Analysis of open and laparoscopic liver resections in a german high-volume liver tumor center

In recent years laparoscopic liver surgery established itself into today’s standard of care regarding surgical liver treatment. It was a long way for minimally invasive liver resection to develop and popularize as it was accompanied by initial reservations and concerns. Some of these already had been clarified while other questions still remain and require further investigation in the complex field of laparoscopic liver surgery. Initial concerns with respect to oncological inferiority and technical inapplicability in contrast to open surgery treatment could have been disproved within the framework of retrospective studies. In contribution to that, the aim of the study was to compare the surgical results and postoperative outcomes of consecutive laparoscopic liver resections (LLR) and open liver resections (OLR) at the high-volume liver tumor center of Leipzig university hospital. Since common classification systems for open liver surgery cannot be applied for LLR, the introduction of specific difficulty scoring systems for LLR helps to assess and classify the complexity of minimal invasive liver resection. With an increase in experience, modification of hybrid surgery and the application of novel visualization techniques such as indocyanine green (ICG) staining or hyperspectral imaging (HSI), more challenging procedures were accomplished, that initially would have been contraindicated for the laparoscopic approach (e.g. perihilar cholangiocarcinoma (pCCA) requiring biliary reconstruction). During the years 2018 and 2019 42% of all liver resections were approached laparoscopically at the Leipzig University hospital. A retrospective data analysis of n=231 patients undergoing LLR or OLR for the years 2018 and 2019 was performed and previously determined variables were collected. As a primary outcome measure, the short-term surgical and postoperative outcome of patients receiving LLR (=LLR group) compared to the patient cohort being treated by open resection (=OLR group) was evaluated. All liver resections were executed or assisted by the same two surgeons. Prior to surgery, every case was reviewed in a multidisciplinary tumor-board meeting and primarily assessed for possible minimal invasive approach. Analysis for patient demographics, pathologic diagnosis, radiologic findings and peri- and intraoperative surgical data was carried out. For LLRs intraoperatively, ICG counter perfusion staining was used in anatomic liver resection and direct ICG tumor staining was employed for tumor demarcation. With respect to classification, the extent of OLR was graded according to the Brisbane 2000 terminology in minor and major resections, whereas LLRs were categorized by means of difficulty (in accordance with Ban et al. and Di Fabio et al.). For measurement of surgical complication and assessment of morbidity, the Clavien-Dindo classification was applied. OLR was performed in n=124 (57%) and LLR in n=93 (43%). From all minimally invasive treated patients, 79% were operated totally laparoscopic and 16% were laparoscopic-hand-assisted due to infeasible lesions in the posterosuperior segments 7, 8 and 4a. In 5 cases a conversion to open surgery was necessary because of inaccessibility, tumor infiltration or morbid obesity. 28% of patients had previous upper abdominal surgery, whereof 36% in the OLR group and 19% in the LLR group. Regarding patient demographics, the mean age was significantly higher in OLR and the sex ratio was in favor of men for both groups. Malignant tumor lesions comprised 77%, while 24% were benign lesions. In both groups this larger number of malignant oncologic operation remained valid. The most common benign indications comprised focal nodular hyperplasia (FNH) and liver adenomas. It was shown that patients with CCA and Colorectal liver metastases (CRLM) were predominantly treated by open surgery, while patients with HCC diagnosis received LLR to a greater extent. Concerning the type of liver resection, non-anatomical resections were the most frequent in the cohort with 47%, thereof 55% LLR and 40% OLR. Followed second most by anatomic right and left hemihepatectomies and third most by left lateral resections, which were predominantly performed in laparoscopic technique. On the other hand, extended resections and trisectionectomies were predominantly operated by OLR. Radical lymphadenectomy was performed to a greater extent during OLR. Results showed that the mean operative time was longer for OLR (341 minutes in median) compared to LLR (273 minutes in median). Also the mean length of hospital stay was shorter for LLR patients, as well as abdominal drains were placed to lesser extent in LLR compared to OLR. In regard to R0-resection, R0-rates were higher in LLR with 98% vs. 86% in OLR. Thereby being highest for CRLM resections, followed by HCC and CCA. Putting all liver resections into classification systems, it was found that of all open procedures, 52% had major and 48% underwent minor resection according to Brisbane 2000. From the LLR group, in accordance with Di Fabio et al. 39% were classified as laparoscopic major hepatectomies, comprising 44% laparoscopic traditional major hepatectomies (LTMH) and 56% laparoscopic posterosuperior major hepatectomies (LPMH), which were technically challenging. The difficulty index stated by Ban et al. was classified as low for 8% of all performed LLRs, intermediate for 45% and of high difficulty in even 47%. Relating to morbidity (=Clavien-Dindo 3b or greater), patients with LLR had significantly lower morbidity compared to OLR. The same applies for in-hospital mortality. Our data show that despite the high number of complex and high-difficulty-classified liver resections that were performed, morbidity and mortality rates were low. As mentioned before, R0 resection rate in the LLR group was better than in the OLR group, however, this was not a case matched study, so a direct comparison is not valid. But still the study could demonstrate that the high number of LLRs being performed at the Leipzig University hospital, did not impair R0-resection rates. With an overall hospital mortality rate of 5.9% in the cohort, good results were achieved. Particularly the low rate of 1% in the LLR group speaks for itself and confirms that the development of a minimal invasive liver resection program should be on the right track. The majority of patients in the LLR and OLR group received an oncologic resection, what also resembles the global attitude that minimally invasive techniques are not reserved for selected tumor entities. Still it should be emphasized, the indication for a liver resection should not be loosened just due to minimal invasive accessibility, especially in benign liver lesions. Nevertheless, in the study the majority of benign lesions was operated by LLR. A few patients diagnosed with CCA received LLR. Thereof predominantly iCCA cases were indicated for a minimal invasive approach without biliary duct reconstruction and satisfying short-term outcomes over OLR could be obtained. However, only one case of pCCA which required Roux-Y bile duct reconstruction was treated with LLR in the study group, so if laparoscopic surgery is capable to replace the open approach in terms of treatment strategies for pCCA remains questionable. Patients with CRLM represent the centerpiece of our study population, still only 13% received LLR. The main reason of applying OLR was the high tumor load requiring future liver remnant augmentation strategies. As liver resection is confirmed to be the approach of choice for patients with HCC in cirrhosis, it is not surprising that HCC diagnosis accounted for the major part of LLRS in our collective.:Vorbemerkung und Bibliographie, 3 Abkürzungsverzeichnis, 4 Einführung, 5 - 1. Development of minimal invasive liver surgery, 5 - 2. Prior concerns of LLR, 6 - 3. Benefits of laparoscopic surgery, 6 3.1 General advantages of minimal invasive surgery, 6 3.2 Specific benefits of applying LLR, 7 - 4. Indications for LLR, 7 4.1 Benign liver lesions, 8 4.2 Malignant liver lesions, 8 4.3 Liver transplantation, 9 - 5. Technical supplement, 9 5.1 Hybrid and hand-assisted techniques, 10 - 6. Classification systems, 11 6.1 Difficulty scoring, 11 6.2 Clavien-Dindo Classification ,12 - 7. Limitations of LLR, 12 - 8. Aim of the study, 13 Publikation, 14 Zusammenfassung, 26 Literaturverzeichnis, 30 Darstellung des eignen Beitrags, 34 Selbstständigkeitserklärung, 3

