Hepatic Arteriography and C-Arm CT-Guided Ablation (HepACAGA) to Improve Tumor Visualization, Navigation and Margin Confirmation in Percutaneous Liver Tumor Ablation.

PURPOSE: We present a technique that combines Hepatic Arteriography with C-arm CT-Guided Ablation (HepACAGA) to improve tumor visualization, navigation and margin confirmation for percutaneous ablation of liver tumors. MATERIALS AND METHODS: All consecutive patients scheduled for HepACAGA between April 20th, 2021, and November 2nd, 2021, were included in this retrospective, cohort study. HepACAGA was performed in an angiography-suite under general anesthesia. The hepatic artery was catheterized for selective contrast injection. C-arm CT and guidance software were then used to visualize the tumor and the microwave antenna was inserted during apnea. Pre- and post-ablation C-arm CTs were performed and ablation margins assessed. Technical success, antenna placement deviation, number of repositions, tumor recurrence, and safety were evaluated. Technical success was defined as a tumor that was ablated according to the HepACAGA technique. RESULTS: A total of 21 patients (28 tumors) were included. The main tumor type was colorectal cancer liver metastases (11/21, 52%), followed by hepatocellular carcinoma (7/21, 33%), neuroendocrine tumor metastases (1/21, 5%), and other tumor types (2/21, 10%). The technical success rate was 93% (26/28 tumors) with two small hypovascular lesions unable to be identified. A single microwave antenna was used in all patients. The median antenna placement deviation was 1 mm (range 0-6 mm). At a median follow-up time of 16 months (range 5-22 months), there was no tumor recurrence in any patient. Safety analysis showed a complication rate of 5% grade 2 and 5% grade 3. CONCLUSION: HepACAGA was demonstrated to be a safe and effective percutaneous ablation technique, without any local tumor recurrence in this study.

Renal biopsies performed before versus during ablation of T1 renal tumors: implications for prevention of overtreatment and follow-up.

PURPOSE: To assess the difference between renal mass biopsy (RMB) performed either before or during the ablation procedure. METHODS: A retrospective multicenter study was performed in patients with a cT1 renal mass treated with ablation between January 2007 and July 2019, including a search in the national pathology database for patients with a RMB planned for ablation. Patient and tumor characteristics and information on malignant, benign, and non-diagnostic biopsy results were collected to establish rates of overtreatment and number of ablations avoided in case of benign or non-diagnostic histology. RESULTS: RMB was performed in 714 patients, of which 231 patients received biopsy before planned ablation, and 483 patients at the time of ablation. Pathology results before ablation were malignant in 63% (145/231), benign in 20% (46/231) and non-diagnostic in 17% (40/231). Pathology results at the time of ablation were malignant in 67.5% (326/483), benign in 16.8% (81/483) and non-diagnostic in 15.7% (76/483), leading to a total of 32.5% of ablation of benign or non-diagnostic lesions. Of the patients with a benign biopsy obtained before ablation, 80.4% (37/46) chose not to undergo ablation. Patients with inconclusive biopsy before planned ablation chose an informed individualized approach including ablation, repeated biopsy, or no intervention in 56%, 34% and 10%. CONCLUSION: This study emphasizes the importance of obtaining a biopsy prior to the ablation procedure in a separate session to lower the rate of potentially unnecessary ablations.

Hospital variation in combined liver resection and thermal ablation for colorectal liver metastases and impact on short-term postoperative outcomes: a nationwide population-based study.

BACKGROUND: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation. METHODS: In this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery. RESULTS: Of 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy. CONCLUSION: Significant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy.

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases: Multidisciplinary Consensus Document from the COLLISION Trial Group.

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.

Phase Ib/II trial testing combined radiofrequency ablation and ipilimumab in uveal melanoma (SECIRA-UM).

