1. Potential game changer in surgery James Kong Yan Chai Hospital

2. Definition Game changer : – a newly introduced element or factor that changes an existing situation or activity in a significant way Source: Merriam-Webster dictionary

3. Cancer Operation Existing situation: – Diathermy for dissection – Frozen section for margin identification

4. Current practice Electrocautery produces “surgical smoke” as a by-product Smoke – mutagenic and therefore genotoxic – irritant Get rid of them – suction – evacuation systems Surg Endosc. 2003 Jun;17(6):979-87

5. Current practice Clear margin – Depends on surgeons visual and tactile feedback – Intraoperative frozen section Time consuming – Increased GA time – Prolongs operation Costly Limited number of sampling points Pathologist dependant esp. in suboptimally prepared or non- oriented specimen New idea?

6. New technology iKnife Diathermy + Rapid evaporative ionization mass spectrometry (REIMS) Standard electrosurgical knife connected to a mass spectrometer which identifies chemicals in a compound based on the mass of the molecules Smoke produced by healthy vaporized tissue differs in chemical composition from cancerous tissue

7. Latest Evidence Sci Transl Med 17 July 2013: Vol. 5, Issue 194, p. 194ra93

10. Methods Collected data ex vivo from benign and malignant gastric, colonic, hepatic, breast, lung, and brain tissue samples from 302 patients Created a histologically specific mass spectral reference library 2933 histologically validated database entries Identified compounds included phosphatidylethanolamines, phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, sphingomyelins, cardiolipins, plasmalogens, and sulfatides

11. Results Most of the lipid species were detected across multiple tissue types Distribution patterns were markedly distinct for healthy versus cancerous tissues  profile of species accounts for histological specificity

12. Healthy tissue Reproducibility of REIMS data sufficiently good for unambiguous identification of major tissue types

13. Solid tumors Complete separation of different histologically specific data points strongly suggests that mass spectrometric identification of different lung tumors is feasible

14. Solid tumors Data points corresponding to bulk tumor tissue separate well from the surrounding healthy liver tissue, and data points collected every 1 cm from the visible tumor indicate a gradual metabolic transition from a benign to a malignant tissue phenotype (arrow)

15. Metastases Astrocytomas with different WHO grades can by clearly differentiated from brain metastases Brain metastases from different primaries show specific lipidomic phenotypes as confirmed by histopathology (colon and lung)

16. Metastases Field transition not observed for metastases Analysed liver metastases from colon Parallel sampling lines 1 to 2 mm apart were taken using a continuous burn, which started in the healthy region and continued through the center of the cancer Correctly identified 73 sampling points, with two false-negative and one false-positive ` Metastasis from colon Adenocarcinoma in liver Healthy liver parenchyma

17. Metastasis from colon Adenocarcinoma in liver Healthy liver parenchyma

18. Results Database used for intraoperative testing 864 spectra were acquired from 81 patients Distinguishing cancer vs. healthy tissue – Sensitivity 97.7% – Specificity 96.5% Subclass analysis: – Primary liver and malignant lung tumors – Specificity 92-94% only

19. Potential ~20% breast cancer patients with lumpectomy require further surgery to clear positive margins 1 Potential to influence “on-table” decision-making and lower reoperation rates Entire procedure including sampling, sample transfer, chemical analysis, data processing, and audiovisual feedback takes ~0.7 to 2.5 s, compared to ~30 min for intraoperative histopathology Could improve cosmetic and functional outcomes by minimizing unnecessary removal of healthy tissue More sampling points than frozen section Potentially shorten surgical procedure Potential to reduce local tumor recurrence rate and the cost of histopathology services and improve overall patient survival 1 R. Jeevan et al. Reoperation rates after breast conserving surgery for breast cancer among women in England: Retrospective study of hospital episode statistics. BMJ 345, e4505 (2012).

20. Far from perfect Observational study, 3 hospitals in Hungary Requires a histologically specific mass spectral library of a good quality – Only determined in retrospective way – Initial stage impossible to identify every tissue type eg. rare tumors Cost and effort of developing device and spectral database Surgeons blinded to test results intraoperatively No solid evidence of advantage with intraoperative use No evidence of survival benefit No evidence it reduces local recurrence rate

21.  Observational study  Limited database  Cost  No study on influence over intraoperative decision making  No RCT to justify its advantage (if any) over current practice  No proven survival benefit  Observational study  Limited database  Cost  No study on influence over intraoperative decision making  No RCT to justify its advantage (if any) over current practice  No proven survival benefit  Speed  Unlimited sampling points  Shorten operative time  Preserve more healthy tissue  Identify exact tissue type  Reduce cost of frozen section  Speed  Unlimited sampling points  Shorten operative time  Preserve more healthy tissue  Identify exact tissue type  Reduce cost of frozen section Summary Negative Positive Negative Positive

22. Conclusion Can it replace intraoperative frozen section? Initial results look promising (as with all new technological innovations) iKnife technology is still in its early stage RCTs are mandatory to justify its use Until it demonstrates a clear benefit to patients and the health care system it would not be widely available

23. The End

25. Mass spectrometry Stage 1: ionization Stage 2: acceleration Stage 3: deflection (by magnetic field) Stage 4: detection