Quantification of fluorescence angiography for visceral perfusion assessment: measuring agreement between two software algorithms.

BACKGROUND: Indocyanine green fluorescence angiography (ICG-FA) may reduce perfusion-related complications of gastrointestinal anastomosis. Software implementations for quantifying ICG-FA are emerging to overcome a subjective interpretation of the technology. Comparison between quantification algorithms is needed to judge its external validity. This study aimed to measure the agreement for visceral perfusion assessment between two independently developed quantification software implementations. METHODS: This retrospective cohort analysis included standardized ICG-FA video recordings of patients who underwent esophagectomy with gastric conduit reconstruction between August 2020 until February 2022. Recordings were analyzed by two quantification software implementations: AMS and CPH. The quantitative parameter used to measure visceral perfusion was the normalized maximum slope derived from fluorescence time curves. The agreement between AMS and CPH was evaluated in a Bland-Altman analysis. The relation between the intraoperative measurement of perfusion and the incidence of anastomotic leakage was determined for both software implementations. RESULTS: Seventy pre-anastomosis ICG-FA recordings were included in the study. The Bland-Altman analysis indicated a mean relative difference of + 58.2% in the measurement of the normalized maximum slope when comparing the AMS software to CPH. The agreement between AMS and CPH deteriorated as the magnitude of the measured values increased, revealing a proportional (linear) bias (R2 = 0.512, p < 0.001). Neither the AMS nor the CPH measurements of the normalized maximum slope held a significant relationship with the occurrence of anastomotic leakage (median of 0.081 versus 0.074, p = 0.32 and 0.041 vs 0.042, p = 0.51, respectively). CONCLUSION: This is the first study to demonstrate technical differences in software implementations that can lead to discrepancies in ICG-FA quantification in human clinical cases. The possible variation among software-based quantification methods should be considered when interpreting studies that report quantitative ICG-FA parameters and derived thresholds, as there may be a limited external validity.

Perfusion assessment by fluorescence time curves in esophagectomy with gastric conduit reconstruction: a prospective clinical study.

BACKGROUND: Intraoperative perfusion assessment with indocyanine green fluorescence angiography (ICG-FA) may reduce postoperative anastomotic leakage rates after esophagectomy with gastric conduit reconstruction. This study evaluated quantitative parameters derived from fluorescence time curves to determine a threshold for adequate perfusion and predict postoperative anastomotic complications. METHODS: This prospective cohort study included consecutive patients who underwent FA-guided esophagectomy with gastric conduit reconstruction between August 2020 and February 2022. After intravenous bolus injection of 0.05-mg/kg ICG, fluorescence intensity was registered over time by PINPOINT camera (Stryker, USA). Fluorescent angiograms were quantitatively analyzed at a region of interest of 1 cm diameter at the anastomotic site on the conduit using tailor-made software. Extracted fluorescence parameters were both inflow (T0, Tmax, Fmax, slope, Time-to-peak) as outflow parameters (T90% and T80%). Anastomotic complications including anastomotic leakage (AL) and strictures were documented. Fluorescence parameters in patients with AL were compared to those without AL. RESULTS: One hundred and three patients (81 male, 65.7 ± 9.9 years) were included, the majority of whom (88%) underwent an Ivor Lewis procedure. AL occurred in 19% of patients (n = 20/103). Both time to peak as Tmax were significantly longer for the AL group in comparison to the non-AL group (39 s vs. 26 s, p = 0.04 and 65 vs. 51 s, p = 0.03, respectively). Slope was 1.0 (IQR 0.3-2.5) and 1.7 (IQR 1.0-3.0) for the AL and non-AL group (p = 0.11). Outflow was longer in the AL group, although not significantly, T90% 30 versus 15 s, respectively, p = 0.20). Univariate analysis indicated that Tmax might be predictive for AL, although not reaching significance (p = 0.10, area under the curve 0.71) and a cut-off value of 97 s was derived, with a specificity of 92%. CONCLUSION: This study demonstrated quantitative parameters and identified a fluorescent threshold which could be used for intraoperative decision-making and to identify high-risk patients for anastomotic leakage during esophagectomy with gastric conduit reconstruction. A significant predictive value remains to be determined in future studies.

Understanding fluorescence time curves during ileal pouch-anal anastomosis with or without vascular ligation.