Approximately, 50% of patients with uveal melanoma develop distant metastasis for which no standard therapy is established. In contrast to cutaneous melanoma, the anti-CTLA-4 antibody ipilimumab showed no clinical activity in uveal melanoma. Liver directed therapies improve local control, but fail to show overall survival (OS) benefit. Preclinical experiments demonstrated that radiofrequency ablation (RFA) induced durable responses in combination with anti-CTLA-4. The aim of this phase Ib/II study was to assess safety and efficacy of RFA plus ipilimumab in uveal melanoma. Patients underwent RFA of one liver lesion and subsequently received four courses ipilimumab 0.3, 3 or 10 mg/kg every 3 weeks in a 3 + 3 design. Primary endpoints were safety in terms of dose limiting toxicities per cohort to define the recommended phase II dose (RP2D) in the phase Ib part and confirmed the objective response rate and disease control rate (DCR) of non-RFA lesions in the phase II part. Secondary endpoints were progression-free survival (PFS) and OS. Ipilimumab 10 mg/kg + RFA was initially defined as the RP2D. However, after 19 patients, the study was amended to adjust the RP2D to ipilimumab 3 mg/kg + RFA, because 47% of patients treated with 10 mg/kg had developed grade 3 colitis. In the 3 mg/kg cohort, also 19 patients have been treated. Immunotherapy-related grade ≥3 adverse events were observed in 53% of patients in the 10 mg/kg cohort versus 32% in the 3 mg/kg cohort. No confirmed objective responses were observed; the confirmed DCR was 5% in the 10 mg/kg cohort and 11% in the 3 mg/kg cohort. Median PFS was 3 months and comparable for both cohorts, median OS was 14.2 months for the 10 mg/kg cohort versus 9.7 months for the 3 mg/kg cohort. Combining RFA with ipilimumab 3 mg/kg was well tolerated, but showed very limited clinical activity in uveal melanoma.

Adjuvant Hepatic Arterial Infusion Pump Chemotherapy After Resection of Colorectal Liver Metastases: Results of a Safety and Feasibility Study in The Netherlands.

BACKGROUND: The 10-year overall survival with adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after resection of colorectal liver metastases (CRLMs) was 61% in clinical trials from Memorial Sloan Kettering Cancer Center. A pilot study was performed to evaluate the safety and feasibility of adjuvant HAIP chemotherapy in patients with resectable CRLMs. STUDY DESIGN: A phase II study was performed in two centers in The Netherlands. Patients with resectable CRLM without extrahepatic disease were eligible. All patients underwent complete resection and/or ablation of CRLMs and pump implantation. Safety was determined by the 90-day HAIP-related postoperative complications from the day of pump placement (Clavien-Dindo classification, grade III or higher) and feasibility by the successful administration of the first cycle of HAIP chemotherapy. RESULTS: A total of 20 patients, with a median age of 57 years (interquartile range [IQR] 51-64) were included. Grade III or higher HAIP-related postoperative complications were found in two patients (10%), both of whom had a reoperation (without laparotomy) to replace a pump with a slow flow rate or to reposition a flipped pump. No arterial bleeding, arterial dissection, arterial thrombosis, extrahepatic perfusion, pump pocket hematoma, or pump pocket infections were found within 90 days after surgery. After a median of 43 days (IQR 29-52) following surgery, all patients received the first dose of HAIP chemotherapy, which was completed uneventfully in all patients. CONCLUSION: Pump implantation is safe, and administration of HAIP chemotherapy is feasible, in patients with resectable CRLMs, after training of a dedicated multidisciplinary team.

Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients.

There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy.

Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: European multicentre study on safety, short-term effects and survival.

