Potential game changer in

surgeryJames Kong

Yan Chai Hospital

Definition

• Game changer : – a newly introduced element or factor that changes an existing

situation or activity in a significant way

Source: Merriam-Webster dictionary

Cancer Operation

• Existing situation:– Diathermy for dissection– Frozen section for margin identification

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

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?

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

Latest Evidence

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

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

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

Healthy tissue• Reproducibility of REIMS data sufficiently good for

unambiguous identification of major tissue types

Solid tumors• Complete separation of different histologically specific

data points strongly suggests that mass spectrometric identification of different lung tumors is feasible

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)

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)

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 colonAdenocarcinoma in liver

Healthy liver parenchyma

Metastasis from colonAdenocarcinoma in liver

Healthy liver parenchyma

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

Potential• ~20% breast cancer patients with lumpectomy require further surgery to clear

positive margins1

• 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

1R. 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).

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

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

NegativeNegativePositivePositive NegativeNegativePositivePositive

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

The End

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