Surgical spectral imaging

Recent technological developments have resulted in the availability of miniaturised spectral imaging sensors capable of operating in the multi- (MSI) and hyperspectral imaging (HSI) regimes. Simultaneous advances in image-processing techniques and artificial intelligence (AI), especially in machine learning and deep learning, have made these data-rich modalities highly attractive as a means of extracting biological information non-destructively. Surgery in particular is poised to benefit from this, as spectrally-resolved tissue optical properties can offer enhanced contrast as well as diagnostic and guidance information during interventions. This is particularly relevant for procedures where inherent contrast is low under standard white light visualisation. This review summarises recent work in surgical spectral imaging (SSI) techniques, taken from Pubmed, Google Scholar and arXiv searches spanning the period 2013–2019. New hardware, optimised for use in both open and minimally-invasive surgery (MIS), is described, and recent commercial activity is summarised. Computational approaches to extract spectral information from conventional colour images are reviewed, as tip-mounted cameras become more commonplace in MIS. Model-based and machine learning methods of data analysis are discussed in addition to simulation, phantom and clinical validation experiments. A wide variety of surgical pilot studies are reported but it is apparent that further work is needed to quantify the clinical value of MSI/HSI. The current trend toward data-driven analysis emphasises the importance of widely-available, standardised spectral imaging datasets, which will aid understanding of variability across organs and patients, and drive clinical translation