OBJECTIVES: Cholangiocarcinoma is the second most common primary liver tumour with a poor overall prognosis. Percutaneous hepatic perfusion (PHP) is a directed therapy for primary and secondary liver malignancies, and its efficacy and safety have been shown in different entities. The purpose of this study was to prove the safety and efficacy of PHP in patients with unresectable intrahepatic cholangiocarcinoma (iCCA). PATIENTS AND METHODS: We retrospectively reviewed data from 15 patients with unresectable iCCA treated with PHP in nine different hospitals throughout Europe. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Adverse events (AEs) and toxicity were evaluated. RESULTS: Fifteen patients were treated with 26 PHPs. ORR was 20%, disease control was achieved in 53% after the first PHP. Median OS was 26.9 months from initial diagnosis and 7.6 months from first PHP. Median PFS and hPFS were 122 and 131 days, respectively. Patients with liver-only disease had a significantly longer median OS compared to patients with locoregional lymph node metastases (12.9 vs. 4.8 months, respectively; p < 0.01). Haematological toxicity was common, but manageable. No AEs of grade 3 or 4 occurred during the procedures. DISCUSSION: PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with iCCA, especially in non-metastatic disease. KEY POINTS: • Percutaneous hepatic perfusion (PHP) offers an additional locoregional therapy strategy for the treatment of unresectable primary or secondary intrahepatic malignancies. • PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with intrahepatic cholangiocarcinoma (iCCA), especially in non-metastatic disease. • Side effects seem to be tolerable and comparable to other systemic or local treatment strategies.

Outcome of sentinel lymph node biopsy in patients with clinically non-metastatic renal cell carcinoma.

OBJECTIVE: To investigate the rate of occult SN metastases, oncological outcome, and association of recurrence with the pattern of lymphatic tumour drainage in RCC. MATERIALS AND METHODS: A pooled RCC sub-group analysis was conducted of secondary endpoints from a published feasibility and a phase II prospective single-arm SN study to investigate oncological outcome. Patients with cT1-3 (<10 cm) cN0M0 RCC of any sub-type were enrolled. After intratumoural injection of Tc99m nanocolloid, pre-operative imaging of SNs with SPECT/CT was followed by (partial) nephrectomy with SN and regional lymph node dissection using a γ-probe. The patients were followed with a risk-adapted surveillance programme. Endpoints of the studies were analysed using Cox proportional hazard models. RESULTS: Sixty-six RCC patients were included. Two patients (3%, 95% CI =0.5-11%) had occult SN metastases and remained free of disease at 57 and 72 months. Ten patients (15%, 95% CI =7-26%) developed recurrences, and four (6%, 95% CI =2.3-14.5%) had died of disease at a median follow-up of 57 months (IQR =18-72 months). Occurrence of distant metachronous metastases were associated with tumour size (HR =1.39, p = 0.02), pT stage (HR =6.83, p < 0.01 for comparison T1 vs T3/4), Grade 3/4 (HR =8.38, p = 0.05 for comparison 1/2 vs 3/4) and interaortocaval sentinel lymph node location (HR =10.52, p = 0.03 for comparison yes vs no). CONCLUSIONS: The rate of occult metastatic SN is low, but long disease-free survival (DFS) was observed in two patients with occult SN metastases. We hypothesize an interaortocaval lymphatic route in thoracic recurrences. Evaluation of the prognostic and therapeutic role of sentinel lymph node biopsy (SLNB) requires a clinical trial in high-risk RCC.

An analysis of SPECT/CT non-visualization of sentinel lymph nodes in renal tumors.

BACKGROUND: Sentinel lymph node biopsy (SLNB) after intratumoral injection of 99mTc labeled nanocolloid and imaging with scintigraphy and SPECT/CT in renal tumors is feasible. However, sentinel lymph node (SN) non-detection rate with scintigraphy and SPECT/CT is high. The aim of the study was to determine factors affecting non-visualization (NV) of SN imaging in renal tumors. Seventy-eight patients with cT1-3 renal tumors received intratumoral injection of 225 MBq 99mTc-labeled nanocolloid 1 day before (partial) nephrectomy. Radiotracer injection was followed by anterioposterior and lateral scintigraphy in combination with SPECT/CT 20 min and 2-4 h after. Surgical treatment of the tumor with sentinel lymph node biopsy by aid of γ-probe and-camera was performed the next day. Scintigraphy and SPECT/CT images were evaluated and patient, tumor, and procedure characteristics were collected for 73 eligible patients used in uni- and multivariable analysis of a potential association with NV. RESULTS: A total of 80 (mean 1.1, IQR 0-2, max 6) sentinel lymph nodes in 46 patients were detected with scintigraphy and SPECT/CT. Preoperative visualization rate and intraoperative detection rate was 63% [95% CI 50-73%] and 61% [95% CI 49-72%], respectively. In uni- and multivariable analysis, the only factor associated with non-visualization was age, showing higher odds of non-visualization with higher age. CONCLUSION: Our study demonstrated that non-visualization of SNs in renal tumors is relatively high and is associated with patient age. Furthermore, kidneys and also its tumors are highly vascularized which may cause a wash-out effect that could be identified with decreased kidney-liver ratios. However, in our data, the effect was statistically inconclusive. Further studies are needed to improve visualization and standardize the procedure of SLNB in renal tumors. The percentage of NV limits the use of SLNB for research and clinical purposes in renal cancer.

