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Purpose: Sinonasal mucosal melanoma (SNMM) is a rare malignancy, characterised by high (local) recurrence rates and poor survival. Comprehensive understanding of tumour etiology is currently lacking, which complicates adequate tumour treatment. Besides examining trends in incidence, this study aims to assess the association between clinical characteristics, treatment practices and patient outcomes, with the objective of establishing a baseline from which SNMM management can be enhanced., Methods: All newly diagnosed SNMM cases in The Netherlands between 2001 and 2021 were included using data from The Netherlands Cancer Registry (NCR)., Results: A total of 320 patients were included. The annual incidence rate for the overall population was stable over the inclusion period with an annual percentage change (APC) of only - 0.01%. The 5-year overall survival (OS) and relative survival (RS) were 24.5 and 32.4%, respectively. Relative survival did not increase over time. The addition of adjuvant radiotherapy to surgery was not associated with a higher OS and RS compared to surgery alone., Conclusion: Sinonasal mucosal melanoma is a rare disease with stable incidence rates in the Netherlands between 2001 and 2021. There has been no improvement in survival over the course of the inclusion period. The study reaffirms that adjuvant radiotherapy does not seem to improve patient outcomes. Given the generally poor outcomes for SNMM patients, novel therapeutic options ought to be considered in order to improve care., (© 2024. The Author(s).)

Novel systemic therapies for advanced melanoma improve survival, but carry potential serious side effects and high costs. This study aimed to assess the timing and use of systemic therapies in the months before death. Patients diagnosed with advanced melanoma (July 2017-June 2020) who died before July 2020 were selected from the Netherlands Cancer Registry. We evaluated the timing of systemic therapies within 30 days and 3 months before death, and studied patient and tumor characteristics associated with systemic therapy use between diagnosis and death. Out of 1097 patients 68% received systemic therapy. Almost 25% and 10% started a new therapy within 90 days and within 30 days before death, respectively. Female sex, elevated LDH, BRAF mutation, poor ECOG performance status (≥3), and high comorbidity index reduced the odds of receiving immune therapy. Poor performance status and high comorbidity decreased the odds for both therapies. A considerable number of patients started systemic therapy shortly before death, emphasizing the importance of considering potential benefits and drawbacks through shared decision-making., (© 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands., Methods: BM-MUP cases were retrieved from the Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses., Results: Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64 years at diagnosis (interquartile range 54-71 years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2 months (95%CI: 3.3-6.2 months) to 9.8 months (95%CI: 7.0-13.2 months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS., Conclusion: Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Mucosal melanoma (MM) is a rare tumour with a poor prognosis. Over the years, immune and targeted therapy have become available and have improved overall survival (OS) for patients with advanced cutaneous melanoma (CM). This study aimed to assess trends in the incidence and survival of MM in the Netherlands against the background of new effective treatments that became available for advanced melanoma., Methods: We obtained information on patients diagnosed with MM during 1990-2019 from the Netherlands Cancer Registry. The age-standardized incidence rate and estimated annual percentage change (EAPC) were calculated over the total study period. OS was calculated using the Kaplan-Meier method. Independent predictors for OS were assessed by applying multivariable Cox proportional hazards regression models., Results: In total, 1496 patients were diagnosed with MM during 1990-2019, mostly in the female genital tract (43%) and the head and neck region (34%). The majority presented with local or locally advanced disease (66%). The incidence remained stable over time (EAPC 3.0%, p = 0.4). The 5-year OS was 24% (95%CI: 21.6-26.0%) with a median OS of 1.7 years (95%CI: 1.6-1.8). Age ≥ 70 years at diagnosis, higher stage at diagnosis, and respiratory tract location were independent predictors for worse OS. Diagnosis in the period 2014-2019, MM located in the female genital tract, and treatment with immune or targeted therapy were independent predictors for better OS., Conclusion: Since the introduction of immune and targeted therapies, OS has improved for patients with MM. However, the prognosis of MM patients is still lower compared to CM, and the median OS of patients treated with immune and targeted therapies remains fairly short. Further studies are needed to improve outcomes for patients with MM.