Diagnosis and Treatment of Small Bowel Disorders

Over the last few decades, remarkable progress has been made in understanding the aetiology and pathophysiology of diseases and many new theories emphasize the importance of the small bowel ‘ecosystem’ in the pathogenesis of acute and chronic illness. Emerging factors such as microbiome, stem cells, innate intestinal immunity and the enteric nervous system along with mucosal and endothelial barriers have key role in the development of gastrointestinal and extra-intestinal diseases. Therefore, the small intestine is considered key player in metabolic disease development, including diabetes mellitus, and other diet-related disorders such as celiac and non-celiac enteropathies. Another major field is drug metabolism and its interaction with microbiota. Moreover, the emergence of gut-brain, gut-liver and gut-blood barriers points toward the important role of small intestine in the pathogenesis of common disorders, such as liver disease, hypertension and neurodegenerative disease. However, the small bowel remains an organ that is difficult to fully access and assess and accurate diagnosis often poses a clinical challenge. Eventually, the therapeutic potential remains untapped. Therefore, it is due time to direct our interest towards the small intestine and unravel the interplay between small-bowel and other gastrointestinal (GI) and non-GI related maladies

Multimodal Multispectral Optical Endoscopic Imaging for Biomedical Applications

Optical imaging is an emerging field of clinical diagnostics that can address the growing medical need for early cancer detection and diagnosis. Various human cancers are amenable to better prognosis and patient survival if found and treated during early disease onset. Besides providing wide-field, macroscopic diagnostic information similar to existing clinical imaging techniques, optical imaging modalities have the added advantage of microscopic, high resolution cellular-level imaging from in vivo tissues in real time. This comprehensive imaging approach to cancer detection and the possibility of performing an ‘optical biopsy’ without tissue removal has led to growing interest in the field with numerous techniques under investigation. Three optical techniques are discussed in this thesis, namely multispectral fluorescence imaging (MFI), hyperspectral reflectance imaging (HRI) and fluorescence confocal endomicroscopy (FCE). MFI and HRI are novel endoscopic imaging-based extensions of single point detection techniques, such as laser induced fluorescence spectroscopy and diffuse reflectance spectroscopy. This results in the acquisition of spectral data in an intuitive imaging format that allows for quantitative evaluation of tissue disease states. We demonstrate MFI and HRI on fluorophores, tissue phantoms and ex vivo tissues and present the results as an RGB colour image for more intuitive assessment. This follows dimensionality reduction of the acquired spectral data with a fixed-reference isomap diagnostic algorithm to extract only the most meaningful data parameters. FCE is a probe-based point imaging technique offering confocal detection in vivo with almost histology-grade images. We perform FCE imaging on chemotherapy-treated in vitro human ovarian cancer cells, ex vivo human cancer tissues and photosensitiser-treated in vivo murine tumours to show the enhanced detection capabilities of the technique. Finally, the three modalities are applied in combination to demonstrate an optical viewfinder approach as a possible minimally-invasive imaging method for early cancer detection and diagnosis

Diffuse Reflectance Spectroscopy to Quantify In Vivo Tissue Optical Properties: Applications in Human Epithelium and Subcutaneous Murine Colon Cancer