Radiofrequency and Microwave Ablation Compared to Systemic Chemotherapy and to Partial Hepatectomy in the Treatment of Colorectal Liver Metastases: A Systematic Review and Meta-Analysis.

PURPOSE: To assess safety and outcome of radiofrequency ablation (RFA) and microwave ablation (MWA) as compared to systemic chemotherapy and partial hepatectomy (PH) in the treatment of colorectal liver metastases (CRLM). METHODS: MEDLINE, Embase and the Cochrane Library were searched. Randomized trials and comparative observational studies with multivariate analysis and/or matching were included. Guidelines from National Guideline Clearinghouse and Guidelines International Network were assessed using the AGREE II instrument. RESULTS: The search revealed 3530 records; 328 were selected for full-text review; 48 were included: 8 systematic reviews, 2 randomized studies, 26 comparative observational studies, 2 guideline-articles and 10 case series; in addition 13 guidelines were evaluated. Literature to assess the effectiveness of ablation was limited. RFA + systemic chemotherapy was superior to chemotherapy alone. PH was superior to RFA alone but not to RFA + PH or to MWA. Compared to PH, RFA showed fewer complications, MWA did not. Outcomes were subject to residual confounding since ablation was only employed for unresectable disease. CONCLUSION: The results from the EORTC-CLOCC trial, the comparable survival for ablation + PH versus PH alone, the potential to induce long-term disease control and the low complication rate argue in favour of ablation over chemotherapy alone. Further randomized comparisons of ablation to current-day chemotherapy alone should therefore be considered unethical. Hence, the highest achievable level of evidence for unresectable CRLM seems reached. The apparent selection bias from previous studies and the superior safety profile mandate the setup of randomized controlled trials comparing ablation to surgery.

Sensitivity and Reproducibility of Automated Feeding Artery Detection Software during Transarterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To evaluate the performance of automated feeder detection (AFD) software (EmboGuide; Philips Healthcare, Best, The Netherlands) on hepatocellular carcinoma (HCC) tumors during transarterial chemoembolization. MATERIALS AND METHODS: Forty-four first-time transarterial chemoembolization patients (37 men; mean age, 62 ± 11 years) were enrolled between May 2012 and July 2013. A total of 86 HCC lesions were treated (2.0 ± 1.4 lesions per patient; 27.6 ± 15.9 mm maximum diameter). One hundred forty-seven feeding arteries were found with digital subtraction angiography (DSA), cone-beam computed tomography (CT), and AFD software with the option of manual adjustment (MA). Three independent interventional radiologists analyzed the cone-beam CT images retrospectively with and without AFD and MA. Compared with the number of treated vessels, the number of true positives, false positives, false negatives, sensitivity, and interreader agreement were determined using clustered binary data analysis. RESULTS: Cone-beam CT enabled detection of 100 ± 3.5 feeding arteries (70% sensitivity) with 68.6% agreement among readers. AFD software significantly improved detection to 127±0.6 feeding arteries (86% sensitivity, P = .008) with 99.7% reader agreement and reduced the number of false negatives from an average of 47 ± 3.5 to 20 ± 0.6 (P = .008). MA of the AFD results produced similar feeding artery detection rates (127 ± 5.1, 86% sensitivity, P = .8), with lower interreader agreement (91.6%) and slightly fewer false positives (16 ± 0.0 to 14 ± 2.5, P = .4). CONCLUSIONS: AFD software significantly improved feeding artery detection rates during transarterial chemoembolization of HCC lesions with better user reproducibility compared with cone-beam CT alone. In conjunction with DSA, AFD enables maximum feeding artery detection in this setting.