Background: Currently, there is no study that has reported on the seasonal trends of skin cancer in the Netherlands. This study aimed to investigate seasonal variation in diagnosis of cutaneous melanoma (CM) and cutaneous squamous cell carcinoma (cSCC) focusing on different subgroups., Methods: CM diagnosed from 2001 till 2019 and cSCCs from 2001 till 2015 were selected from the Netherlands Cancer Registry. The monthly distribution of CM and cSCC diagnoses were evaluated. Summer-to-winter ratios (SWRs) were calculated overall and stratified by patient and tumour characteristics., Results: Significant increases in melanoma incidence were noted over the summer months (SWR 1.39 (CI 1.37-1.40)). This increase was less apparent for cSCCs, as higher incidence rates were observed in the months September-November (SWR 1.13 (CI 1.12-1.14)). The seasonal variation of CM was greater in women and younger people, in superficial spreading melanoma and lentigo maligna melanoma, for the extremities, in thinner lesions, and for stage I at diagnosis. The seasonal variation of cSCC was similar for both sexes, most marked in patients 45-69 and ≥ 70, and for the extremities., Conclusions: Our findings showed a pronounced seasonal variation in the diagnosis of CM with a peak in the summer months. For cSCC, no evident peak was observed, but an increase in diagnosis was noted in fall. Both CM and cSCC showed strong seasonal effects for the extremities., Competing Interests: Conflict of interest The authors do not declare any conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The COVID-19 pandemic reduced the number of skin cancer diagnoses, potentially causing a progression to unfavourable tumour stages., Objectives: To identify the impact of delayed diagnostics on primary invasive melanoma and cutaneous squamous cell carcinoma (cSCC) by comparing tumour (pT) stage, Breslow thickness and invasion depth from before to after the first and second lockdown periods., Methods: In this population-based cohort study, histopathology reports registered between 1 January 2018 and 22 July 2021 were obtained from the nationwide histopathology registry in the Netherlands. The Breslow thickness of melanomas, invasion depth of cSCCs, and pT stage for both tumour types were compared across five time periods: (i) pre-COVID, (ii) first lockdown, (iii) between first and second lockdowns, (iv) second lockdown and (v) after second lockdown. Breslow thickness was compared using an independent t-test. pT-stage groups were compared using a χ 2 -test. Outcomes were corrected for multiple testing using the false discovery rate., Results: In total, 20 434 primary invasive melanomas and 68 832 cSCCs were included in this study. The mean primary melanoma Breslow thickness of the prepandemic era (period i) and the following time periods (ii-v) showed no significant difference. A small shift was found towards unfavourable pT stages during the first lockdown compared with the pre-COVID period: pT1 52·3% vs. 58·6%, pT2 18·9% vs. 17·8%, pT3 13·2% vs. 11·0%, pT4 9·1% vs. 7·3% (P = 0·001). No relevant changes were seen in subsequent periods. No significant change in pT stage distribution was observed between the pre-COVID (i) and COVID-affected periods (ii-v) for cSCCs., Conclusions: To date, the diagnostic delay caused by COVID-19 has not resulted in relatively more unfavourable primary tumour characteristics of melanoma or cSCC. Follow-up studies in the coming years are needed to identify a potential impact on staging distribution and survival in the long term., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: The COVID-19 pandemic impacted Dutch society and the healthcare system. Focus switched to care for COVID-19 patients, thereby altering care for non-COVID patients. Non-urgent medical visits were cancelled or postponed and patients were reluctant to visit healthcare services., Objectives: This study aimed to investigate the impact of the COVID-19 pandemic on trends in diagnoses of keratinocyte carcinoma (cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC)) and to assess the magnitude of diagnostic delays., Methods: The number of cSCC and BCC diagnoses in each month of 2020 was compared to the expected number of diagnoses for these months, using data from the Netherlands Cancer Registry. Expected diagnoses for 2020 were used as a reference to take the yearly increase in keratinocyte carcinoma incidence into account and were calculated by extrapolating the trends observed in 2017-2019. Comparisons were further stratified by age, sex and region. Estimates of diagnostic delays were calculated and corrected for the influence of excess mortality due to the pandemic on keratinocyte carcinoma incidence., Results: The number of cSCC and BCC diagnoses substantially decreased when compared to the number of diagnoses expected from March to May 2020 (cSCC -29%, BCC -50%). These decreases were observed across all age groups, both sexes, and all regions. From June to September the number of cSCC and BCC diagnoses was higher than expected, after which it slightly dropped below expected in October to December. In total, 2020 keratinocyte carcinoma diagnoses continued to trail those expected, with a backlog of around 1150 cSCCs and 11 767 BCCs remaining at the end of the year., Conclusion: Diagnosis of keratinocyte carcinoma was suboptimal during the COVID-19 pandemic, due to diagnostic delays likely resulting from both patient and health system-related delay. Further studies will need to determine the effects of these diagnostic delays on outcomes., (© 2022 European Academy of Dermatology and Venereology.)

Background: Basal cell carcinoma (BCC) is the most frequently diagnosed malignancy worldwide and an ever increasing annual incidence is observed. However, nationwide registries of BCCs are very rare, and often extrapolation of the data has been necessary to estimate the absolute number of diagnoses. As of September 2016, all histopathologically confirmed BCCs are registered in the Netherlands, due to developments in automatic notification and import in the Netherlands Cancer Registry. This offers the unique possibility to assess the nationwide population-based incidence of first and multiple BCCs., Objectives: To assess the nationwide incidence and trends of first and multiple BCCs in the Netherlands and to predict incidence rates up to 2029., Methods: All patients with histopathologically confirmed BCC between 2001 and 2019 were selected from the population-based Netherlands Cancer Registry. Age-standardized incidence rates were calculated and trends were analysed with use of the estimated annual percentage change. Prediction of BCC incidence rates up to 2029 was based on a regression model., Results: In total, 601 806 patients were diagnosed with a first BCC over the period 2001-2019. The age-standardized incidence rates for both men and women with a first BCC increased over these years, from 157 to 304 and from 124 to 274 per 100 000 person-years, respectively. For male and female patients aged 30-39 years, decreases in annual incidences of -3·6% and -3·0%, respectively, were found in recent years. For patients aged 50 years or older an ever increasing trend was found. One-quarter of the patients with a first primary BCC developed one or more subsequent BCCs within 3 years. Increases in incidence of 30·4% (male) and 25·3% (female) are expected in the next 10 years., Conclusions: BCC incidence has doubled over the past two decades. Trends have seemed to stabilize in recent years for patients aged < 50 years. This might be a first sign of a decreasing trend. The incidence continues to rise in patients aged 50 years and older. In the next decade a further increase in BCC incidence is expected., (© 2021 British Association of Dermatologists.)

