Author Correction: Tertiary lymphoid structures improve immunotherapy and survival in melanoma.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tertiary lymphoid structures improve immunotherapy and survival in melanoma.

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.

Prognostic Significance of Sentinel Lymph Node Status in Thick Primary Melanomas (> 4 mm).

BACKGROUND: The key prognostic factors for staging patients with primary cutaneous melanoma are Breslow thickness, ulceration, and sentinel lymph node (SLN) status. The multicenter selective lymphadenectomy trial (MSLT-I) verified SLN status as the most important prognostic factor for patients with intermediate-thickness melanoma (Breslow thickness, 1-4 mm). Although most international guidelines recommend SLN biopsy (SLNB) also for patients with thick (> 4 mm, pT4) melanomas, its prognostic role has been questioned. The primary aim of this study was to establish whether SLN status is prognostic in T4 melanoma tumors. METHODS: Data for all patients with a diagnosis of primary invasive cutaneous melanoma of Breslow thickness greater than 1 mm in Sweden between 2007 and 2020 were retrieved from the Swedish Melanoma Registry, a large prospective population-based registry. A multivariable Cox proportional hazard model for melanoma-specific survival (MSS) was constructed based on Breslow thickness stratified for SLN status. RESULTS: The study enrolled 10,491 patients, 1943 of whom had a Breslow thickness greater than 4 mm (pT4). A positive SLN was found for 34% of these pT4 patients. The 5-year MSS was 71%, and the 10-year MSS was 62%. There was a statistically significant difference in MSS between the patients with a positive SLN and those with a negative SLN (hazard ratio of 2.4 (95% confidence interval CI 1.6-3.5) for stage T4a and 2.0 (95% CI 1.6-2.5) for satage T4b. CONCLUSION: Sentinel lymph node status gives important prognostic information also for patients with thick (> 4 mm) melanomas, and the authors thus recommend that clinical guidelines be updated to reflect this.

Association of metformin use and survival in patients with cutaneous melanoma and diabetes.

BACKGROUND: Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive. OBJECTIVES: To investigate the association between metformin use and survival among patients with CM and diabetes. METHODS: All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses. RESULTS: Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4-6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57-0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86-0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97-0.98) for 0-6 months to 0.59 (0.49-0.70) for 24-30 months of use. No association was found for metformin use and MSS. CONCLUSIONS: Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose-response pattern. However, further research regarding the underlying mechanisms is warranted.

Clinical performance of a novel hyperspectral imaging device for cutaneous melanoma and pigmented skin lesions in Caucasian skin.

BACKGROUND: The quest for diagnostic tools for the detection of cutaneous malignant melanoma (cMM) is ongoing. A challenge in cMM care is not overlooking cMM at an early stage, while simultaneously avoiding unnecessary biopsies or excisions of benign pigmented skin lesions (PSLs). A novel hyperspectral imaging (HSI) device is shown to have potential for differentiating equivocal PSLs in Asian skin types. Our objective was to assess the accuracy of the HSI device in distinguishing between cMM and benign PSLs in patients with Caucasian skin types. METHODS: Patients with Caucasian skin types (Fitzpatrick I-II), enrolled for excisional biopsies of PSLs were included and examined using the HSI device. The discrimination index (DI) was used to demonstrate the sensitivity (SE) and specificity (SP) in comparison with the re-evaluated histopathology diagnoses. RESULTS: In 186 patients, 202 pigmented skin lesions were included. The sensitivity to detect cMM was 96.7% (87/90), and the specificity for benign lesions was 42.1% (45/107). The AUC was 0.800 (95% confidence interval (CI): 0.740-0.861). CONCLUSIONS: Our novel HSI device showed a high sensitivity in detecting malignant lesions in patients with Caucasian skin types. Compared with analogous technologies, as multispectral imaging or electrical impedance spectroscopy, our device showed similar or better accuracy in differentiating cMM from benign PSLs. Therefore, it might be a useful clinical tool in skin types I-IV and where further triage of pigmented skin lesions is important.

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: long-term follow-up of a multicentre, randomised trial.

BACKGROUND: The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort. METHODS: In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492. FINDINGS: Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200-260), 621 deaths were reported-304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83-1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma-192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78-1·16, p=0·61). INTERPRETATION: A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice. FUNDING: The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. METHODS: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. DISCUSSION: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. RESULTS: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients.

In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of 'missing proteins' (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.

Participation in a Prospective Cohort Study on Melanoma did not Affect the Incidence and Mortality of the Studied Disease.

Prospective observational studies have shown previously that study participants have lower morbidity and mortality than non-participants. The aim of the current study was to determine whether participants in a prospective cohort study on melanoma have a different incidence and mortality of melanoma compared with non-participants and the background population. Information was collected from Swedish National Registers on participants (n = 30,501) and non-participants (n = 10,499) in the "Melanoma In Southern Sweden" (MISS) study and the background population (n = 243,032). Hazard ratios were calculated for overall incidence of cancer and melanoma, and all-cause and melanoma-specific mortality, using Cox regression. Participants had a lower overall incidence of cancer and all-cause mortality than non-participants and the background population. There was no difference in incidence of melanoma or melanoma-specific characteristics between participants and the background population. In conclusion, participants in the MISS study have a slightly better general health, but are a representative sample of the population with regard to studies of melanoma risk factors.

Automatic diagnosis of melanoma using hyperspectral data and GoogLeNet.