Lymphatic Drainage from Renal Tumors In Vivo: A Prospective Sentinel Node Study Using SPECT/CT Imaging.

PURPOSE: Lymphatic drainage from renal tumors is unpredictable. In vivo drainage studies of primary lymphatic landing sites may reveal the variability and dynamics of lymphatic connections. The purpose of this study was to investigate the lymphatic drainage pattern of renal tumors in vivo with single photon emission/computerized tomography after intratumor radiotracer injection. MATERIALS AND METHODS: We performed a phase II, prospective, single arm study to investigate the distribution of sentinel nodes from renal tumors on single photon emission/computerized tomography. Patients with cT1-3 (less than 10 cm) cN0M0 renal tumors of any subtype were enrolled in analysis. After intratumor ultrasound guided injection of 0.4 ml 99mTc-nanocolloid we performed preoperative imaging of sentinel nodes with lymphoscintigraphy and single photon emission/computerized tomography. Sentinel and locoregional nonsentinel nodes were resected with a γ probe combined with a mobile γ camera. The primary study end point was the location of sentinel nodes outside the locoregional retroperitoneal templates on single photon emission/computerized tomography. Using a Simon minimax 2-stage design to detect a 25% extralocoregional retroperitoneal template location of sentinel nodes on imaging at α = 0.05 and 80% power at least 40 patients with sentinel node imaging on single photon emission/computerized tomography were needed. RESULTS: Of the 68 patients 40 underwent preoperative single photon emission/computerized tomography of sentinel nodes and were included in primary end point analysis. Lymphatic drainage outside the locoregional retroperitoneal templates was observed in 14 patients (35%). Eight patients (20%) had supradiaphragmatic sentinel nodes. CONCLUSIONS: Sentinel nodes from renal tumors were mainly located in the respective locoregional retroperitoneal templates. Simultaneous sentinel nodes were located outside the suggested lymph node dissection templates, including supradiaphragmatic sentinel nodes in more than a third of the patients.

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.

BACKGROUND: Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient. METHODS: We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed. RESULTS: A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions. CONCLUSIONS: We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours' phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation. TRIAL REGISTRATION: European Clinical Trials Database(EudraCT): 2009-016675-29 , registered 17 March 2010; EudraCT: 2006-004511-21 , registered 09 March 2007; EudraCT: 2006-006491-38 , registered 22 December 2006.

In vivo tumor identification of colorectal liver metastases with diffuse reflectance and fluorescence spectroscopy.

BACKGROUND AND OBJECTIVE: Over the last decade, an increasing effort has been put towards the implementation of optical guidance techniques to aid surgeons during cancer surgery. Diffuse reflectance spectroscopy (DRS) and fluorescence spectroscopy (FS) are two of these new techniques. The objective of this study is to investigate whether in vivo optical spectroscopy is able to accurately discriminate colorectal liver metastases (CRLM) from normal liver tissue in vivo. MATERIALS AND METHODS: DRS and FS were incorporated at the tip of a needle and were used for in vivo tissue differentiation during resection of CRLM. Measurements were taken in and around the tumor lesions and measurement sites were marked and correlated to histology (i.e., normal liver tissue or tumor tissue). Patients with and without neoadjuvant systemic chemotherapy were included into the study. RESULTS: Four hundred and eighty-four measurements were taken in and near 19 liver lesions prior to resection. Overall sensitivity and specificity for DRS was 95% and 92%, respectively. Bile was the most discriminative parameter. The addition of FS did not improve the overall accuracy. Sensitivity and specificity was not hampered by neo-adjuvant chemotherapy; sensitivity and specificity after neo-adjuvant chemotherapy were 92% and 100%, respectively. CONCLUSION: We have successfully integrated spectroscopy technology into a disposable 15 Gauge optical needle and we have shown that DRS and FS can accurately discriminate CRLM from normal liver tissue in the in vivo setting regardless of whether the patient was pre-treated with systemic therapy. This technique makes in vivo guidance accessible for common surgical practice. Lasers Surg. Med. 48:820-827, 2016. © 2016 Wiley Periodicals, Inc.