Background: Because of continuous hyperglycemia and hyperinsulinemia and the use of photosensitizing drug, hydrochlorothiazide (HCTZ), the risk of cutaneous squamous cell carcinoma (cSCC) might be increased among patients with diabetes. This study aimed to estimate the risk of cSCC among HCTZ users with type 2 diabetes, and to determine whether thiazide-like diuretics, another drug in the same class with HCTZ, would be safer., Methods: We linked the benchmarking database in Dutch primary care, the Netherlands Cancer Registry, and the Dutch Personal Records Database (1998-2019). All 71,648 patients were included, except for those who had a history of skin cancer prior to cohort entry. We used Cox modeling to estimate the HRs and 95% confidence intervals for cSCC. The model was adjusted by cumulative exposure to each antihypertensive, age, sex, smoking, body mass index, blood pressure, serum creatinine, other confounding drug use at cohort entry, and cohort entry year., Results: There were 1,409 cSCC events (23 among thiazide-like diuretics users), during a follow-up of 679,789 person-years. Compared with no HCTZ use, the adjusted HRs for HCTZ use were 1.18 (1.00-1.40) for ≤2 years, 1.57 (1.32-1.88) for 2 to 4 years, and 2.09 (1.73-2.52) for >4 years. The HR was 0.90 (0.79-1.03) for an additional year of thiazide-like diuretic use., Conclusions: In patients with diabetes, exposure to HCTZ for >2 years is associated with an increased risk of cSCC, whereas no increased risk associated with thiazide-like diuretics was observed., Impact: The potential increased risk of cSCC should be a consideration when prescribing HCTZ, with thiazide-like diuretics offering a safer alternative., (©2021 American Association for Cancer Research.)

Objective: To examine stage-specific trends in the incidence and survival of cutaneous melanoma in the Netherlands between 2003 and 2018, as well as the uptake of the sentinel lymph node biopsy (SLNB) and novel drugs during that period., Methods: Data were obtained from the nationwide population-based Netherlands Cancer Registry for all patients diagnosed with invasive primary cutaneous melanoma (n = 60,267). We presented age-standardized incidence rates, the proportion of patients with an SLNB, the proportion of patients who received a novel drug (for their primary diagnosis) and one- and five-year relative survival rates., Results: Between 2003 and 2018, the incidence rate increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. This increase reflected the increasing incidence rate of patients with stage I and III. The proportion of patients with an SLNB increased from 23% to 64%. A reasonable increase was observed in the proportion of patients with a positive outcome (from 2% to 11%). For patients with stage IV, there was a shift from chemotherapy towards novel drugs as from 2013. The five-year relative survival rate increased from 81% to 92% for men and from 88% to 96% for women. This increase reflected the increasing five-year relative survival rate of patients with stage II, III, and IV., Conclusion: We observed an increase in incidence for patients with stage I and III and an improvement in survival for patients with stage II, III and IV. These trends can be partly explained by the introduction of the SLNB and the novel drugs., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Van Akkooi reports grants from Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Sanofi, Pierre Fabre, Sirius Medical and 4SC, outside the submitted work. Haanen reports grants and other support from BMS, MSD, Novartis, BioNTech and Amgen; other support from GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm and Achilles Tx; and personal fees from Neogene Tx, outside the submitted work. Wakkee reports grants from Novartis, Merck MSD, BMS and Pierre Fabre, outside the submitted work. Franken reports grants from Roche Nederland B.V., Daiichi Sankyo, Abbvie, Gilead Sciences Netherlands BV and Astellas Pharma BV, outside the submitted work. The remaining authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Little is known about the impact of keratinocyte cancer (KC) and its treatment on health-related quality of life (HRQoL)., Objectives: The objectives of the present study were (1) to evaluate HRQoL among patients with KC in a population-based setting and compare this with an age- end sex-matched normative population and (2) to compare HRQoL, satisfaction with care, and cosmetic results among patients who underwent conventional excision, Mohs' micrographic surgery, or radiotherapy., Method: A random sample of 347 patients diagnosed with cutaneous basal cell or squamous cell carcinoma in the head and neck area between January 1, 2010, and December 31, 2014, were selected from the Netherlands Cancer Registry (NCR) and were invited to complete a questionnaire on HRQoL, satisfaction with care, and cosmetic results. Data were collected within Patient-Reported Outcomes Following Initial Treatment and Long-term Evaluation of Survivorship (PROFILES). Outcomes were compared to an age- and sex-matched normative population., Results: Two hundred fifteen patients with KC returned a completed questionnaire (62% response). Patients with KC reported better global quality of life (79.6 vs. 73.3, p < 0.01) and less pain (p < 0.01) compared to the normative population. No statistically significant differences in HRQoL, satisfaction with care, and cosmetic results were found between patients with KC who underwent conventional excision, Mohs' micrographic surgery, or radiotherapy., Conclusions: The impact of KC and its treatment seems relatively low and more positive than negative as patients reported better HRQoL compared to an age- and sex-matched normative population, probably due to adaptation. No statistically significant differences between treatment types were found concerning HRQoL, patient satisfaction, and cosmetic results. This information could be used by healthcare professionals involved in KC care to improve patients' knowledge about different aspects of the disease as patient's preference is an important factor for treatment choice., (The Author(s). Published by S. Karger AG, Basel.)

