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Summary: Background: The incidence of cutaneous malignant melanoma (CMM) continues to increase in most countries worldwide and the majority are diagnosed with thin tumours (≤ 1 mm). Objectives: The aim of the present study was to investigate the melanoma‐specific survival (MSS) as well as conditional MSS (CMSS) in patients with thin CMM in Sweden. Patients and methods: Clinical and histological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with thin CMM between 1990 and 2017. Patients were followed until the end of 2017. MSS as well as CMSS for different thickness groups were calculated using the Kaplan–Meier method and Cox regression analyses were used to calculate for survival differences between thickness groups. Results: There were 31 670 patients included for final analyses. The overall 10‐ and 20‐year MSS for thin CMMs was 97% [95% confidence interval (CI) 97–97] and 95% (95% CI 95–96), respectively. From 0·7 mm and above, MSS decreased significantly with increasing thickness level. All thickness groups had an increased survival over time. The lowest CMSS was confirmed for men with 1·0 mm in thickness but their 10‐year CMSS increased steadily over time. Women had overall better MSS as well as CMSS than men. However, the relation between MSS and CMSS was similar for both sexes. Conclusions: MSS was confirmed as excellent for patients with thin CMMs in Sweden. Although we could show a decreased MSS for patients with 0·7 mm thickness and above, the long‐term survival and, in addition, a very favourable CMSS for those patients do not support more extended follow‐up programmes than the current recommendations in Sweden. What is already known about this topic? The majority of patients with cutaneous malignant melanoma are diagnosed with thin melanomas (≤ 1 mm) and the survival is generally reported as favourable. What does this study add? Our national population‐based designed study, including 31 670 patients with thin melanomas, is exclusive when it comes to melanoma survival data, as many former studies are based on selected and smaller cohorts of patients (e.g. referral centres/hospital‐based registries).In addition to an excellent overall melanoma‐specific survival (MSS), we could also report an increasing conditional MSS with time from diagnosis for patients with thin melanomas in Sweden. Linked Comment:Hollestein and Nijsten. Br J Dermatol 2021; 184:4. Plain language summary available online [ABSTRACT FROM AUTHOR]

Background/Aims: Two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), have previously been shown to reduce postoperative intra-abdominal adhesions. This study aims to investigate the possible toxic effects and to establish a lowest effective antiadhesive dose. Methods: 152 mice were investigated with a well-known adhesion model and given different concentrations of the two differently charged polypeptides as well as only the cationic PL. Results: For the first time, a probable toxic level of PL given intraperitoneally (40 mg/kg) and the lowest significant concentration of PL and PG for antiadhesive purposes (1.6 mg/kg) could be established. Conclusion: The gap between the possible toxicity level of PL and the lowest efficient antiadhesive dose is probably too narrow, and the shape and charge of PL warrant continuous research for another polycation in the concept of differently charged polypeptides used as antiadhesive agents. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Unlabelled: Incubator covers are increasingly being used in neonatal care as part of minimal disturbance strategies. The aim of this study was to examine possible effects of incubator covers on sleep patterns in stable premature infants. Quiet sleep (QS) can be investigated by amplitude-integrated electroencephalography (aEEG) at 32-34 wk gestational age. In nine premature infants (gestational ages 26-32 wk, median 29) QS periods were measured at a postconceptional age of 32-34 wk (median 34) during two consecutive 24 h periods, one period with a padded dark cover over the incubator and one period without the cover, in a randomized order. There were no significant differences between the two 24 h periods (with incubator cover and without cover, respectively) regarding the duration of the QS periods, the percentage of QS of the total recording time (%QS) or the duration of QS intervals. However, there was a positive correlation between postnatal age in days and the mean duration of QS periods when incubator covers were used (r = 0.90, p = 0.001). When the covers were used there was a difference between the girls and the boys in the duration of QS intervals (p = 0.032); the QS intervals increased in the five girls from median (range) 63.2 (49.4-94.6) min to 77.2 (59.3-100.9) min (p = 0.043). There was no difference in the duration of QS periods between girls and boys.Conclusion: Incubator covers seem to have some short-term effects on sleep quality in premature infants but the clinical significance and possible long-term effects are not known. [ABSTRACT FROM AUTHOR]