In vivo characterization of colorectal metastases in human liver using diffuse reflectance spectroscopy: toward guidance in oncological procedures.

There is a strong need to develop clinical instruments that can perform rapid tissue assessment at the tip of smart clinical instruments for a variety of oncological applications. This study presents the first in vivo real-time tissue characterization during 24 liver biopsy procedures using diffuse reflectance (DR) spectroscopy at the tip of a core biopsy needle with integrated optical fibers. DR measurements were performed along each needle path, followed by biopsy of the target lesion using the same needle. Interventional imaging was coregistered with the DR spectra. Pathology results were compared with the DR spectroscopy data at the final measurement position. Bile was the primary discriminator between normal liver tissue and tumor tissue. Relative differences in bile content matched with the tissue diagnosis based on histopathological analysis in all 24 clinical cases. Continuous DR measurements during needle insertion in three patients showed that the method can also be applied for biopsy guidance or tumor recognition during surgery. This study provides an important validation step for DR spectroscopy-based tissue characterization in the liver. Given the feasibility of the outlined approach, it is also conceivable to make integrated fiber-optic tools for other clinical procedures that rely on accurate instrument positioning.

Spectral sensing for tissue diagnosis during lung biopsy procedures: The importance of an adequate internal reference and real-time feedback.

OBJECTIVES: Difficulties in obtaining a representative tissue sample are a major obstacle in timely selecting the optimal treatment for patients with lung cancer or other malignancies. Having a modality to provide needle guidance and confirm the biopsy site selection could be of great clinical benefit, especially when small masses are targeted. The objective of this study was to evaluate whether diffuse reflectance spectroscopy (DRS) at the tip of a core biopsy needle can be used for biopsy site confirmation in real time, thereby enabling optimized biopsy acquisition and improving diagnostic capability. MATERIALS AND METHODS: We included a total of 23 patients undergoing a routine computed tomography (CT) guided transthoracic needle biopsy of a lesion suspected for lung cancer or metastatic disease. DRS measurements were acquired during needle insertion and clinically relevant parameters were extracted from the spectral data along the needle paths. Histopathology results were compared with the DRS data at the final measurement position. RESULTS: Analysis of the collective data acquired from all enrolled subjects showed significant differences (p<0.01) for blood content, stO2, water content, and scattering amplitude. The identified spectral contrast matched the final pathology in 20 out of 22 clinical cases that could be used for analysis, which corresponds with an overall diagnostic performance of 91%. Three cases underlined the importance of adequate reference measurements and the need for real time diagnostic feedback. Continuous real time DRS measurements performed during a biopsy procedure in one patient provided clear information with respect to the variation in tissue and allowed identification of the tumour boundary. CONCLUSIONS: The presented technology creates a basis for the design and clinical implementation of integrated fibre-optic tools for a variety of minimal invasive applications.

Baseline tumor volume in assessing prognosis of patients with intermediate-risk synchronous metastatic renal cell carcinoma.

