is necessary for adjuvant treatment recommendations and would largely correspond to lobular cancers with a luminal A-like molecular subtype. The challenge of de-escalating axillary surgery in lobular cancer is thus unresolved.

The consequence of understaging of the axilla in lobular cancer in terms of clinical outcome is, however, unclear while the responsiveness of chemotherapy in lobular cancer is considered poorer than the corresponding effect in non-lobular cancer. Despite the findings from neoadjuvant trials, lobular cancer is included in general recommendations on adjuvant chemo-endocrine therapy due to the lack of data specific for lobular cancer. The ongoing randomized trial SENOMAC holds some promise to shed light on the outcome for lobular cancers in the experimental arm in which adjuvant recommendations are not based on complete axillary staging. A strong recommendation for the future is to always include data on histological subtype in clinical trials to be able to stratify the cohort in future analysis. The small but aggressive molecular subtypes, triple-negative and HER2-positive, represent subgroups as small as the lobular histological subtype and today clin.trials.gov is overloaded by adjuvant and neoadjuvant treatment protocols specific for these molecular subtypes. So isn´t it time to reconsider protocols on invasive lobular breast cancer with luminal A-like subtypes? The phenotype indicates cancers at low-risk of distant spread which is balanced by a higher stage at diagnosis associated with a substantial risk of recurrence and death after long-term follow-up. The role of neoadjuvant endocrine therapy in this subgroup is far from settled and might open up for de-escalating surgery of the breast and axilla and shed light on the fascinating biology of lobular breast cancer.

Tsunami of systematic reviews and meta-analyses

Guest blog: A tsunami of overlapping reviews in surgery

Morihiro Katsura, Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan and Department of Surgery, Okinawa Chubu Hospital, Okinawa, Japan
Yasushi Tsujimoto, Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan and Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
Shingo Fukuma, Associate Professor – Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
Toshi A Furukawa, Professor – Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan

As systematic review papers on the same topic continue to be published, a massive amount of information pours down on the readers, a trend that gradually amplifies like a tsunami every year1. This phenomenon is still not well unknown in our field for surgeons. A meta-epidemiological study conducted by our research team showed that considerable variability in results and methodological quality can be found among multiple systematic reviews and meta-analyses (SRs/MAs) on the same topic. Additionally, high methodological quality in the systematic review evaluation is independently associated with increased citation counts in the subsequent five years after adjusting for journal impact factors and other covariates. These results highlight the current situation wherein surgeons seeking high-quality “evidence-based surgery do not know which review results to believe in the clinical setting, even though SRs/MAs are central to evidence-based medicine. To reduce the burden on busy surgeons in finding the most relevant evidence, this study suggests that quality evaluations should play a complementary role, and researchers and journal editors should concentrate their efforts on reviews of more limited quantity but higher quality. 

These results highlight the current situation wherein surgeons seeking high-quality “evidence-based surgery do not know which review results to believe in the clinical setting

Many clinicians and researchers have felt the wastefulness of the recent explosion of similar review articles1,2. Several descriptive studies regarding duplicate review articles on pharmacological intervention have been reported3,4 but particularly in surgery, this is rarely discussed. Therefore, we hypothesized that there are many redundant overlapping SR/MA publications with conflicting results and variable qualities, even in the field of surgery5. We first identified all SRs/MAs focusing on surgical interventions published in 2015 via PubMed. We then searched for SRs/MAs of similar RCTs published within the preceding five years (between 2011 and 2015). As the research progressed, an interesting idea arose among our research team to examine the number of citations as a measure of scientific impact after publication; therefore, we decided to investigate factors associated with the number of five-year citations through 2020 (Figure 1). This research was conducted in collaboration with the Research Group on Meta-epidemiology at Kyoto University School of Public Health.The results of this study were published online in the British Journal of Surgery on 17th November 2021.

Figure 1. Study schema outlining the steps of our search

Omission and commission phenomenon

Figure 2. Image of omission and commission phenomena (Blue circle, publication year of each RCT; Green circle, previous systematic review published in 2013; Red circle, recent systematic review published in 2015)

Ideally, all randomized controlled trials (RCTs) included in previous SRs/MAs should also be included in subsequently published SRs/MAs. In the real world, however, some of them have been omitted (Figure 2). We attempted to visualize this omission and commission phenomenon and compared the coverage probabilities of all RCTs that were published until the publication year of each SR/MA (one example is shown in Table 2). As a result, we found that there was considerable variability in coverage probability for relevant RCTs, and this was observed on almost every topic except the Cochrane update review.

Table 1. Coverage probabilities of 5 overlapping systematic reviews and meta-analyses on a single topic (‘Early vs. Delayed laparoscopic cholecystectomy for acute cholecystitis’) between 2011 and 2015

Discrepant results among overlapping systematic reviews

We found discrepancies among overlapping SRs/MAs on the same topic, such as different effect sizes, different statistical precisions, and even different directions of effect for many topics. Of course, although this is only the result of a sample within a wide surgical field, we believe that it is highly representative.

