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Background: Immune checkpoint inhibitors (ICIs) have significantly improved the overall survival of patients with metastatic melanoma. It is unclear how the growing group of metastatic melanoma survivors resume their lives after treatment, and which needs they have regarding survivorship care (SSC). Objectives: To gain an in‐depth understanding of metastatic melanoma survivors' experiences of resuming life after ICIs and their associated SSC needs. Methods: A qualitative study was conducted among 20 patients with metastatic melanoma in whom ICIs had been discontinued after ongoing tumour response. One focus group (n = 9) was held, which was complemented by 11 individual interviews. Purposive sampling was used to select a variable sample in terms of sex, age, time since discontinuation of ICIs, and perceived impact of the disease. A topic guide was used to structure the (group) interviews, which were transcribed verbatim and analysed in a thematic content analysis, using several phases of coding. Results: In resuming life after ICIs, the prognosis switch often caused mixed feelings among patients, mainly because of the uncertainty about the future. Demands and expectations from self and others, persistent complaints and new problems in different life domains often make it challenging to proceed with life as it was prior to metastatic cancer. Patients indicated they needed to find a new balance, which included learning to cope with uncertainty and a changed perspective on life and close relationships. In terms of SSC needs, patients particularly stressed the need for more tailored patient information, available at one location. In addition, they emphasized the need to know who to turn to in case of questions and indicated the need for psychosocial support, also for their close relatives. Conclusions: Metastatic melanoma survivors face various challenges in resuming life after ICIs and are left with several unmet SSC needs. Efforts should be focused on offering psychosocial supportive care in addition to medical care, from diagnosis onwards, taking into account the patient's close relatives. A single point of contact and personalized survivorship care plan (SCP) could be of added value in guiding them through the patient journey, which is, given its multidisciplinary nature, particularly important in melanoma care. What is already known about this topic?Since the introduction of immune checkpoint inhibitors (ICIs) the overall survival of patients with metastatic melanoma has improved significantly, leading to a growing group of melanoma survivors.Melanoma survivors may face various problems and challenges in resuming life after treatment, which may be associated with unmet survivorship care (SSC) needs.An in‐depth understanding of their experiences with resuming life and the associated SSC needs is currently lacking. What does this study add?Metastatic melanoma survivors experience various challenges after immunotherapy, from the uncertain prognosis switch to the struggle of finding a new balance in life.Besides negative aspects, such as complaints in different life domains, the patient journey is often accompanied by positive outcomes, for example a changed perspective on life.They stress the need for tailored patient information and broader supportive care, also for their close relatives. What are the clinical implications of this work?In addition to medical care, efforts should be focused on offering psychosocial supportive care, including return‐to‐work issues, from diagnosis onwards, ideally taking into account the patient's close relatives.To guide them through the patient journey, a single point of contact and a personalized survivorship care plan (SCP) could be of added value.The latter is particularly important in melanoma care, given its multidisciplinary nature. With this qualitative study we provided an in‐depth understanding of metastatic melanoma survivors' experiences of resuming life after ICIs and their associated SSC needs. They face various challenges in resuming life and efforts should be focused on offering psychosocial supportive care, in addition to medical care, from diagnosis onwards, taking into account the patient's close relatives. A single point of contact and personalized survivorship care plan (SCP) could be of added value in guiding them through the patiënt journey which is, given its multidisciplinary nature, particularly important in melanoma care. Linked Comment:E.N. Clarke. Br J Dermatol 2022; 187:286–287. [ABSTRACT FROM AUTHOR]

ILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM). In this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs). A total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms. For patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial. [ABSTRACT FROM AUTHOR]

The extent of surgical management of regional lymph nodes in the treatment of cutaneous head and neck melanoma on and anterior to O'Brien's watershed line is controversial. By comparing patients' cohorts of two separate melanoma expert centers we investigate the effectiveness of comprehensive versus (super-) selective neck dissection approach. Sixty patients with macroscopic (palpable) neck node metastases (N2b) from anterior scalp and face melanoma were retrospectively studied. Forty therapeutic modified radical neck dissections (MRND; levels I–V) combined with elective parotidectomy from The Netherlands Cancer Institute (NCI) were compared with 16 (super-) selective neck dissections [(S)SND; 3–4 levels] and 4 solely MRNDs from Erasmus Medical Center (EMC). Cohorts were analyzed for site of recurrence, overall survival (OS), melanoma-specific survival (MSS), and disease-free survival (DFS). Clinical characteristics of patients were equal in both groups. In the NCI cohort 62.5% (n = 25) of patients recurred versus 65% (n = 13) in the EMC cohort. None of the NCI recurrences affected the parotid gland in contrast to 3 patients in the EMC group. Survival characteristics were not different between the two groups: OS (p = 0.56), MSS (p = 0.98), DFS (p = 0.92). This study does not support to continue the practice of routine elective parotidectomy and MRND in melanoma patients undergoing a lymph node dissection for macroscopic (palpable) nodal disease and justifies (S)SND. [ABSTRACT FROM AUTHOR]