BACKGROUND: Intraoperative indocyanine green fluorescence angiography (ICG-FA) may be of added value during pouch surgery, in particular after vascular ligations as lengthening maneuver. The aim was to determine quantitative perfusion parameters within the efferent/afferent loop and explore the impact of vascular ligation. Perfusion parameters were also compared in patients with and without anastomotic leakage (AL). METHODS: All consenting patients that underwent FA-guided ileal pouch-anal anastomosis (IPAA) between July 2020 and December 2021 were included. After intravenous bolus injection of 0.1 mg/kg ICG, the near-infrared camera (Stryker Aim 1688) registered the fluorescence intensity over time. Quantitative analysis of ICG-FA from standardized regions of interests on the pouch was performed using software. Fluorescence parameters were extracted for inflow (T0, Tmax, Fmax, slope, Time-to-peak) and outflow (T90% and T80%). Change of management related to FA findings and AL rates were recorded. RESULTS: Twenty-one patients were included, three patients (14%) required vascular ligation to obtain additional length, by ligating terminal ileal branches in two and the ileocolic artery (ICA) in one patient. In nine patients the ICA was already ligated during subtotal colectomy. ICG-FA triggered a change of management in 19% of patients (n = 4/21), all of them had impaired vascular supply (ligated ileocolic/ terminal ileal branches). Overall, patients with intact vascular supply had similar perfusion patterns for the afferent and efferent loop. Pouches with ICA ligation had longer Tmax in both afferent as efferent loop than pouches with intact ICA (afferent 51 and efferent 53 versus 41 and 43 s respectively). Mean slope of the efferent loop diminished in ICA ligated patients 1.5(IQR 0.8-4.4) versus 2.2 (1.3-3.6) in ICA intact patients. CONCLUSION: Quantitative analysis of ICG-FA perfusion during IPAA is feasible and reflects the ligation of the supplying vessels.

The role of fluorescence angiography in colonic interposition after esophagectomy.

Colonic interposition is an alternative for gastric conduit reconstruction after esophagectomy. Anastomotic leakage (AL) occurs in 15-25% of patients and may be attributed to reduced blood supply after vascular ligation. Indocyanine green fluorescence angiography (ICG-FA) can visualize tissue perfusion. We aimed to give an overview of the first experiences of ICG-FA and AL rate in colonic interposition. This study included all consecutive patients who underwent a colonic interposition between January 2015 and December 2021 at a tertiary referral center. Surgery was performed for the following indications: inability to use the stomach because of previous surgery or extensive tumour involvement, cancer recurrence in the gastric conduit, or because of complications after initial esophagectomy. Since 2018 ICG-FA was performed before anastomotic reconstruction by administration of ICG injection (0.1 mg/kg/bolus), using the Spy-phi (Stryker, Kalamazoo, MI). Twenty-eight patients (9 female, mean age 62.8), underwent colonic interposition of whom 15 (54%) underwent ICG-FA-guided surgery. Within the ICG-FA group, three (20%) AL occurred, whereas in the non-ICG-FA group, three AL and one graft necrosis (31%) occurred (P=0.67). There was a change of management due to the FA assessment in three patients in the FA group (20%) which led to the choice of a different bowel segment for the anastomosis. Mean operative times in the ICG-FA and non-ICG-FA groups were 372±99 and 399±113 minutes, respectively (P=0.85). ICG-FA is a safe, easy and feasible technique to assess perfusion of colonic interpositions. ICG-FA is of added value leading to a change in management in a considerable percentage of patients. Its role in prevention of AL remains to be elucidated.

Fluorescence perfusion assessment of vascular ligation during ileal pouch-anal anastomosis.

BACKGROUND: Intraoperative fluorescence angiography (FA) is of potential added value during ileal pouch-anal anastomosis (IPAA), especially after vascular ligation as part of lengthening measures. In this study, time to fluorescent enhancement during FA was evaluated in patients with or without vascular ligation during IPAA. METHODS: This is a retrospective cohort study of all consecutive patients that underwent FA-guided IPAA between August 2018 and December 2019 in our tertiary referral centre. Vascular ligation was defined as disruption of the ileocolic arcade or ligation of interconnecting terminal ileal branches. FA was performed before and after ileoanal anastomotic reconstruction. During FA, time to fluorescent enhancement was recorded at different sites of the pouch. RESULTS: Thirty-eight patients [55.3% male, median age 45 years (IQR 24-51 years)] were included, of whom the majority (89.5%) underwent a modified-2-stage restorative proctocolectomy. Vascular ligation was performed in 15 patients (39.5%), and concerned central ligation of the ileocolic arcade in 3 cases, interconnecting branches in 10, and a combination in 2. For the entire cohort, time between indocyanine green (ICG) injection and first fluorescent signal in the pouch was 20 s (IQR 15-31 s) before and 25 s (IQR 20-36 s) after anal anastomotic reconstruction. Time from ICG injection to the first fluorescent signal at the inlet, anvil and blind loop of the pouch were non-significantly prolonged in patients that received vascular ligation. CONCLUSIONS: Results from this study indicate that time to fluorescence enhancement during FA might be prolonged due to arterial rerouting through the arcade or venous outflow obstruction in case of vascular ligation.

