*Pathology*

The underlying diseases are listed in Table 3 (Tab 3). Pathologic assessment yielded specimens without tumor lacerations in all patients with malignant disease. Histology revealed free resection margins in 27 (100%) of 27 specimens and 13 (100%) of 13 specimens in SP-MajH and MP-MajH patients, respectively. During a median oncologic follow-up of 61 and 56 months (SP-MajH and MP-MajH), four (14.8%) and five (38.5%) patients suffered from recurrent diseases (apart from the resection plane or metastatic disease), whereas two patients (7.4% and 15.4%) in either SP-MajH or MP-MajH died during the observation period.


**Table 3.** Underlying diseases.

### **4. Discussion**

During the past decade, SP minor liver resection has been increasingly seen to make good surgical sense due to its proven benefits of minimal invasiveness and optimal cosmetic outcome [3,4,12–15]. Unfortunately, the SP concept is bothersome for the surgeon as it involves an uncommon type of triangulation and a limited number of deployed instruments. Bleeding control is crucial and technically demanding in all types of laparoscopic liver surgery as reduced bleeding can contribute to prolonged disease-free survival and overall survival [16]. Therefore, the possible high risks of intraoperative bleeding, longer procedural time and greater personal workload are the feared drawbacks of SP-MajH that make surgeons reluctant to offer this minimized approach technique to their patients. A meta-analysis evaluating patients with SP hepatectomies found a significant reduction in blood loss as compared to conventional laparoscopic liver resection [4]. This finding was confirmed in our study as the number of patients with intraoperative bleeding and the total amount of blood loss were significantly larger in the multitrocar population than in the SP cohort. However, this finding might be misleading: when substantial bleeding occurred in SP-MajH, almost two thirds of these patients required RBC transfusions. When more complex instrument manipulation is required during intraoperative emergencies in SP-MajH, meticulous dissection and hemostasis maneuvers, especially suture techniques, might be hampered. Delivering additional trocars for procedural safety in 8.8% of such interventions did not compensate this disadvantage in the study population. This unfavourable technical characteristic in SP surgery is of even more importance since the procedural difficulty index was significantly higher in MP-MajH in this study. With the intent to alleviate parenchymal transection, inline pre-coagulation by means of radiofrequency [7] did not meet the primary endpoint of sufficient bleeding control as a stand-alone technique in laparoscopic major hepatectomies (SP-MajH and MP-MajH) in about one third of procedures. When dealing with more challenging anatomical situations defined by a significantly higher difficulty index in comparison to minor hepatic resections, pre-coagulation techniques are therefore not regarded as the gold standard in parenchymal transection in minimally invasive major hepatectomy [9].

It is of note that a meta-analysis [17] documented better bleeding control but a higher rate of postoperative abscess formation but not biliary leakage or blood transfusion in the inline pre-coagulation group than for crush–clamp liver resections. The complication rates in SP-MajH and MP-MajH presented here reflect the complexity of the underlying disease and are more than acceptable in comparison to complication rates published for open or laparoscopic major hepatectomies (25.9% and 22.4%) [18]. The meta-analysis by Wang et al. showed no significant difference in terms of procedural time when comparing conventional laparoscopy and SP liver surgery [4]. When considering the fact that about two thirds of all study patients underwent combined procedures, the median operative time of less than three hours and the calculated median time for major hepatectomy of about two hours are comparable to procedural times published for laparoscopic and open liver resections [19,20]. The study presented here is embedded in our SP experience exceeding 5000 procedures. Having performed the first MP laparoscopic major hepatectomy and the first pure SP minor hepatectomy in 2008 [21], we further developed SP-MajH in a group of highly selected patients when overcoming an SP-specific learning curve of more than 1000 performed procedures. In addition to all intraabdominal manipulations, the incisional length allows adequate pathohistologic specimen harvest and an optimal cosmetic result in all patients with SP-MinH or SP-MajH. In MP-MajH, specimen retrieval is performed mostly via a Pfannenstiel incision for reduced wound complication rates and improved function and cosmesis [22]. Our standard of care in major hepatectomies includes an intensive care unit (ICU) treatment for the first two days and an observation at the normal ward for another eight days at least, regardless of an open or laparoscopic approach. This is closely related to national insurance policies and the resulting case-specific reimbursement, hampering any reasonable comparison between the groups. Remarkably, during a five-year follow-up, no wound complication occurred in the entire study population. As the SP concept itself