We show some examples of the discrepancies of pooled effect estimates among overlapping SRs/MAs in Table 2. For the topic ‘Appendectomy vs. Antibiotic treatment for acute appendicitis’, while the largest odds ratio (OR) was 8.13, the smallest was 0.54, a difference by a factor of 15.06 (Table 2), which was the largest difference among the 29 surgical topics which we reviewed in this study. We hypothesize that the major reasons why the pooled effect estimates are so different among overlapping SRs/Mas are related to differences in coverage probability for relevant RCTs (Table 1) and differences among the study subjects. Of course, there could be many other reasons, so we expect further research to shed light on some of them. Interestingly, overlapping publications have continued to increase since 2015, according to an updated PubMed search, particularly for topics with a large discrepancy in the study results.

Table 2. Differences in pooled effect estimates among overlapping systematic reviews between 2011 and 2015: Five representative examples from the 29 topics
(PCI, Percutaneous coronary intervention; CABG, Coronary artery bypass graft; PD, Pancreaticoduodenectomy)

How do you select a systematic review paper for citation?

When we write a scientific paper, what important factors are considered when picking systematic review articles to cite for our research? Many researchers may answer that it is the journal’s name recognition or impact factor. We used a mixed-effects regression model with a random intercept for surgical topics, which has been used as an analytical method in previous meta-epidemiological studies6, to investigate factors associated with the five-year citation counts of each SR/MA. As expected, a high journal impact factor (5.50 counts more per 1-point increment; 95% CI, 3.97 to 7.03; P <.001) was associated with a greater 5-year citation count. In addition, after adjusting for journal impact factors and other covariates, a high quality score (AMSTAR score 8-11) was independently associated with greater 5-year citation counts with a low quality score (AMSTAR score of 0-3) used as a reference (33.36 counts more; 95% CI, 16.20 to 50.51; P <.001). It is natural for researchers to evaluate the quality of the papers they would cite.

Implication for research and practice

Surgical SRs/MAs rarely include RCTs but instead focus on many nonrandomized trial designs. In this study, we evaluated SRs/MAs with only RCTs, which means that most SRs/MAs were excluded, and therefore, the situation is expected to be more serious in the real world. Surgical SRs/MAs may also be conducted predominantly by surgeons, lacking the involvement of methodologists or evidence synthesis experts, which could limit the quality of the research. There may be a significant risk of accepted wisdom concerning the hierarchy of evidence levels if numerous SRs/MAs on the same topic show high variability in the results and methodological quality. To prevent unnecessary duplication, the international Prospective Register for Systematic Reviews (PROSPERO) was launched in 2011; today, however, it may rarely work properly in practice and may only be considered as a courtesy7. Another novel approach, the “Living systematic review“, has been proposed: SRs are continually updated, incorporating relevant new evidence as it becomes available. It may be time to seek such new and more efficient methods8. Prior to initiating a project in surgical SRs/MAs, adequate communication and team building between surgeons and methodologists are critical in preventing duplication of research efforts and ensuring methodological rigor and currency. While further study is needed to discuss the problems of overlapping publications in surgical SRs/MAs, findings from our study may help guide clinicians, researchers and journal editors.

Researchers and journal editors should concentrate their efforts on reviews of more limited quantity but higher quality.

References

  1. Ioannidis JP. The mass production of redundant, misleading, and conflicted systematic reviews and meta-analyses. Milbank Q 2016;94:485-514.
  2. Créquit P, Trinquart L, Yavchitz A, Ravaud P. Wasted research when systematic reviews fail to provide a complete and up-to-date evidence synthesis: the example of lung cancer. BMC Med 2016;14:8.
  3. Siontis KC, Hernandez-Boussard T, Ioannidis JP. Overlapping meta-analyses on the same topic: survey of published studies. BMJ 2013;347:f4501.
  4. Hacke C, Nunan D. Discrepancies in meta-analyses answering the same clinical question were hard to explain: a meta-epidemiological study. J Clin Epidemiol 2020;119:47-56
  5. Katsura M, Kuriyama A, Tada M, Yamamoto K, Furukawa TA. Redundant systematic reviews on the same topic in surgery: a study protocol for a meta-epidemiological investigation. BMJ Open 2017;7(8):e017411.
  6. Tsujimoto Y, Fujii T, Onishi A, Omae K, Luo Y, Imai H, et al. No consistent evidence of data availability bias existed in recent individual participant data meta-analyses: a meta-epidemiological study. J Clin Epidemiol 2020;118:107-114.
  7. Moher D, Booth A, Stewart L. How to reduce unnecessary duplication: use PROSPERO. BJOG 2014;121:784-786.
  8. Hilton J, Tovey D, Shemilt I, Thomas J; Living Systematic Review Network. Living systematic review: 1. Introduction-the why, what, when, and how. J Clin Epidemiol 2017;91:23-30.

The illustration was created by the Tsuchimochi design office. Image source: hand drawing/Shutterstock.com under license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.