Background: Older people have the highest incidence of melanoma and the population in most Western countries is ageing. We evaluated how the gap in incidence and survival between younger and older patients has developed during the past decades. Material and methods: All patients diagnosed with cutaneous melanoma between 1989 and 2015 ( n  = 84,827) were identified from the Netherlands Cancer Registry. Elderly were defined as aged ≥70 years. Differences in patient and tumor characteristics were described, age-specific incidence rates were calculated, and relative survival (RS) and multivariable analyses estimating the Relative Excess Rate of dying (RER) were conducted Results: In older men, the melanoma age-standardized incidence increased from 18 to 103/100,000 person-years (py) between 1989 and 2015 and in older women from 23 to 70/100,000 py. In younger men and women, it increased from 8 to 21 and from 13 to 28/100,000 py, respectively. Median Breslow thickness declined from 1.8 to 1.1 mm and from 1.6 to 1.1 mm in older men and women (2003 versus 2015), and from 1.1 to 0.9 mm and 0.9 to 0.8 mm in younger men and women. In older men, 5-year RS increased from 67% (95% CI: 63%-72%) in 1989-1997 to 85% (95% CI: 83%-87%) in 2007-2015 and in older women from 81% (95% CI: 78%-85%) to 89% (95% CI: 87%-91%). In younger men and women, RS increased from 82% (95% CI: 81%-83%) to 90% (95% CI: 90%-91%) and from 92% (95% CI: 92%-93%) to 96% (95% CI: 95%-96%). After case-mix correction , older men and women no longer showed an improved survival over time (RER 2010-2015 versus 2003-2009: 0.97; 95% CI: 0.81-1.16 and 0.95; 95% CI: 0.79-1.16). Whereas in younger men and women survival remained improved (RER 0.75; 95% CI: 0.67-0.83 and 0.77; 95%CI: 0.67-0.89). Conclusion: The gap in melanoma incidence between younger and older people is increasing due to a strong increase in incidence in older adults. Disparities in survival are declining, related to a narrowing gap in Breslow thickness.

Background: In Europe, one of the highest melanoma incidences is found in the Netherlands. Like in several other European countries, females are more prone to develop melanoma as compared to males, although survival is worse for men., Objective: To identify clinicopathological gender-related differences that may lead to gender-specific preventive measures., Methods: Data from the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) were retrieved from patients with primary, cutaneous melanoma in the Netherlands between 2000 and 2014. Patients initially presenting as stage I, II and III without clinically detectable nodal disease were included. Follow-up data were retrieved from the Netherlands Cancer Registry. Gender-related differences were assessed, and to compare relative survival between males and females, multivariable relative excess risks (RER) were calculated., Results: A total of 54.645 patients were included (43.7% men). In 2000, 41.7% of the cohort was male, as compared to 47.3% in 2014 (P < 0.001). Likewise, in 2000, 51.5% of the deceased cohort was male compared to 60.1% in 2014 (P < 0.001). Men had significantly thicker melanomas at the time of diagnosis [median Breslow thickness 1.00 mm (interquartile range (IQR): 0.60-2.00) vs. 0.82 mm (IQR: 0.50-1.50) for females] and were significantly older at the time of diagnosis, more often had ulcerated melanomas and melanomas localized on the trunk or head and neck. Over time, survival for females improved while that of men decreased (P < 0.001). RER for dying was 1.37 (95% CI: 1.31-1.45) for men in multivariable analysis., Conclusion: There are evident clinicopathological differences between male and female melanoma patients. After multivariable correction for all these differences, relative survival remains worse for men. Clinicians as well as persons at risk for melanoma should be aware of these differences, as awareness and prevention might lead to a lower incidence and mortality of melanoma. This indicates the need of prevention campaigns integrating and targeting specific risk profiles., (© 2019 European Academy of Dermatology and Venereology.)