OBJECTIVE: To analyze if prediction of survival for patients with synchronous metastatic renal cell cancer (mRCC) could be further refined by baseline volume of the primary tumor, the metastases, or the remaining volume after surgery; this study was performed because survival expectancies of patients with intermediate-risk mRCC vary substantially. MATERIAL AND METHODS: The predictive value of the different volumes on overall survival (OS) was analyzed retrospectively in patients with intermediate Memorial Sloan-Kettering Cancer Center (MSKCC) risk profile and ≤3 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) factors, who received sunitinib in our institute. Tumor volumes were calculated on segmented computed tomography using in-house developed software. A multivariate analysis was performed including number of metastatic sites and baseline tumor burden (TB). RESULTS: A total of 68 patients were included. Median OS for patients without cytoreductive nephrectomy (CN) was 6 months (95% CI: 3.0-8.9mo) vs. 31 months (95% CI: 23.1-38.8mo) for those with CN, respectively. More second-line treatment was given after CN (49% vs. 17%, P = 0.125). There was no correlation between tumor volume and TB measured by Response Evaluation Criteria in Solid Tumors. Of all included clinical and volumetric parameters, remaining volume after CN, CN status and 2 vs. 3 IMDC factors were significantly correlated with OS. In the Cox regression analysis, CN was the only remaining significant parameter (P = 0.003). CONCLUSIONS: None of the baseline volumetric parameters is an independent prognostic factor in patients with intermediate MSKCC risk mRCC with≤3 IMDC factors receiving sunitinib. Only CN status correlated significantly with prognosis. None of the baseline volumes nor TB by Response Evaluation Criteria in Solid Tumors was associated with CN status, suggesting that extent of disease had no significant influence on the decision to perform surgery.

Real-time In Vivo Tissue Characterization with Diffuse Reflectance Spectroscopy during Transthoracic Lung Biopsy: A Clinical Feasibility Study.

PURPOSE: This study presents the first in vivo real-time tissue characterization during image-guided percutaneous lung biopsies using diffuse reflectance spectroscopy (DRS) sensing at the tip of a biopsy needle with integrated optical fibers. EXPERIMENTAL DESIGN: Tissues from 21 consented patients undergoing lung cancer surgery were measured intraoperatively using the fiber-optic platform capable of assessing various physical tissue properties highly correlated to tissue architecture and composition. In addition, the method was tested for clinical use by performing DRS tissue sensing during 11 routine biopsy procedures in patients with suspected lung cancer. RESULTS: We found that water content and scattering amplitude are the primary discriminators for the transition from healthy lung tissue to tumor tissue and that the reliability of these parameters is not affected by the amount of blood at the needle tip. In the 21 patients measured intraoperatively, the water-to-scattering ratio yielded a 56% to 81% contrast difference between tumor and surrounding tissue. Analysis of the 11 image-guided lung biopsy procedures showed that the tissue diagnosis derived from DRS was diagnostically discriminant in each clinical case. CONCLUSIONS: DRS tissue sensing integrated into a biopsy needle may be a powerful new tool for biopsy guidance that can be readily used in routine diagnostic lung biopsy procedures. This approach may not only help to increase the successful biopsy yield for histopathologic analysis, but may also allow specific sampling of vital tumor tissue for genetic profiling.

Diffuse reflectance spectroscopy: toward real-time quantification of steatosis in liver.

Assessment of fatty liver grafts during orthotopic liver transplantation is a challenge due to the lack of real-time analysis options during surgery. Diffuse reflectance spectroscopy (DRS) could be a new diagnostic tool to quickly assess steatosis. Eight hundred and seventy-eight optical measurements were performed in vivo in 17 patients in liver tissue during surgery and ex vivo on liver resection specimens from 41 patients. Liver steatosis was quantified from the collected optical spectra and compared with the histology analysis from the measurement location by three independent pathologists. Twenty two patients were diagnosed with <5% steatosis, 15 patients had mild steatosis, and four had moderate steatosis. Severe steatosis was not identified. Intraclass correlation between the pathologists analysis was 0.949. A correlation of 0.854 was found between the histology and DRS analyses of liver steatosis ex vivo. For the same liver tissue, a correlation of 0.925 was demonstrated between in vivo and ex vivo DRS analysis for steatosis quantification. DRS can quantify steatosis in liver tissue both in vivo and ex vivo with good agreement compared to histopathology analysis. This analysis can be performed real time and may therefore be useful for fast objective assessment of liver steatosis in liver surgery.