Purpose: Sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive technique for nodal staging. Since associated morbidity is not negligible, it is highly relevant to pursue a more minimally invasive alternative. The purpose of this study was to prospectively evaluate the sensitivity of fine needle aspiration cytology (FNAC) with combined gamma probe and ultrasound (US) guidance in comparison with the gold standard histology of the sentinel node (SN) after SLNB for detecting metastasis.Methods: The study was designed as a prospective, multicentre, open-label, single-arm trial enrolling patients with newly diagnosed cutaneous melanoma or breast cancer between May 2015 and August 2017. Sample radioactivity was measured using a Mini 900 scintillation monitor. After FNAC, all patients underwent SLNB. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated.Results: Accrual was terminated early following an unplanned interim analysis indicating that a FNAC sensitivity of at least 80% could not be achieved. In total 58 patients of the originally planned 116 patients underwent FNAC with gamma probe and US guidance. There were no true-positive FNAC results, 14 false-negative results and one false-positive result, and thus the sensitivity, specificity, PPV and NPV of FNAC were 0%, 98%, 0% and 75%, respectively. At least 75% of the FNAC samples had a radioactivity signal higher than the background signal.Conclusion: FNAC with gamma probe and US guidance is not able to correctly detect metastases in the SN and is therefore not able to replace SLNB. Gamma probe-guided US is a highly accurate method for correctly identifying the SN, which offers possibilities for future research. [ABSTRACT FROM AUTHOR]

Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma of the skin is the most lethal form of skin cancer. Almost 40% of the patients who die of metastatic melanoma did not have metastases at first diagnosis. More knowledge about patient and tumour characteristics as well as patterns of disease progression is needed. We described the characteristics and disease patterns of early-stage melanomas that progress into metastatic disease. We observed that more than half of the patients with metastases were initially diagnosed with early-stage disease. Additionally, we found that melanomas in some specific body sites were likely to metastasize to certain organs. Our finding that a substantial proportion of patients with metastases were initially diagnosed with early-stage disease highlights the need to investigate who these high-risk patients are. The characteristics and disease patterns of primary stage I and II cutaneous melanomas that progress to stage III or IV disease were investigated based on data from the Netherlands Cancer Registry (NCR). Data on stage III or IV melanomas at first diagnosis or during follow-up between 2017 and 2019 were retrieved. Patient and primary tumour characteristics were investigated in relation to time to disease progression and the number of organ sites with metastatic disease using regression models. In total, 2763 patients were included, of whom 1613 were diagnosed with stage IV disease. Among the patients with stage IV disease, 60% (n = 963) were initially diagnosed with stage I or II disease. The proportion of patients who received a sentinel lymph node biopsy increased after the introduction of adjuvant therapy in 2019 from 61% to 87%. Among all patients with stage III disease who were eligible for adjuvant systemic therapy (n = 453) after 2019, 37% were not treated with this therapy. Among patients with stage IV disease, lung metastases were most often detected as the first metastatic site and females presented with more metastatic sites than males. Most patient and primary tumour characteristics were not associated with the distant metastatic organ site, except melanoma localisation in the lower extremities and the head or neck. Our observation that most stage IV patients were initially diagnosed with early-stage disease highlights the need for more accurate risk prediction models. [ABSTRACT FROM AUTHOR]

B Background: b Isolated limb perfusion (ILP) is a treatment option for patients with melanoma in-transit metastases of the extremities. B Conclusions: b The NivoILP trial is a randomized controlled trial evaluating the effect of a single dose of nivolumab for patients with in-transit melanoma metastases treated with isolated limb perfusion. [Extracted from the article]

