A prediction model for response to immune checkpoint inhibition in advanced melanoma

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal–external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence—all at start of ICI—, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64–0.66). The range of predicted response probabilities was 7%–81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P &lt;.001) and median overall survival (62.0 vs 8.0 months; P &lt;.001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.</p

Prediction in cutaneous melanomas : A multicontinental approach

This thesis is a collaboration between the University Medical Center Utrecht and Melanoma Institute Australia, Sydney, Australia. One in 5 Dutch people will get diagnosed with skin cancer in their life. In 10% of cases this concerns a melanoma. Although melanoma is not the most common form of skin cancer, it is responsible for 70-90% of skin-cancer related deaths. Melanoma cells can spread through the lymphatic system. The sentinel node is the first lymph node that melanoma cells spread to. On average, 1 in 5 sentinel node biopsies contains metastatic melanoma cells. This thesis investigates how often the sentinel node procedure has been enacted in the Netherlands in the last years, the chance of metastatic cells in the sentinel node, and the additional prognostic value of sentinel node status over basic clinicopathological features of a melanoma. In addition, the concordance of sentinel node biopsies that were initially diagnosed positive for melanoma metastases has been reviewed, as well as the effect of time interval between melanoma diagnosis and sentinel node biopsy on survival and on the size of metastatic tumour deposits. The impact of several clinicopathological characteristics on survival are evaluated in this thesis, e.g. sex, melanoma subtype and the presence of multiple primary melanomas. Finally, two prediction models are developed: one to predict recurrence of disease in patients with thin melanomas, and one to accurately predict the chance of metastatic cells in the sentinel node

Prediction in cutaneous melanomas : A multicontinental approach

This thesis is a collaboration between the University Medical Center Utrecht and Melanoma Institute Australia, Sydney, Australia. One in 5 Dutch people will get diagnosed with skin cancer in their life. In 10% of cases this concerns a melanoma. Although melanoma is not the most common form of skin cancer, it is responsible for 70-90% of skin-cancer related deaths. Melanoma cells can spread through the lymphatic system. The sentinel node is the first lymph node that melanoma cells spread to. On average, 1 in 5 sentinel node biopsies contains metastatic melanoma cells. This thesis investigates how often the sentinel node procedure has been enacted in the Netherlands in the last years, the chance of metastatic cells in the sentinel node, and the additional prognostic value of sentinel node status over basic clinicopathological features of a melanoma. In addition, the concordance of sentinel node biopsies that were initially diagnosed positive for melanoma metastases has been reviewed, as well as the effect of time interval between melanoma diagnosis and sentinel node biopsy on survival and on the size of metastatic tumour deposits. The impact of several clinicopathological characteristics on survival are evaluated in this thesis, e.g. sex, melanoma subtype and the presence of multiple primary melanomas. Finally, two prediction models are developed: one to predict recurrence of disease in patients with thin melanomas, and one to accurately predict the chance of metastatic cells in the sentinel node

Correlation between E-cadherin and p120 expression in invasive ductal breast cancer with a lobular component and MRI findings

Invasive breast cancer comprises a spectrum of histological changes with purely lobular cancer on one side and purely ductal cancer on the other, with many mixed lesions in between. In a previous study, we showed that in patients with any percentage lobular component at core needle biopsy, preoperative MRI leads to the detection of clinically relevant additional findings in a substantial percentage of patients, irrespective of the percentage of the lobular component. Detection of a small lobular component may however not be reproducible among pathologists. Loss of membrane expression of E-cadherin or p120 is useful biomarkers of ILC and may therefore support a more objective diagnosis. All patients diagnosed with breast cancer containing a lobular component of any percentage between January 2008 and October 2012 were prospectively offered preoperative MRI. Clinically relevant additional findings on MRI were verified by pathology evaluation. Expression patterns of E-cadherin and p120 were evaluated by immunohistochemistry on the core needle biopsy. MRI was performed in 109 patients. The percentage of lobular component was significantly increased in cases with aberrant E-cadherin or p120 expression (both p = <0.001). However, aberrant expression of E-cadherin and p120 was not related to the probability of detecting relevant additional MRI findings. E-cadherin and p120 did not appear to be useful objective biomarkers for predicting additional relevant findings on MRI in patients with a lobular component in the core needle of their breast cancer

Desmoplastic melanoma : The role of pure and mixed subtype in sentinel lymph node biopsy and survival