by no means confirms increased hernia rates, we currently aim for a total percentage of 2% late onset hernias in ten years of advanced SP surgery at our department. Due to the heterogeneity of our study collective with regard to tumor entity, it is difficult to assess oncological safety other than to document tumor lacerations, free resection margins and local recurrence. In contrast to non-ablative techniques, it is under debate whether margins extending into the ablation zone should be regarded as R1 resection (which did not occur in any of the study patients). Moreover, none of the patients developed local recurrence at the hepatic resection plane during the follow-up period, which speaks for both the accuracy of the SP technique and the value of inline pre-coagulation as an applicable transection mode. However, the authors are certain that meticulous anatomical preparation in all types of liver surgery with tumors adjacent to vital hepatic pedicles or the vena cava must be performed with instruments capable of more precise manipulation such as CUSA, hydro-jet and crush–clamp in combination with clips, staplers or sutures. The argumen<sup>t</sup> for the cost effectiveness (direct cost savings of 27.6% of disposables) enabling inline radiofrequency pre-coagulation is certainly not tenable in patients with SP-MajH when there is a substantial risk of perioperative bleeding. The literature has demonstrated convincingly that perioperative complications turned out to determine the financial burden [23]. It should be noted that certain factors might limit the study. The non-randomized study design and strict patient selection following the aforementioned exclusion criteria should be regarded as a limiting factor before generalizing these results. It must be emphasized that, if the required safety could not be guaranteed with SP, a decision for conventional surgery was made at the discretion of the surgeon. A significantly higher difficulty index in the MP-MajH group and a trend to a longer surgery time might be interpreted as a consequence of this. Hospital stay did not serve as a valid outcome parameter for patient recovery in order to compare groups, as hospital and insurance policies—instead of the patient condition alone—were determining factors in the duration of hospital stay. Quality of life was not assessed in this study, but it has been reported that SP results in better quality of life [11,12] than does conventional surgery. The evaluation of any additional benefit other than a reduction in abdominal wall trauma (shorter skin incisions) in the single-port versus the multiport approach was not scientifically targeted. This includes, but is not limited to, biomarkers, such as circulating tumor cells, circulating nucleic acids, extracellular vesicles and proteins. Targeting these biomarkers might have unravelled differences in some oncological entity more sophistically and represents an interesting future perspective. Emphasizing the calculated overall survival and disease-free survival would have no basis for justification due to the heterogeneity of the study population with malignancies and again was not the aim of this study. Therefore, we did not match open cohorts with the study population.

### **5. Conclusions**

Intraoperative bleeding, although not common in minimally invasive liver resection, requires unrestricted immediate manipulation, which might be hampered in SP-MajH. Inline radiofrequency pre-coagulation failed to achieve sufficient hemostasis in laparoscopic major hepatectomies. With sufficient experience in both SP and liver surgery, a low complication rate and good oncologic outcome represented by surrogate parameters in strictly selected patients could be demonstrated in our study. However, SP-MajH should still be considered experimental at this time.

**Author Contributions:** Conceptualization, C.M., M.W. and H.W.; methodology, E.B. and J.S.; formal analysis, T.H.; investigation, C.M., M.W., J.S., E.B., K.F., C.O., M.d.C., V.K., E.G.; statistical analysis T.H.; writing—original draft preparation, all authors; writing—review and editing, all authors; administration, H.W. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the local ethics committee "Salzburger Ethikkommission" (protocol number 415-EP/73/25-2011).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the hospital's privacy policy.

**Acknowledgments:** The authors gratefully acknowledge the valuable discussions with Peter Paal.

**Conflicts of Interest:** The authors declare no conflict of interest.