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma for which clinical examination up to 10 years is recommended. The objective of this study was to identify prognostic factors for recurrences and metastases that can be used to evaluate the validity of follow-up schedules after treatment for DFSP.Methods: Patients with DFSP who received treatment between 1991 and 2016 at 3 tertiary centers were included. Cox regression analyses were conducted to identify variables associated with the primary endpoints.Results: In total 357 patients were included, with a median age of 38 years (age range, 2-87 years) and a median follow-up of 60 months (interquartile range, 24-115 months). Eighty-one patients developed recurrent disease (22.7%), and the median time to recurrence was 55.5 months (interquartile range, 20-90 months). Of these, 50 tumors (61.7%) were identified by patient self-examination, whereas 3 recurrences (3.7%) were identified at clinical surveillance. For the remaining 28 tumors, no information was available on how the recurrences were identified (34.6%). Fibrosarcomatous change (hazard ratio, 21.865; P < .001), and positive resection margins (hazard ratio, 14.645; P < .001), were independent prognostic factors for recurrence. Metastases occurred in 4 patients (1.1%). All tumors were identified by imaging after patients presented with symptomatic metastases. Fibrosarcomatous change (P < .001) and tumor size >5 cm (P = .014) were associated with the development of metastases.Conclusions: Disease recurrence after resection of DFSP remains a significant issue, whereas metastases are uncommon. The majority of recurrences are identified by patient self-examination. Consideration should be given to individualized follow-up schedules based on risk factors for recurrences and metastases. [ABSTRACT FROM AUTHOR]

CD4+type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Usingex vivoisolated cells from individuals with hepatocellular carcinoma (HCC;n= 39) or liver metastases from colorectal cancer (LM-CRC;n= 60) we identify a CD4+FoxP3−IL-13−IL-10+T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention. [ABSTRACT FROM AUTHOR]

Large inter-surgeon variability exists in technical anatomical resectability assessment of colorectal cancer liver-only metastases (CRLM) following induction systemic therapy. We evaluated the role of tumour biological factors in predicting resectability and (early) recurrence after surgery for initially unresectable CRLM. 482 patients with initially unresectable CRLM from the phase 3 CAIRO5 trial were selected, with two-monthly resectability assessments by a liver expert panel. If no consensus existed among panel surgeons (i.e. same vote for (un)resectability of CRLM), conclusion was based on majority. The association of tumour biological (sidedness, synchronous CRLM, carcinoembryonic antigen and RAS / BRAF V600E mutation status) and technical anatomical factors with consensus among panel surgeons, secondary resectability and early recurrence (<6 months) without curative-intent repeat local treatment was analysed by uni- and pre-specified multivariable logistic regression. After systemic treatment, 240 (50%) patients received complete local treatment of CRLM of which 75 (31%) patients experienced early recurrence without repeat local treatment. Higher number of CRLM (odds ratio 1.09 [95% confidence interval 1.03–1.15]) and age (odds ratio 1.03 [95% confidence interval 1.00–1.07]) were independently associated with early recurrence without repeat local treatment. In 138 (52%) patients, no consensus among panel surgeons was present prior to local treatment. Postoperative outcomes in patients with and without consensus were comparable. Almost a third of patients selected by an expert panel for secondary CRLM surgery following induction systemic treatment experience an early recurrence only amenable to palliative treatment. Number of CRLM and age, but no tumour biological factors are predictive, suggesting that until there are better biomarkers; resectability assessment remains primarily a technical anatomical decision. • Role of tumour biological factors in resectability assessment of colorectal cancer liver-only metastases was evaluated. • 31% of locally treated patients had early recurrence without repeat local treatment. • Number of colorectal cancer liver-only metastases and age are predictive for early recurrence without repeat local treatment. • Resectability assessment remains primarily a technical anatomical decision. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a prediction model for 10-year overall survival (OS) after resection of colorectal liver metastasis (CRLM) based on patient, tumour and treatment characteristics. Consecutive patients after complete resection of CRLM were included from two centres (1992–2019). A prediction model providing 10-year OS probabilities was developed using Cox regression analysis, including KRAS, BRAF and histopathological growth patterns. Discrimination and calibration were assessed using cross-validation. A web-based calculator was built to predict individual 10-year OS probabilities. A total of 4112 patients were included. The estimated 10-year OS was 30% (95% CI 29–32). Fifteen patient, tumour and treatment characteristics were independent prognostic factors for 10-year OS; age, gender, location and nodal status of the primary tumour, disease-free interval, number and diameter of CRLM, preoperative CEA, resection margin, extrahepatic disease, KRAS and BRAF mutation status, histopathological growth patterns, perioperative systemic chemotherapy and hepatic arterial infusion pump chemotherapy. The discrimination at 10-years was 0.73 for both centres. A simplified risk score identified four risk groups with a 10-year OS of 57%, 38%, 24%, and 12%. Ten-year OS after resection of CRLM is best predicted with a model including 15 patient, tumour, and treatment characteristics. The web-based calculator can be used to inform patients. This model serves as a benchmark to determine the prognostic value of novel biomarkers. • A prediction model for a 10-year OS after colorectal liver metastasis resection was developed. • Fifteen characteristics were independent factors (discrimination: 0.73). • A risk score identified four groups with a 10-year OS of 57%, 38%, 24% and 12%. [ABSTRACT FROM AUTHOR]