Fluorescence angiography after vascular ligation to make the ileo-anal pouch reach.

The two most essential technical aspects of any gastrointestinal anastomosis are adequate perfusion and sufficient reach. For ileal pouch-anal anastomosis (IPAA), a trade-off exists between these two factors, as lengthening manoeuvers to avoid tension may require vascular ligation. In this technical note, we describe two cases in which we used indocyanine green (ICG) fluorescence angiography (FA) to assess perfusion of the pouch after vascular ligation to acquire sufficient reach. In both cases, FA allowed us to distinguish better between an arterial inflow problem and venous congestion than white light assessment. Both pouches remained viable and no anastomotic leakage occurred. Our results indicate that ICG FA is of great value after vascular ligation to obtain reach during IPAA.

The value of a dedicated multidisciplinary expert panel to assess treatment strategy in patients suffering from colorectal cancer liver metastases.

BACKGROUND: For patients with colorectal cancer liver metastases (CRLM), local treatment is the only treatment with curative intent. The majority of patients with CRLM are however evaluated in multidisciplinary teams of colorectal cancer specialists often lacking expertise in local treatment of liver tumors. The aim of this study was therefore to assess the value of a dedicated multidisciplinary panel consisting of hepatobiliary surgeons and interventional radiologists for patients suffering from liver-only CRLM. METHODS: Patients diagnosed with liver-only CRLM in 2016 were identified in a tertiary referral hospital, and two of the referring hospitals in the Netherlands. Diagnostic imaging was independently reviewed by a panel of four hepatobiliary surgeons and two interventional radiologists to re-evaluate treatment strategy retrospectively. If two or more panelists assessed all lesions eligible for resection and/or ablation, patients were deemed eligible for local treatment with curative intent. Interrater reliability between hepatobiliary surgeons was assessed through intraclass correlation coefficient (ICC) and weighted Cohen's kappa. RESULTS: Diagnostic imaging of 61 patients with liver-only metastases were reviewed. Local treatment strategies appeared feasible in 40/61 (65.6%) patients. Five out of 25 patients (20.0%) initially assigned to systemic therapy were deemed eligible for upfront local treatment with curative intent (p = 0.015). In this subgroup, interrater reliability between hepatobiliary surgeons was substantial (ICC: 0.704, 95% CI: 0.536-0.838, n = 25). CONCLUSION: Assessment of treatment strategy by a dedicated multidisciplinary panel including liver experts may result in an increased number of patients eligible for potentially curative treatment and reduce undertreatment of patients suffering from liver-only CRLM.

Stage I-II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) lobectomy and stereotactic ablative radiotherapy (SABR) are both used for early-stage non-small-cell lung cancer. We carried out a propensity score-matched analysis to compare locoregional control (LRC). PATIENTS AND METHODS: VATS lobectomy data from six hospitals were retrospectively accessed; SABR data were obtained from a single institution database. Patients were matched using propensity scores based on cTNM stage, age, gender, Charlson comorbidity score, lung function and performance score. Eighty-six VATS and 527 SABR patients were matched blinded to outcome (1:1 ratio, caliper distance 0.025). Locoregional failure was defined as recurrence in/adjacent to the planning target volume/surgical margins, ipsilateral hilum or mediastinum. Recurrences were either biopsy-confirmed or had to be PET-positive and reviewed by a tumor board. RESULTS: The matched cohort consisted of 64 SABR and 64 VATS patients with the median follow-up of 30 and 16 months, respectively. Post-SABR LRC rates were superior at 1 and 3 years (96.8% and 93.3% versus 86.9% and 82.6%, respectively, P = 0.04). Distant recurrences and overall survival (OS) were not significantly different. CONCLUSION: This retrospective analysis found a superior LRC after SABR compared with VATS lobectomy, but OS did not differ. Our findings support the need to compare both treatments in a randomized, controlled trial.

Cryosurgery of tumor tissue causes endotoxin tolerance through an inflammatory response.

