Survival and Quality of Life after Isolated Hepatic Perfusion with Melphalan as a Treatment for Uveal Melanoma Liver Metastases - Final Results from the Phase III Randomized Controlled Trial SCANDIUM.

OBJECTIVE: To investigate overall survival (OS) and health-related quality of life (HRQOL) of first-line isolated hepatic perfusion (IHP) compared to best alternative care (BAC) for patients with uveal melanoma liver metastases. SUMMARY BACKGROUND DATA: Approximately half of patients with uveal melanoma develop metastatic disease, most commonly in the liver and systemic treatment options are limited. Isolated hepatic perfusion (IHP) is a locoregional therapy with high response rates but with unclear effect on overall survival (OS). METHODS: In this phase III randomized controlled multicenter trial (the SCANDIUM trial) patients with previously untreated isolated uveal melanoma liver metastases were included between 2013-2021, with at least 24 months of follow-up. The planned accrual was 90 patients randomized 1:1 to receive a one-time treatment with IHP or BAC. Crossover to IHP was not allowed. The primary endpoint was the 24-month OS rate, with the hypothesis of a treatment effect leading to a 50% OS rate in the IHP group compared to 20% in the control group. HRQOL was measured by the EuroQol 5-domains 3-levels (EQ-5D-3L) questionnaire over 12 months. RESULTS: The intention-to-treat (ITT) population included 87 patients randomized to the IHP group (43 patients; 41 [89%] received IHP) or the control group (44 patients). The control group received chemotherapy (49%), immunotherapy (39%), or localized interventions (9%). In the ITT population, the median PFS was 7.4 months in the IHP group compared with 3.3 months in the control group, with a hazard ratio of 0.21 (95% CI, 0.12-0.36). The 24-month OS rate was 46.5% in the IHP group versus 29.5% in the control group (P=0.12). The median OS was 21.7 months versus 17.6 months, with a hazard ratio of 0.64 (95% CI, 0.37-1.10). EQ-5D-3L showed a sustained high health status for the IHP group over 12 months, compared to a deteriorating trend in the control group. CONCLUSIONS: For patients with liver metastases from uveal melanoma, IHP offers high response rates translating to a benefit in PFS including a trend of better HRQOL compared to the control group. However, the primary endpoint of OS at 24 months was not met.

Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.

BACKGROUND & AIMS: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies. METHODS: Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia. RESULTS: Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN. CONCLUSIONS: BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations. IMPACT AND IMPLICATIONS: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN.

Variation in response rates to isolated limb perfusion in different soft-tissue tumour subtypes: an international multi-centre study.

OBJECTIVE: The aim of this study was to investigate the response rates of different extremity soft-tissue sarcoma subtypes (eSTS) after isolated limb perfusion (ILP), based on an international multi-centre study. MATERIALS AND METHODS: The retrospective cohort comprised eSTS patients from 17 specialised ILP centres that underwent melphalan-based ILP, with or without recombinant human tumour necrosis factor (rhTNFα) (TM-ILP and M-ILP, respectively). Response was measured on imaging (magnetic resonance imaging) and/or clinical response, for which M-ILPs were excluded. RESULTS: A total of 1109 eSTS patients were included. The three most common histological subtypes were undifferentiated pleomorphic sarcoma (17%, n = 184), synovial sarcoma (16%, n = 175) and myxofibrosarcoma (8%, n = 87). rhTNFα was used in 93% (TM-ILP) and resulted in a significantly better overall response rate (ORR, p = 0.031) and complete responses (CR, p < 0.001) in comparison to M-ILP, without significant differences among histological subgroups. The ORR of TM-ILP was 68%, including 17% CR. Also, 80% showed progressive disease. Significantly higher response rates were shown for Kaposi sarcoma (KS) with 42% CR and 96% ORR (both p < 0.001), and significantly higher CR rates for angiosarcoma (AS, 45%, p < 0.001) and clear cell sarcoma (CCS, 31%, p = 0.049). ILP was followed by resection ≤ 6 months in 80% of the patients. The overall limb salvage rate was 88%, without significant differences among histological subgroups, but was significantly higher for ILP responders compared to non-responders (93% versus 76%, p < 0.001). CONCLUSION: ILP resulted in high response and LRS among all eSTS subtypes, however, with significant differences between subtypes with most promising results for KS, AS and CCS.

Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial).

PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

Effects of the Introduction of Modern Immunotherapy on the Outcome of Isolated Limb Perfusion for Melanoma In-Transit Metastases.