Background: Merkel cell carcinoma (MCC) is a rare and potentially lethal skin cancer. MCC is known for its potential rapid growth and its propensity to metastasize., Objective: To describe the incidence, treatment, and survival of MCC in a population-based setting., Methods: All MCCs diagnosed in The Netherlands between 1993 and 2016 were selected from the Netherlands Cancer Registry. Patient and tumor characteristics, therapy, and vital status were obtained. Cox proportional hazards were computed, and relative survival analyses were performed., Results: Our cohort included 1977 patients with MCC. Incidence increased from 0.17 per 100,000 person-years in 1993 to 0.59 per 100,000 in 2016. The mean age at diagnosis was 75.5. Most MCCs (59.8%) were treated with surgery alone. Relative 5-year survival was low (63.0%) and did not improve. Mortality was higher among males (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.11-1.39), higher age (HR, 1.07; 95% CI, 1.06-1.07), and nodal (HR, 1.26; 95% CI, 1.08-1.48) and distant spread of disease (HR, 2.44; 95% CI, 1.99-2.99)., Limitations: We lacked data on cause of death, comorbidity, and pathologic margins, which may have led to misinterpretation of the data., Conclusion: This study shows continuously increasing incidence rates of MCC in The Netherlands. Survival after a diagnosis of MCC remained low. Our results emphasize the need for implementation of new therapies., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The original version of this article, published on 17 April 2018, unfortunately contained a mistake.

Objectives: To analyse which mammographic and tumour characteristics led to concordant versus discordant recalls at blinded double reading to further optimise our breast cancer screening programme., Methods: We included a consecutive series of 99,013 screening mammograms obtained between July 2013 and January 2015. All mammograms were double read in a blinded fashion. Discordant readings were routinely recalled without consensus or arbitration. During the 2-year follow-up, relevant data of the recalled women were collected. We compared mammographic characteristics, screening outcome and tumour characteristics between concordant and discordant recalls., Results: There were 2,543 concordant recalls (71.4%) and 997 discordant recalls (28.0%). The positive predictive value of a concordant recall was significantly higher (23.5% vs. 10.0%, p < 0.001). The proportion of BI-RADS 0 was significantly higher in the discordant recall group (75.7% vs. 56.3%, p < 0.001). Discordant recalls were more often an asymmetry or architectural distortion (21.8% vs. 13.2% and 9.3% vs. 6.5%, respectively, p < 0.001). There were no differences in the distribution of DCIS and invasive cancers and tumour characteristics were comparable for the two groups, except for a more favourable tumour grade in the discordant recall group (54.7% vs. 39.9% grade I tumours, p = 0.022)., Conclusions: Screen-detected cancers detected by a discordant reading show a more favourable tumour grade than cancers diagnosed after a concordant recall. The higher proportion of asymmetries and architectural distortions in this group provide a possible target for improving screening programmes by additional training of screening radiologists and the implementation of digital breast tomosynthesis., Key Points: • With blinded double reading of screening mammograms, screen-detected cancers detected by a discordant reading show a more favourable tumour grade than cancers diagnosed after a concordant recall. • The proportions of asymmetries and architectural distortions are higher in case of a discordant reading. • Possible improvement strategies could target additional training of screening radiologists and the implementation of digital breast tomosynthesis in breast cancer screening programmes.

Background: Long-term trends of sinonasal cancer in The Netherlands have been investigated with particular attention on adenocarcinoma for which wood or leather dust is a well-known risk factor., Methods: All 4345 patients (1989-2014) registered in the Netherlands Cancer Registry were included. Standardized 3-year moving incidence rates per 1 000 000/person-years, and estimated annual percentage change (EAPC) were calculated., Results: Forty-seven percent of the patients had squamous cell carcinoma (SCC), 12% had lymphoma, and 12% had adenocarcinoma. Sixty-one percent of the tumors were located in the nasal cavity, 22% in the maxillary, and 11% in the ethmoidal sinus. Male incidence decreased to 11.5/1 000 000 due to less SCC (EAPC -0.9%; 95% confidence interval [CI] -1.6 to 0.3) and adenocarcinoma (EAPC -4.3%; 95% CI -5.5 to 3.1). Female incidence increased to 7/1 000 000 (EAPC +2.0%; 95% CI +1.1 to +3.0) due to more SCC (EAPC +2.2%; 95% CI +1.0 to +3.5), whereas adenocarcinoma remained stable (0.6/1 000 000; EAPC +1.1%; 95% CI -6.0 to +8.7). Tumors of the nasal cavity increased in women (EAPC +3.3%; 95% CI +2.0 to 4.7)., Conclusion: The decrease of male sinonasal adenocarcinoma may be the result of preventive measures combined with less workers in high-risk occupations., (© 2018 Wiley Periodicals, Inc.)