Colorectal cancer is the 4th most common and 2nd deadliest cancer. Problems exist with predicting which patients will respond best to certain therapy regimens. Diffuse reflectance spectroscopy has been suggested as a candidate to optically monitor a patient’s early response to therapy and has been received favorably in experimentally managing other cancers such as breast and skin. In this dissertation, two diffuse reflectance spectroscopy probes were designed: one with a combined high-resolution microendoscopy modality, and one that was optimized for acquiring data from subcutaneous murine tumors. For both probes, percent errors for estimating tissue optical properties (reduced scattering coefficient and absorption coefficient) were less than 5% and 10%, respectively. Then, studies on tissue-simulating phantoms were performed to test probe sensitivity and to serve as testing platforms for investigators in biomedical optics. Next, the diffuse reflectance spectroscopy probe was applied to subcutaneous murine colon tumors (n=61) undergoing either antibody immunotherapy or standard 5-fluorouracil chemotherapy. Mice treated with a combination of these therapies showed reduced tumor growth compared to saline control, isotype control, immunotherapy, and chemotherapy groups (p\u3c0.001, \u3c0.001, \u3c0.001, and 0.046, respectively) 7 days post-treatment. Additionally, at 7 days post-treatment, oxyhemoglobin, a marker currently being explored as a functional prognostic cancer marker, trended to increase in immunotherapy, chemotherapy, and combination therapy groups compared to controls (p=0.315, 0.149, and 0.190). Also of interest, an oxyhemoglobin flare (averageincrease of 1.44x from baseline, p=0.03 compared to controls) was shown in tumors treated with chemotherapy, indicating that diffuse reflectance spectroscopy may be useful as a complimentary tool to monitor early tumor therapeutic response in colon cancer. However, subject-to-subject variability was high and studies correlating survival to early oxyhemoglobin flares are suggested

Near-infrared narrowband imaging of tumors using gold nanoparticles

textA significant challenge in the surgical resection of tumors is accurate identification of tumor margins. Current methods for margin detection are time-intensive and often result in incomplete tumor excision and recurrence of disease. The objective of this project was to develop a near-infrared narrowband imaging (NIR NBI) system to image tumor and its margins in real-time during surgery utilizing the contrast provided by gold nanoparticles (GNPs). NIR NBI images narrow wavelength bands to enhance contrast from plasmonic particles in a widefield, portable and non-contact device that is clinically compatible for real-time tumor margin demarcation. GNPs have recently gained significant traction as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with NIR light, produce sufficient heat to treat tumor tissue. The NIR NBI system consists of 1) two LED's: green (530 nm) and NIR (780 nm) LED for illuminating the blood vessels and GNP, respectively, 2) a filter wheel for wavelength selection, and 3) a CCD to collect reflected light from the sample. The NIR NBI system acquires and processes images at a rate of at least 6 frames per second. We have developed custom control software with a graphical user interface that handles both image acquisition and processing/display in real-time. We used mice with a subcutaneous tumor xenograft model that received intravenous administration and topical administration of gold nanoshells and gold nanorods. We determined the GNP's distribution and accumulation pattern within tumors using NIR NBI. Ex vivo NIR NBI of tumor xenografts accumulated with GNPs delivered systemically, demonstrated a highly heterogeneous distribution of GNP within the tumor with higher accumulation at the cortex. GNPs were observed in unique patterns surrounding the perivascular region. The GNPs clearly defined the tumor while surrounding normal tissue did not indicate the presence of particles. In addition, we present results from NBI of tumors that received topical delivery of conjugated GNPs. We determined that tumor labeling using topical delivery approach resulted in a more homogenous distribution of GNPs compared to the systemic delivery approach. Finally, we present results from the on-going in vivo tumor margin imaging studies using NIR NBI. Our results demonstrate the feasibility of NIR NBI in demarcating tumor margins during surgical resection and potentially guiding photo-thermal ablation of tumors.Biomedical Engineerin

Advanced Optical Imaging-Guided Nanotheranostics toward Personalized Cancer Drug Delivery

Nanomedicine involves the use of nanotechnology for clinical applications and holds promise to improve treatments. Recent developments offer new hope for cancer detection, prevention and treatment; however, being a heterogenous disorder, cancer calls for a more targeted treatment approach. Personalized Medicine (PM) aims to revolutionize cancer therapy by matching the most effective treatment to individual patients. Nanotheranostics comprise a combination of therapy and diagnostic imaging incorporated in a nanosystem and are developed to fulfill the promise of PM by helping in the selection of treatments, the objective monitoring of response and the planning of follow-up therapy. Although well-established imaging techniques, such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT), are primarily used in the development of theranostics, Optical Imaging (OI) offers some advantages, such as high sensitivity, spatial and temporal resolution and less invasiveness. Additionally, it allows for multiplexing, using multi-color imaging and DNA barcoding, which further aids in the development of personalized treatments. Recent advances have also given rise to techniques permitting better penetration, opening new doors for OI-guided nanotheranostics. In this review, we describe in detail these recent advances that may be used to design and develop efficient and specific nanotheranostics for personalized cancer drug delivery. © 2022 by the authors. Licensee MDPI, Basel, Switzerland