BACKGROUND: Melanoma is a type of superficial tumor. As advanced melanoma has a poor prognosis, early detection and therapy are essential to reduce melanoma-related deaths. To that end, there is a need to develop a quantitative method for diagnosing melanoma. This paper reports the development of such a diagnostic system using hyperspectral data (HSD) and a convolutional neural network, which is a type of machine learning. MATERIALS AND METHODS: HSD were acquired using a hyperspectral imager, which is a type of spectrometer that can simultaneously capture information about wavelength and position. GoogLeNet pre-trained with Imagenet was used to model the convolutional neural network. As many CNNs (including GoogLeNet) have three input channels, the HSD (involving 84 channels) could not be input directly. For that reason, a "Mini Network" layer was added to reduce the number of channels from 84 to 3 just before the GoogLeNet input layer. In total, 619 lesions (including 278 melanoma lesions and 341 non-melanoma lesions) were used for training and evaluation of the network. RESULTS AND CONCLUSION: The system was evaluated by 5-fold cross-validation, and the results indicate sensitivity, specificity, and accuracy of 69.1%, 75.7%, and 72.7% without data augmentation, 72.3%, 81.2%, and 77.2% with data augmentation, respectively. In future work, it is intended to improve the Mini Network and to increase the number of lesions.

The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast.

PURPOSE: According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC). METHODS: Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets. RESULTS: AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3-20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1-7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not. CONCLUSIONS: AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.

Clinical protein science in translational medicine targeting malignant melanoma.

Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry-based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

BACKGROUND: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. METHODS: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. RESULTS: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. CONCLUSION: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.

Sunbed Use Increases Cutaneous Squamous Cell Carcinoma Risk in Women: A Large-scale, Prospective Study in Sweden.

The incidence of cutaneous squamous cell carcinoma has increased rapidly in Sweden in the past decades. Here, we present a prospective study of the Melanoma in Southern Sweden (MISS)-cohort, with 29,460 participating women in southern Sweden that investigates the risk factors for cutaneous squamous cell carcinoma. Data on the host and skin cancer risk factors were collected through questionnaires and then matched with the National Cancer Registry. Statistical analyses were based on uni- and multivariable Cox proportional hazards models, using age as the time-scale. We found that sunbed use (hazard ratio (HR) 1.2, 95% CI: 1.1-1.4), red and light blond hair (HR 1.6, 95% CI: 1.1-2.3), freckles (HR 1.4, 95% CI: 1.1-1.8) and immunosuppressive medications (HR 2.1, 95% CI: 1.3-4.5) were independent risk factors. Furthermore, we observed a dose-dependent relationship between sunbed use and the development of cutaneous squamous cell carcinoma. Our findings support the idea of integrating dermatological follow-up examinations for immunosuppressed patients and banning the use of sunbeds in order to prevent cutaneous squamous cell carcinoma.

Increasing preoperative body size in breast cancer patients between 2002 and 2016: implications for prognosis.

Overweight and obesity are increasing worldwide, but the extent in breast cancer patients is unknown. The two aims were to study secular trends in preoperative body mass index (BMI), waist circumference, and breast volume and their impacts on clinical outcome. BMI, waist circumference, and breast volume were measured preoperatively in 24-99-year-old primary breast cancer patients (n = 640) in Sweden 2002-2016. The measurements were analyzed alone and combined in relation to recurrence and overall survival (OS). BMI, waist circumference, and breast volume increased 2002-2016 (ptrends < 0.0001). Of these, a breast volume ≥ 850 mL was associated with the strongest recurrence-risk (adjusted hazard ratio [adjHR] 1.67; 95% CI 1.17-2.39), especially combined with waist circumference ≥ 80 cm (adjHR 2.07; 95% CI 1.25-3.44), while BMI ≥ 25 kg/m2 or large waist circumference conferred almost a twofold risk for death (both Log-Rank p ≤ 0.0001). Chemotherapy seemed to counteract the negative impact of a high BMI or large waist circumference on OS. Large breast volume was the strongest predictor for recurrence in all treatment groups. In conclusion, preoperative BMI, waist circumference, and breast volume increased between 2002 and 2016. Larger body size negatively impacted breast cancer-free interval and OS. If confirmed, body measurements may help select patients requiring more individualized treatment.

Sentinel lymph node biopsy in patients with thin melanomas: Frequency and predictors of metastasis based on analysis of two large international cohorts.

BACKGROUND: Sentinel lymph node (SLN) metastasis in patients with thin melanomas (≤1 mm) is uncommon but adverse prognostic factors may indicate an increased risk. We sought to determine how often SLN biopsy (SLNB) was performed in patients with thin melanomas, establish the frequency of SLN metastasis and evaluate the predictive value of ulceration, tumor mitotic rate, and thickness for SLN involvement. METHODS: Melanoma patients with a Breslow thickness greater than or equal to 0.5 to less than or equal to 1 mm, diagnosed 2009-2016, were identified in the Swedish Melanoma Register (SMR) and the Melanoma Institute Australia (MIA) Database. RESULTS: In total 8165 patients were included from the SMR and 1603 from MIA. SLNB was performed in 9.5% and 16.2% of patients, respectively. Corresponding figures for T1b (American Joint Committee on Cancer [AJCC] 7th Edition) were 19.5% and 24.6%. The SLN positivity rate were 4.4% (Sweden) and 5.8% (MIA). SLN metastasis was more frequent in tumors with ulceration, mitoses, and Breslow thickness greater than or equal to 0.9 mm but none were statistically significant. Younger age was identified as a significant risk factor for SLN positivity at MIA. CONCLUSIONS: A minority of patients with thin melanomas had SLNB performed and the SLN positivity rate was low. This study did not confirm tumor ulceration, mitoses, or thickness as statistically significant predictors for SLN metastasis.