Background: Unilateral interval breast cancers show less favourable prognostic features than unilateral screen-detected cancers, but data on tumour characteristics of bilateral interval cancers in a systematically screened population are sparse. Therefore, we compared tumour characteristics of bilateral interval cancers with those of bilateral screen-detected cancers., Methods: We included all 468,720 screening mammograms of women who underwent biennial screening mammography in the South of the Netherlands between January 2005 and January 2015. We collected breast imaging reports, biopsy results and surgical reports of all recalled women and of all women who presented with interval breast cancer. In women with synchronous bilateral breast cancer, the tumour with the highest tumour stage was defined as the index cancer. For comparison of data between both groups Fisher exact test and Chi-square test were used., Results: Synchronous bilateral cancer was diagnosed in 2.2% of screen-detected cancers (64/2947) and in 3.2% of interval cancers (24/753) (P = 0.1). Index tumours of bilateral screen-detected cancers and interval cancers showed similar characteristics, except for a larger proportion of T-stage 2 or worse (T2+) cancers among interval cancers (16/24 (66.7%) versus 23/58 (39.7%) (P = 0.03). Index cancers, compared to contralateral cancers, were less frequently stage T1 in both bilateral screen-detected cancers and bilateral interval cancers (35/64 (60.3%) versus 40/64 (88.9%) (P = 0.001) and 8/24 (33.3%) versus 18/24 (85.7%) (P < 0.001), respectively). In bilateral screen-detected cancers, contralateral cancers were more often stage 1a-c (P < 0.001) compared to index cancers. In bilateral index cancers, index cancers were more often of the lobular subtype (P < 0.001)., Conclusion: Index cancers of bilateral screen-detected cancers and bilateral interval cancers show significant differences in tumour size, whereas nodal status, receptor status and final surgical treatment are comparable. In bilateral screen-detected cancer, index cancers had a significantly higher tumour stage. In bilateral screen-detected cancer, index cancers were more often the ductal invasive subtype compared to contralateral cancers., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: To determine the frequency and characteristics of contralateral, non-recalled breast abnormalities following recall at screening mammography., Methods: We included a series of 130,338 screening mammograms performed between 1 January 2014 and 1 January 2016. During the 1-year follow-up, clinical data were collected for all recalls. Screening outcome was determined for recalled women with or without evaluation of contralateral breast abnormalities., Results: Of 3,995 recalls (recall rate 3.1%), 129 women (3.2%) underwent assessment of a contralateral, non-recalled breast abnormality. Most lesions were detected at clinical mammography and/or breast tomosynthesis (101 women, 78.3%). The biopsy rate was similar for recalled lesions and contralateral, non-recalled lesions, but the positive predictive value of biopsy was higher for recalled lesions (p = 0.01). A comparable proportion of the recalled lesions and contralateral, non-recalled lesions were malignant (p = 0.1). The proportion of ductal carcinoma in situ was similar for both groups, as well as invasive cancer characteristics and type of surgical treatment., Conclusions: About 3% of recalled women underwent evaluation of contralateral, non-recalled breast lesions. Evaluation of the contralateral breast after recall is important as we found that 15.5% of contralateral, non-recalled lesions were malignant. Contralateral cancers and screen-detected cancers show similar characteristics, stage and surgical treatment., Key Points: • 3% of recalled women underwent evaluation of contralateral, non-recalled lesions • One out of seven contralateral, non-recalled lesions was malignant • A contralateral cancer was diagnosed in 0.5% of recalls • Screen-detected cancers and non-recalled, contralateral cancers showed similar histological characteristics • Tumour stage and surgical treatment were similar for both groups.

Purpose: We determined whether the addition of the technologist's opinion may be helpful in deciding if discordant readings at blinded double reading should be recalled., Methods: A consecutive series of 99,013 digital screening mammograms, obtained between July 2013 and January 2015, were included. All mammograms were first interpreted by a technologist and then double read in a blinded fashion by a team of 13 screening radiologists. All concordant and discordant positive readings among radiologists were recalled., Results: Out of 3562 recalls, 998 women were recalled after a discordant reading. Of these women, 337 (33.8%) had a positive technologist assessment, of which 40 (11.9%) were diagnosed with breast cancer. Sixty women with a negative technologist assessment (60/661, 9.1%) were diagnosed with breast cancer (p = 0.16). Recall rate would have decreased with technologist arbitration (3.6% vs. 2.9%, p < 0.001). Cancer detection rate decreased with 8.5%, from 7.1/1000 screens to 6.5/1000 screens (p = 0.10). Among women with a positive technologist assessment, the probability of breast cancer was highest in case of suspicious microcalcifications and lowest for suspicious masses (30.4% (17/56) versus 7.0% (16/212), p < 0.001). Breast cancers were diagnosed in all groups of mammographic abnormalities, except in women with a suspicious asymmetry and a negative technologist assessment., Conclusions: Assessment by a technologist does not provide a significant discriminating ability in case of a discordant radiologist reading and, taking into account the decrease in cancer detection rate, does not appear to be a suitable arbitration strategy for discordant recalls at blinded double reading.