Isolated limb perfusion (ILP) is an effective locoregional treatment for melanoma in-transit metastasis, but the advent of modern effective immunotherapy, such as ICI (immune checkpoint inhibitors), has changed the treatment landscape. The primary aims of this study were to compare the characteristics of the patient population receiving ILP before and after the introduction of modern systemic treatments and to assess if outcomes after ILP were influenced by previous immunotherapy treatment. A single-centre analysis of patients that underwent ILP for melanoma in-transit metastasis between 2010 and 2021 was conducted, with patients grouped and compared by treatment time period: pre-ICI era (2010-2014) and ICI era (2017-2021). 218 patients were included. Patients undergoing ILP in the ICI era were slightly older (median age 73 vs. 68 years) compared to the pre-ICI era, with no other difference found. The overall response rate (ORR) was 83% vs. 84% and the complete response (CR) rate was 52% vs. 47% for the pre-ICI era and the ICI era, respectively. For patients that had received and failed immunotherapy prior to ILP (n = 20), the ORR was 75% and the CR rate was 50%. Melanoma-specific survival has improved, with a 3-year survival rate of 54% in the pre-ICI era vs. 86% in the ICI era. The patient population undergoing ILP for in-transit melanoma is largely unchanged in the current era of effective systemic treatments. Response rates have not decreased, and prior ICI treatment did not affect response rates, making ILP still a valid treatment option for this patient group.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

Using a Clinicopathologic and Gene Expression (CP-GEP) Model to Identify Stage I-II Melanoma Patients at Risk of Disease Relapse.

Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I−II melanoma) is watchful waiting, while >40% of patients with stage IB−IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I−II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I−II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4−96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3−84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41−6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a 'low risk' of recurrence (96.8% 5-year RFS (95%CI 91.6−98.8), n = 130), 49% as 'intermediate risk' (88.4% 5-year RFS (95%CI 83.6−91.8), n = 261), and 26% as 'high risk' (61.1% 5-year RFS (95%CI 51.9−69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I−II melanoma into two groups differentiated by RFS.

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy Trial II (MSLT-2).

BACKGROUND: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown. METHODS: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment. CONCLUSIONS: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients. LAY SUMMARY: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

Surveillance of Sentinel Node-Positive Melanoma Patients with Reasons for Exclusion from MSLT-II: Multi-Institutional Propensity Score Matched Analysis.

BACKGROUND: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown. STUDY DESIGN: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared. RESULTS: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin-only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86). CONCLUSIONS: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.

Presence of tumor-infiltrating CD8+ T cells and macrophages correlates to longer overall survival in patients undergoing isolated hepatic perfusion for uveal melanoma liver metastasis.

Uveal melanoma is a malignant tumor of the eye that often metastasizes to the liver conferring poor prognosis. When comparing immune profiles in peripheral blood of untreated patients with uveal melanoma liver metastasis and healthy blood donors, it was observed that immune cells of uveal melanoma patients carried immunosuppressive features. Patient blood contained an increased content of CD14+HLA-DR-/low M-MDSCs and inflammatory CD16+ monocytes, while their dendritic cells expressed lower levels of activation markers. Melanoma patients also harbored an enhanced fraction of CD4+Foxp3+ regulatory T cells, while their effector T cells expressed lower levels of the activation marker HLA-DR. Biopsies from liver metastases were obtained from patients with uveal melanoma that subsequently underwent hyperthermic isolated hepatic perfusion (IHP) with melphalan. There were trends indicating a positive correlation between a high infiltration of CD8+ T cells in metastases and an activated immune cell profile in blood. High metastatic infiltration of CD8+ T cells and CD68+ macrophages, but not of immunosuppressive CD163+ macrophages, correlated to a longer overall survival in patients treated with IHP. Hence, while the immune system of patients with uveal melanoma shows signs of immunosuppression, the presence of activated immune cells may correlate to a longer survival, at least following IHP treatment.

Systematic Review and Meta-analysis: Partial External Biliary Diversion in Progressive Familial Intrahepatic Cholestasis.