No studies extensively compared the young adults (YA, 18–39 years), middle-aged (40–69 years), and elderly (≥70 years) population with primary high-grade extremity soft tissue sarcoma (eSTS). This study aimed to determine whether the known effect of age on overall survival (OS) and disease progression can be explained by differences in tumour characteristics and treatment protocol among the YA, middle-aged and elderly population in patients with primary high-grade eSTS treated with curative intent. In this retrospective multicentre study, inclusion criteria were patients with primary high-grade eSTS of 18 years and older, surgically treated with curative intent between 2000 and 2016. Cox proportional hazard models and a multistate model were used to determine the association of age on OS and disease progression. A total of 6260 patients were included in this study. YA presented more often after 'whoops'-surgery or for reresection due to residual disease, and with more deep-seated tumours. Elderly patients presented more often with grade III and larger (≥10 cm) tumours. After adjustment for the imbalance in tumour and treatment characteristics the hazard ratio for OS of the middle-aged population is 1.47 (95% confidence interval [CI]: 1.23–1.76) and 3.13 (95% CI: 2.59–3.78) in the elderly population, compared with YA. The effect of age on OS could only partially be explained by the imbalance in the tumour characteristics and treatment variables. The threefold higher risk of elderly could, at least partially, be explained by a higher other-cause mortality. The results might also be explained by a different tumour behaviour or suboptimal treatment in elderly compared with the younger population. • Young adults presented more often after 'whoops'-surgery or reresection. • Elderly patients presented more often with grade III and larger tumours. • With increasing age, overall survival decreases and recurrence rates increases. • This could partially be explained by the imbalance in tumour/treatment variables. [ABSTRACT FROM AUTHOR]

Based on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making. • Advances in treatment of sentinel node–positive melanoma prompt new stratification. • Outcome predictions are based on factors from the primary melanoma and sentinel node. • Predictions are presented in the form of a nomogram. • Models are successful in external validation using a large prospective German cohort. • Information on non-sentinel nodes after completion dissection is not necessary. [ABSTRACT FROM AUTHOR]

Background Sentinel node biopsy (SNB) is essential for adequate melanoma staging. Most melanoma guidelines advocate to perform wide local excision and SNB as soon as possible, causing time pressure. Objective To investigate the role of time interval between melanoma diagnosis and SNB on sentinel node (SN) positivity and survival. Methods This is a retrospective observational study concerning a cohort of melanoma patients from four European Organization for Research and Treatment of Cancer Melanoma Group tertiary referral centres from 1997 to 2013. A total of 4124 melanoma patients underwent SNB. Patients were selected if date of diagnosis and follow-up (FU) information were available, and SNB was performed in <180 d. A total of 3546 patients were included. Multivariable logistic regression and Cox regression analyses were performed to investigate how baseline characteristics and time interval until SNB are related to positivity rate, disease-free survival (DFS) and melanoma-specific survival (MSS). Findings Median time interval was 43 d (interquartile range [IQR] 29–60 d), and 705 (19.9%) of 3546 patients had a positive SN. Sentinel node positivity was equal for early surgery (≤43 d) versus late surgery (>43 d): 19.7% versus 20.1% (p = 0.771). Median FU was 50 months (IQR 24–84 months). Sentinel node metastasis (hazard ratio [HR] 3.17, 95% confidence interval [95% CI] 2.53–3.97), ulceration (HR 1.99, 95% CI 1.58–2.51), Breslow thickness (HR 1.06, 95% CI 1.04–1.08), and male gender (HR 1.58, 95% CI 1.26–1.98) (all p < 0.00001) were independently associated with worse MSS and DFS; time interval was not. Interpretation No effect of time interval between melanoma diagnosis and SNB on 5-year survival or SN positivity rate was found for a time interval of up to 3 months. This information can be used to counsel patients and remove strict time limits from melanoma guidelines. [ABSTRACT FROM AUTHOR]