Background: To determine the impact of the second reader on screening outcome at blinded double reading of digital screening mammograms., Methods: We included a consecutive series of 99,013 digital screening mammograms, obtained between July 2013 and January 2015 and double read in a blinded fashion. During 2-year follow-up, we collected radiology, surgery and pathology reports of recalled women., Results: Single reading resulted in 2928 recalls and 616 screen-detected cancers (SDCs). The second reader recalled another 612 women, resulting in 82 additional SDCs. Addition of the second reader increased the recall rate (3.0% to 3.6%, p < 0.001), cancer detection rate (6.2-7.0 per 1000 screens, p < 0.001) and false positive recall rate (24.4-28.7 per 1000 screens, p < 0.001). Positive predictive value of recall (21.0% vs. 19.7%, p = 0.20) and of biopsy (52.1% vs. 50.9%, p = 0.56) were comparable for single reading and blinded double reading. Tumour characteristics were comparable for cancers detected by the first reader and cancers additionally detected by the second reader, except of a more favourable tumour grade in the latter group., Conclusions: At blinded double reading, the second reader significantly increases the cancer detection rate, at the expense of an increased recall rate and false positive recall rate.

The aim of this population-based study was to identify the factors associated with clinical outcomes in vemurafenib-treated patients and to evaluate outcomes across subgroups of patients with different risk profiles. Data were retrieved from the Dutch Melanoma Treatment Registry. Time to next treatment (TTNT) and overall survival (OS) of all metastatic melanoma patients who received vemurafenib between 2012 and 2015 were assessed using Kaplan-Meier estimates. A risk score was developed on the basis of all prognostic factors associated with TTNT and OS derived from multivariable Cox regression analyses. Patients were stratified according to the presence of prognostic risk factors by counting the number of factors, ranging from 0 to 6. A total of 626 patients received vemurafenib with a median follow-up of 35.8 months. The median TTNT and OS were 4.7 months [95% confidence intervals (CI): 4.4-5.1] and 7.3 months (95% CI: 6.6-8.0). The strongest prognostic factors were serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance score, number of organ sites involved and brain metastases. Patients with a favourable risk profile (no risk factors) had a median TTNT and OS of 7.1 (95% CI: 5.8-8.5) and 15.4 months (95% CI: 10.0-20.9). The median OS more than halved for patients with greater than or equal to 2 risk factors compared with patients with no risk factors. The clinical outcomes of vemurafenib in metastatic melanoma patients with a favourable risk profile are comparable with the results of the trials. Combining prognostic factors into a risk score could be valuable to stratify patients into favourable and poor-prognosis groups.

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry. Costs were determined by applying unit costs to individual patient resource use. A total of 807 patients who were diagnosed between July 2012 and July 2015 received ipilimumab in Dutch practice. The mean (median) episode duration was 6.27 (4.61) months (computed from the start of ipilimumab until the start of a next treatment, death, or the last date of follow-up). The average total healthcare costs amounted to &OV0556;81 484, but varied widely (range: &OV0556;18 131-&OV0556;160 002). Ipilimumab was by far the most important cost driver (&OV0556;73 739). Other costs were related to hospital admissions (&OV0556;3323), hospital visits (&OV0556;1791), diagnostics and imaging (&OV0556;1505), radiotherapy (&OV0556;828), and surgery (&OV0556;297). Monthly costs for resource use other than ipilimumab were &OV0556;1997 (SD: &OV0556;2629). Treatment-naive patients (n=344) had higher total costs compared with previously-treated patients (n=463; &OV0556;85 081 vs. &OV0556;78 811). Although patients with colitis (n=106) had higher costs for resource use other than ipilimumab (&OV0556;11 426) compared with patients with other types of immune-related adverse events (n=90; &OV0556;9850) and patients with no immune-related adverse event (n=611; &OV0556;6796), they had lower total costs (&OV0556;76 075 vs. &OV0556;87 882 and &OV0556;81 480, respectively). In conclusion, this nation-wide study provides valuable insights into the healthcare costs of advanced cutaneous melanoma patients who were treated with ipilimumab in clinical practice. Most of the costs were attributable to ipilimumab, but the costs and its distribution varied considerably across subgroups.

Phase III trials with ipilimumab showed an improved survival in patients with metastatic melanoma. We evaluated the use and safety of ipilimumab, and the survival of all patients with metastatic cutaneous melanoma (N=807) receiving ipilimumab in real-world clinical practice in The Netherlands using data from the Dutch Melanoma Treatment Registry. Patients who were registered between July 2012 and July 2015 were included and analyzed according to their treatment status: treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of treatment-naive patients and 62% of previously-treated patients received all four planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. Median time to first event was 5.4 months [95% confidence interval (CI): 4.7-6.5 months] in treatment-naive patients and 4.4 months (95% CI: 4.0-4.7 months) in previously-treated patients. Median overall survival was 14.3 months (95% CI: 11.6-16.7 months) in treatment-naive patients and 8.7 months (95% CI: 7.6-9.6 months) in previously-treated patients. In both patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. These real-world outcomes of ipilimumab slightly differed from outcomes in phase III trials. Although phase III trials are crucial for establishing efficacy, real-world data are of great added value enhancing the generalizability of outcomes of ipilimumab in clinical practice.