INTRODUCTION: Earlier reports on animal studies showed inhibition of secondary tumor growth and metastases after cryoablation, probably mediated by an inflammatory response. In this study enhancement of this inflammatory response and its possible additive antitumor effect is evaluated in a mouse tumor model. MATERIALS AND METHODS: Mice received two subcutaneously implanted C--26B tumors on, respectively, day 0 (thigh) and day 7 (flank). The thigh tumor was treated by either cryoablation or resection. In addition the animals received a single dose of lipopolysaccharide (LPS) or anti-IL10 together with, or two days after, surgical treatment. The growth of the flank tumor was followed and plasma levels of IL-1 alpha and TNF-alpha were measured. RESULTS: Compared to excision of the primary tumor, cryosurgery clearly induced inhibition of secondary tumor growth while plasma levels of TNF (0.09) and IL-1 (0.06) were significantly elevated after cryosurgery when compared to excision (TNF 0.0, IL-1 0.03; p < 0.01). Administration of LPS two days after cryosurgery did not lead to extra inhibition of secondary tumor growth, even at high doses. Remarkably, dose--response studies with LPS administered two days after treatment showed a high mortality at a dose of 200 micrograms (75%) in the excision group while mortality in the cryo-treated group was 13% (p < 0.02). Mortality was directly related to cytokine levels that were significantly higher in the excision group (TNF 3.60, IL-1 0.30) when compared to the cryo-treated group (TNF 1.0, IL-10.15; p < 0.01). In contrast, when 25 micrograms LPS was given at the same time as treatment of the primary tumor either by cryosurgery or excision, mortality in the cryo-treated group (85%) was higher than in the excision group (14%, p < 0.05). Again mortality was related to post-treatment cytokine levels which now were significantly higher in the cryo-treated animals (TNF 1.30, IL-10.35) than in animals treated by excision (TNF 0.60, IL-10.10; p < 0.01). Administration of anti IL-10 did not lead to extra tumor growth inhibition. CONCLUSION: These experiments confirm the hypothesis that cryosurgery leads to a systemic inflammatory response. This reaction can lead to the inhibition of tumor growth. Administration of LPS after cryosurgery does not lead to an extra anti-tumor response; animals appear to become endotoxin tolerant. Adversely, when LPS is administered together with cryosurgery, the animals are extremely sensitive to LPS. These findings are in accordance with the clinical observation of cryoshock after cryoablation of liver metastases.

In vivo destruction of tumor tissue by cryoablation can induce inhibition of secondary tumor growth: an experimental study.

BACKGROUND: Cryoablation has been used successfully for the local treatment of several cancers. Besides local destruction, a systemic antitumor response has been postulated after cryoablation of tumor tissue. In this study we evaluate the possible systemic antitumor response induced by cryodestruction of tumor tissue in two mouse tumor models. METHODS: Mice received two subcutaneously placed tumor implants (thigh and flank) of the nonimmunogenic mouse colon tumor cell line, colon 26-B. After 7 days, the thigh implant was treated by cryoablation or excision and the effect on secondary tumor growth was determined by volume measurement of the nontreated flank tumor. Cytokine (IL-1alpha and TNF-alpha) levels in plasma were measured after treatment. Similar experiments were performed in nude mice using a human melanoma cell line (MV3). Moreover, in this model the effect of cryoablation on development of spontaneous lung metastases was evaluated. RESULTS: In the colon 26-B tumor model treatment of primary tumor implants by cryoablation resulted in a significant inhibition of secondary tumor growth compared to animals treated by surgical excision (P < 0.01). Six hours after treatment, plasma levels of IL-1alpha and TNF-alpha were higher after cryoablation than after excision (P < 0.01). Also in the nude mice model cryoablation resulted in inhibition of secondary tumor growth, though not significant. Mice treated by cryoablation showed significantly less lung metastases compared to those treated by excision (P = 0.03). CONCLUSIONS: Cryoablation of tumor tissue can result in inhibition of secondary and metastatic tumor growth. A cytokine response induced by cryoablation of tumor tissue may attribute to this feature.

Intraoperative lymphatic mapping and the sentinel node concept in colorectal carcinoma.

BACKGROUND: Orderly progression of nodal metastases has been described for melanoma and breast cancer. The first draining lymph node, the sentinel node, is also the first to contain metastases and accurately predicts nodal status. The aim of this study was to assess the feasibility of lymphatic mapping and sentinel node biopsy in colorectal cancer. METHODS: In 50 patients with colorectal cancer patent blue dye was injected around the tumour. After resection of the tumour the specimen was examined to identify blue-stained lymph nodes. Routine histopathological examination was performed on all nodes and the blue, haematoxylin and eosin-stained tumour-negative nodes were tested immunohistochemically. RESULTS: Lymphatic mapping was possible in 35 of 50 patients (70 per cent). Pathological examination with haematoxylin and eosin staining showed lymph node metastases in 20 of 35 patients. In eight of these 20 patients the blue nodes showed tumour, while in 12 the blue nodes were not involved. This represents a false-negative rate of 60 per cent. CONCLUSION: Lymphatic mapping using patent blue dye is feasible in colorectal cancer. The blue-stained nodes do not predict nodal status of the remaining lymph nodes in the resected specimen. The concept of lymphatic mapping and sentinel node identification is not valid for colorectal cancer.