Background: Desmoplastic melanoma (DM) is an uncommon type of melanoma. Two histological subtypes of DM can be distinguished: pure and mixed (PDM and MDM). We hypothesized that discrimination between these subtypes is associated with sentinel lymph node biopsy (SLNB) status and survival. Methods: Clinicopathological data from PALGA, the Dutch Pathology Register were retrieved from patients diagnosed with DM in The Netherlands between 2000 and 2014. Clinical and pathological variables were extracted from pathology text files, including pure or mixed desmoplastic morphology. A Cox proportional hazard model was performed for overall and recurrence-free survival (OS and RFS). Results: A total of 239 patients with DM were included, representing 0.4% of all primary cutaneous melanoma in The Netherlands. A total of 114 PDM and 125 MDM patients were identified. MDM was significantly associated with positive SLNB status (P =.035). In multivariable analysis, age (HR 1.10, 95% CI 1.07-1.14, P <.001) and ulceration (HR 1.98, 95% CI 1.05-3.75, P =.036) were significant predictors for OS. For RFS, mixed subtype (HR 2.72 95% CI 1.07-6.89, P =.035), male gender (HR 2.54, 95% CI 1.03-6.27, P =.043), and Breslow thickness (HR 1.13 per mm, 95% CI 1.05-1.21, P =.001) were significant predictors. Conclusion: MDM is significantly associated with a positive SLNB status. Mixed subtype is significantly correlated with RFS, but not with OS. The distinction between pure and mixed desmoplastic subtype therefore seems to be of clinical importance

Trends in Sentinel Lymph Node Biopsy Enactment for Cutaneous Melanoma

Background: Over recent years, sentinel lymph node biopsy (SLNB) recommendations in guidelines for cutaneous melanoma have changed considerably. We aimed to assess trends in enactment of SLNB to evaluate to what extent guidelines were adhered to, and to identify clinical and pathological determinants of (non-)adherence. Methods: Clinicopathological data from the Dutch nationwide network and registry of histopathology and cytopathology were retrieved from patients diagnosed with primary cutaneous melanoma in The Netherlands between 2003 and 2014. SLNB enactment was analyzed per year. Multivariable regression models were developed to assess the determinants of SLNB enactment. Results: A total of 51,510 primary cutaneous melanomas in 49,514 patients were diagnosed, of which 24,603 melanomas were eligible for SLNB as they were staged T1b or higher. In practice, only 9761 (39.7%) patients underwent SLNB, with an increasing trend from 39.1% in 2003 to 47.8% in 2014 (p < 0.001). A total of 759 (2.9%) of 26,426 patients without SLNB indication underwent SLNB anyway. Variables significantly associated with enactment of SLNB were male sex, younger age, and melanoma on sites other than the head and neck. Conclusions: Although there was an increasing trend in time in SLNB enactment, enactment of SLNB did not comply well with recommendations in (inter)national guidelines. Female sex, higher age, and melanoma located on the head and neck were associated with non-enactment of SLNB

Desmoplastic melanoma : The role of pure and mixed subtype in sentinel lymph node biopsy and survival

Background: Desmoplastic melanoma (DM) is an uncommon type of melanoma. Two histological subtypes of DM can be distinguished: pure and mixed (PDM and MDM). We hypothesized that discrimination between these subtypes is associated with sentinel lymph node biopsy (SLNB) status and survival. Methods: Clinicopathological data from PALGA, the Dutch Pathology Register were retrieved from patients diagnosed with DM in The Netherlands between 2000 and 2014. Clinical and pathological variables were extracted from pathology text files, including pure or mixed desmoplastic morphology. A Cox proportional hazard model was performed for overall and recurrence-free survival (OS and RFS). Results: A total of 239 patients with DM were included, representing 0.4% of all primary cutaneous melanoma in The Netherlands. A total of 114 PDM and 125 MDM patients were identified. MDM was significantly associated with positive SLNB status (P =.035). In multivariable analysis, age (HR 1.10, 95% CI 1.07-1.14, P <.001) and ulceration (HR 1.98, 95% CI 1.05-3.75, P =.036) were significant predictors for OS. For RFS, mixed subtype (HR 2.72 95% CI 1.07-6.89, P =.035), male gender (HR 2.54, 95% CI 1.03-6.27, P =.043), and Breslow thickness (HR 1.13 per mm, 95% CI 1.05-1.21, P =.001) were significant predictors. Conclusion: MDM is significantly associated with a positive SLNB status. Mixed subtype is significantly correlated with RFS, but not with OS. The distinction between pure and mixed desmoplastic subtype therefore seems to be of clinical importance