OBJECTIVES: We assessed available data on impact of partial external biliary diversion (PEBD) surgery on clinical outcomes in patients with progressive familial intrahepatic cholestasis (PFIC). METHODS: We performed a systematic literature review (PubMed) and meta-analysis to evaluate relationships between liver biochemistry parameters (serum bile acids, bilirubin, and alanine aminotransferase [ALT]) and early response (pruritus improvement) or long-term outcomes (need for liver transplant) in patients with PFIC who underwent PEBD. RESULTS: Searches identified 175 publications before September 2018; 16 met inclusion criteria. Receiver operating characteristic (ROC) analysis examined ability of liver biochemistry parameters to discriminate patients who demonstrated early and long-term response to PEBD from those who did not. Regarding pruritus improvement in 155 included patients in aggregate, 104 (67%) were responders, 14 (9%) had partial response, and 37 (24%) were nonresponders. In ROC analyses of individual patient data, post-PEBD serum concentration of bile acids, in particular, could discriminate responders from nonresponders for pruritus improvement (area under the curve, 0.99; P < 0.0001; n = 42); to a lesser extent, this was also true for bilirubin (0.87; P = 0.003; n = 31), whereas ALT could not discriminate responders from nonresponders for pruritus improvement (0.74; P = 0.06; n = 28). Reductions from pre-PEBD values in serum bile acid concentration (0.89; P = 0.0003; n = 32) and bilirubin (0.98; P = 0.002; n = 18) but not ALT (0.62; P = 0.46; n = 18) significantly discriminated decreased aggregate need for liver transplant. CONCLUSION: Changes in bile acids seem particularly useful in discriminating early and long-term post-PEBD outcomes and may be potential biomarkers of response to interruption of enterohepatic circulation in patients with PFIC.

Is blood a necessary component of the perfusate during isolated limb perfusion - a randomized controlled trial.

Background: Isolated limb perfusion (ILP) is a treatment option for malignancies localized to an extremity and is performed by surgical isolation of the limb which is connected to an extracorporeal circulation system. A high concentration of a chemotherapeutic agent is perfused through the limb, while systemic toxicity is avoided. Currently, the use of packed red blood cells in the priming solution is the norm during ILP. The aim of this study was to investigate the possibility to replace an erythrocyte-based prime solution with a crystalloid-based prime solution while maintaining the regional metabolic oxygen demand during ILP. Methods: In a single-center, randomized controlled, non-blinded, non-inferiority clinical trial, 21 patients scheduled for treatment with ILP were included and randomized 1:1 to either an erythrocyte-based prime solution (control) or a crystalloid-based prime solution (intervention). Results: There was a significant difference in lactate level (mmol/L) during the perfusion between the intervention group and the control group (1.6 ± 0.4 vs. 3.6 ± 0.7, p = .001). No significant differences in oxygen extraction (%) (22 ± 11 vs. 14 ± 4, p = .06), oxygen delivery (ml/min) (90 ± 49 vs. 108 ± 38, p = .39), oxygen consumption (ml/min) (14 ± 2 vs. 14 ± 5, p = .85), regional central venous saturation (%) (83 ± 10 vs. 91 ± 4, p = .07) or INVOS (%) (76 ± 14 vs. 81 ± 11, p = .42) were found between the intervention group and the control group. Conclusion: This study showed no significant improvement with the addition of packed red blood cells into the prime solution in ensuring the metabolic oxygen demand in the treated extremity during ILP, and we, therefore, recommend that a crystalloid-based prime solution should be used.

Leakage through the bone-marrow during isolated limb perfusion in the lower extremity.

Isolated limb perfusion (ILP) is used for melanoma in-transit metastases of the extremities. The use of Melphalan and TNF-alpha, necessitates monitoring of possible systemic leakage throughout the perfusion. It has been suspected that leakage through bone marrow is possible. We present the case of a patient with in-transit melanoma metastases in the lower extremity, who underwent minimally invasive ILP, according to our new protocol through percutaneous insertion of the catheters under fluoroscopy. Following cannulation of the vessels a high leakage rate was recorded. The procedure was converted to open with clamping of the artery and vein, however the leakage was not possible to control, and venography showed that this was due to bone marrow veins. To the best of our knowledge this is the first case of a verified leakage during ILP through bone marrow veins. We believe that some minor leakages registered under ILP could be attributed to this leakage route.

BRAF status as a predictive factor for response in isolated limb perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution. METHODS: Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria. RESULTS: Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months. CONCLUSION: In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.

Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma.

BACKGROUND: Isolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP. METHOD: Between 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68 second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien-Dindo). RESULTS: The results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p = 0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93 months (p = 0.02). CONCLUSION: As a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.

Sentinel node for malignant melanoma: An observational study of a consecutive single centre experience.