Background: Detected by screening mammography, bilateral breast cancer has a different pathological profile compared to unilateral breast cancer. We investigated the incidence of bilateral interval breast cancers and compared their characteristics with those of unilateral interval breast cancers., Methods: We included all 468,720 screening mammograms of women who underwent biennial screening mammography in the South of the Netherlands between January 2005 and January 2015. We collected breast imaging reports, biopsy results and surgical reports of all referred women and of all women who presented with interval breast cancer. The tumour with the highest tumour stage (index cancer) was used for comparison with unilateral interval cancers., Results: A total of 753 interval cancers were detected, of which 24 (3.2%) were bilateral. Among the invasive interval cancers, bilateral cancers more frequently showed a lobular histology than unilateral cancers (37.5% (9/24) vs. 16.1% (111/691), P = .01). There is a trend towards a larger proportion of bilateral than unilateral interval cancers graded 1 (45.8% (11/24) vs. 27.8% (192/691), P = .08). There were no other statistically significant differences in tumour characteristics. Also, the proportion of interval cancers showing significant mammographic abnormalities at the latest screen was comparable for unilateral and bilateral interval cancers (23.0% vs. 25.0%, P = .9)., Discussion: Bilateral interval cancers comprise a small proportion of all interval cancers. Except of a higher proportion of invasive lobular cancers and a more favourable histological grade of invasive cancers, tumour characteristics are comparable for bilateral and unilateral interval breast cancers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness., Material and Methods: Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database., Results: Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases., Discussion: The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: To determine the proportion of "true" interval cancers and tumor characteristics of interval breast cancers prior to, during and after the transition from screen-film mammography screening (SFM) to full-field digital mammography screening (FFDM)., Methods: We included all women with interval cancers detected between January 2006 and January 2014. Breast imaging reports, biopsy results and breast surgery reports of all women recalled at screening mammography and of all women with interval breast cancers were collected. Two experienced screening radiologists reviewed the diagnostic mammograms, on which the interval cancers were diagnosed, as well as the prior screening mammograms and determined whether or not the interval cancer had been missed on the most recent screening mammogram. If not missed, the cancer was considered an occult ("true") interval cancer., Results: A total of 442 interval cancers had been diagnosed, of which 144 at SFM with a prior SFM (SFM-SFM), 159 at FFDM with a prior SFM (FFDM-SFM) and 139 at FFDM with a prior FFDM (FFDM-FFDM). The transition from SFM to FFDM screening resulted in the diagnosis of more occult ("true") interval cancers at FFDM-SFM than at SFM-SFM (65.4% (104/159) versus 49.3% (71/144), P < 0.01), but this increase was no longer statistically significant in women who had been screened digitally for the second time (57.6% (80/139) at FFDM-FFDM versus 49.3% (71/144) at SFM-SFM). Tumor characteristics were comparable for the three interval cancer cohorts, except of a lower porportion (75.7 and 78.0% versus 67.2% af FFDM-FFDM, P < 0.05) of invasive ductal cancers at FFDM with prior FFDM., Conclusions: An increase in the proportion of occult interval cancers is observed during the transition from SFM to FFDM screening mammography. However, this increase seems temporary and is no longer detectable after the second round of digital screening. Tumor characteristics and type of surgery are comparable for interval cancers detected prior to, during and after the transition from SFM to FFDM screening mammography, except of a lower proportion of invasive ductal cancers after the transition.

Background: Full-field digital mammography (FFDM) has replaced screen-film mammography (SFM) in most breast screening programs. We analyzed the impact of this replacement on the screening outcome., Patients and Methods: The study population consisted of a consecutive series of 60 770 analog and 63 182 digital screens. During a 1-year follow-up, we collected breast imaging reports, biopsy results and surgical reports of all the referred women., Results: The referral rate and the cancer detection rate at FFDM were, respectively, 3.0% and 6,6‰, compared with 1.5% (P < 0.001) and 4.9‰ (P < 0.001) at SFM. Positive predictive values of referral and percutaneous biopsies were lower at FFDM, respectively, 21.9% versus 31.6% (P < 0.001) and 42.9% versus 62.8% (P < 0.001). Per 1000 screened women, there was a significant increase with FFDM versus SFM in the detection rate of low- and intermediate-grade ductal carcinoma in situ (DCIS) (+0.7), invasive T1a-c cancers (+0.9), invasive ductal cancers (+0.9), low-grade (+1.1), node-negative invasive cancers (+1.2), estrogen-receptor or progesterone-receptor-positive invasive cancers (respectively, +0.9 and +1.1) and Her2/Neu-negative (+0.8) invasive cancers. Mastectomy rates were stable at 1.1 per 1,000 screens., Conclusions: FFDM significantly increased the referral rate and cancer detection rate, at the expense of a lower positive predictive value of referral and biopsy. Extra tumors detected at FFDM were mostly low-intermediate grade DCIS and smaller invasive tumors, of more favorable tumor characteristics. Mastectomy rates were not increased in the FFDM population, while increased over-diagnosis cannot be excluded.