INTRODUCTION: Sentinel node biopsy (SNB) for melanoma gives prognostic information, however the success is dependent on several factors. The aim of this study was to describe outcome data after the introduction of the technique at our centre, including analysis of false negative rate (FNR), predictive factors for positive sentinel node (SN) and non-sentinel node (NSN), as well as prognostic factors for melanoma-specific survival (MSS). MATERIALS AND METHODS: This is a retrospective observational study of a prospectively kept database at Sahlgrenska University Hospital. Between March 2000 and December 2013, 769 consecutive patients with cutaneous malignant melanoma undergoing SNB were included. The median follow-up time was 55 months (2-179 months). Tumour load in the SN was categorized according to the largest tumour deposit, low when ≤1 mm and high when >1 mm. RESULTS: The FNR was 20% and the SN positivity rate was 14% with a decrease in both FNR and SN positivity rate during the study period. In multivariate analysis the only predictive factor for a positive SN was Breslow thickness. The 5-year melanoma specific survival (MSS) was 81% and in multivariate analysis the prognostic factors were SN-status (low metastatic load HR = 2.6, p = 0.001; high metastatic load HR = 2.7, p = 0.004) followed by Breslow thickness and ulceration. CONCLUSIONS: In this study Breslow thickness was the only independent predictive factor for a positive SN, no predictive factors were identified for NSN. Independent prognostic factors for MSS were SN status, Breslow thickness and ulceration. Interestingly, there was no survival difference depending on SN tumour burden when using 1 mm as cut-off.

Minimally invasive isolated limb perfusion - technical details and initial outcome of a new treatment method for limb malignancies.

OBJECTIVE: Isolated limb perfusion (ILP) and isolated limb infusion (ILI) are treatment options for patients with locally advanced melanomas and sarcomas of the extremities. ILP potentially have higher response rates, but requires open surgery for vascular access, whereas ILI is minimally invasive and easier to perform. We now present the technical details and outcome of a new approach to ILP by a minimally invasive vascular access (MI-ILP). METHODS: Six patients, five with melanoma in-transit metastases and one with squamous cell carcinoma, were included in a phase I feasibility trial. Percutaneous vascular access of the extremity vessels was performed and the inserted catheters were then connected to a perfusion system. RESULTS: All six treated patients underwent the procedure without the need for conversion to open surgery. The median operating time was 164 min and the median leakage rate was 0.1%. The complete response rate was 67%. Four patients (67%) had a Wieberdink grade II reaction and two patients (33%) had a grade III reaction. CONCLUSIONS: MI-ILP is feasible and gives the same treatment characteristics as open ILP, but with the advantage of a minimally invasive vascular access.

The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is used to treat in-transit metastases of melanoma of the extremities when surgical excision is not possible. The optimal setting concerning temperature and perfusion time is unknown. The purpose of this study was to analyze these factors concerning their effects on response, toxicity, and survival. METHODS: A retrospective analysis of 284 consecutive stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period (July 1986-May 2017), was performed. Our series was divided in four time periods, according to perfusion temperature and duration. Demographical data, stage, number, and size of lesions were retrieved from our prospective database. RESULTS: Overall response (OR) rate 83% and a complete response (CR) rate of 59%. Significant predictive factors for CR in multivariate analysis were non-bulky tumor, fewer metastases, and a perfusion time of 120 min. Predictive factors for increased local toxicity were femoral ILP and higher perfusion temperatures. The median overall survival was 30 months, and the independent negative prognostic factors were lymph-node status, bulky tumors, response, upper limb perfusion, and 120 min perfusion at 39-40 °C. CONCLUSIONS: Modern ILP uses diminished perfusion time and lower temperature, leading to a decrease in toxicity. However, our data also show a decrease in response, which indicates that optimal perfusion time and temperature regimen remain to be determined.

Evaluation of intraoperative touch imprint cytology on axillary sentinel lymph nodes in invasive breast carcinomas, a retrospective study of 1227 patients comparing sensitivity in the different tumor subtypes.

BACKGROUND: Intraoperative evaluation of the axillary sentinel lymph node (SLN) in patients with breast carcinoma reduces the need of re-operations in cases where an axillary completion lymph node dissection (CLND) is indicated. Different methods have been used to determine the SLN status intraoperatively, e.g. frozen section histology (FS) and touch imprint cytology (TIC). The sensitivity of intraoperative TIC examination on SLN is not consistent between different studies and varies according to different tumor histologic subtypes, tumor size and the age of the patient. The aim of this study was to describe the specificity and sensitivity of TIC and to compare TIC sensitivity in the different histological subtypes of breast carcinoma. METHODS: A retrospective review was performed of 1227 consecutive clinically node negative breast cancer patients treated with sentinel lymph node biopsy (SLNB) with intraoperative TIC between the years 2003 and 2008. The SLN was bisected and stained using the May-Grünwald-Giemsa method and immunocytochemically with the antibody MNF-116. RESULTS: The overall sensitivity of the TIC test was 68.6% and the specificity was 99.8%. There was no statistically significant difference between the detection of SLN metastases from ductal carcinoma versus lobular carcinoma. The sensitivity improved over the period of the study. CONCLUSION: TIC is highly specific with an acceptable overall sensitivity. The sensitivity increased under the period of the study and it was higher in cases with larger size of the primary tumor. There was no difference in TIC sensitivity between the different histological subtypes.