Importance: Over the past decades, many global regions have experienced a steady increase in the incidence of cutaneous melanoma. However, more recently, a downward trend has been observed in the younger age groups in Australia and the US. Yet, in Europe, none of the countries have reported any significant decline in melanoma incidence for any age group., Objective: To assess melanoma incidence and mortality trends in Sweden, with a focus on individuals younger than the average age of melanoma onset., Design, Setting, and Participants: This cohort study used data on the national population from the Swedish Melanoma Registry and the Swedish Cancer Registry, which cover more than 99% of all primary invasive cutaneous melanomas diagnosed in the country. All patients diagnosed from 1990 to 2022 were included., Main Outcomes and Measures: Incidence and mortality rates per 100 000 inhabitants were calculated for each year and shown as average annual rates for every 5-year period from 1990 to 2022. Joinpoint regression models were used to evaluate statistical significance of temporal trends and points of change., Results: There were 34 800 primary invasive cutaneous melanomas (19 582 [56.3%] in females and 15 218 [43.7%] in males) reported in 33 324 individuals younger than 60 years (median [IQR] age, 48 [36-58] years) from 1990 to 2022. A consistent rise in melanoma incidence was observed among those 50 to 59 years old. The age groups from 20 to 29 years, 30 to 39 years, and 40 to 49 years showed an incidence peak in 2013 to 2015 followed by stable or significantly declining rates until 2022. In patients younger than 20 years, melanoma incidence remained low with no significant trends. There was also a significant decline in melanoma mortality among 30- to 59-year-old individuals, but not in those 60 years and older., Conclusions and Relevance: The findings of this cohort study showed a significant recent downward trend in both melanoma incidence and melanoma mortality in the age group 30 to 49 years in Sweden. The reasons for these declines are unclear but may include UV protection, public health campaigns, changing population demographics, and the introduction of effective melanoma treatment. None of these possibilities were evaluated; further study is needed.

Background: Obesity, assessed by body mass index (BMI), is an established risk factor for 13 cancers. We aimed to identify further potential obesity-related cancers and to quantify their association with BMI relative to that of established obesity-related cancers., Methods: Using Cox regression models on 4,142,349 individuals in Sweden (mean age 27.1 years at weight measurement), we calculated hazard ratios (HRs) for the association between BMI and the risk of 122 cancers and cancer subtypes, grouped by topography and morphology. Cancers with a positive association (i.e., HR >1) at an α-level of 0.05 for obesity (BMI ≥30 kg/m 2 ) vs. normal weight (BMI 18.5-24.9 kg/m 2 ) or per 5 kg/m 2 higher BMI, for which obesity is not an established risk factor, were considered potentially obesity related., Findings: After 100.2 million person-years of follow-up, 332,501 incident cancer cases were recorded. We identified 15 cancers in men and 16 in women as potentially obesity related. These were cancers of the head and neck, gastrointestinal tract, malignant melanoma, genital organs, endocrine organs, connective tissue, and haematological malignancies. Among these, there was evidence of differential associations with BMI between subtypes of gastric cancer, small intestine cancer, cervical cancer, and lymphoid neoplasms (P values for heterogeneity in HRs <0.05). The HR (95% confidence interval) per 5 kg/m 2 higher BMI was 1.17 (1.15-1.20) in men and 1.13 (1.11-1.15) in women for potential obesity-related cancers (51,690 cases), and 1.24 (1.22-1.26) in men and 1.12 (1.11-1.13) in women for established obesity-related cancers (84,384 cases)., Interpretation: This study suggests a large number of potential obesity-related cancers could be added to already established ones. Importantly, the magnitudes of the associations were largely comparable to those of the already established obesity-related cancers. We also provide evidence of specific cancer subtypes driving some associations with BMI. Studies accounting for cancer-specific confounders are needed to confirm these findings., Funding: Swedish Research Council, Swedish Cancer Society, Mrs. Berta Kamprad's Cancer Foundation, Crafoord Foundation, Cancer Research Foundation at the Department of Oncology, Malmö University Hospital, and China Scholarship Council., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

Acral melanoma is a clinical subtype of melanoma with high mortality, on which research is limited in scope. This study aimed to assess incidence trends and melanoma-specific survival rates for acral melanoma in the Swedish population from 1990 to 2020.This cross-sectional study included patients with an acral melanoma diagnosis from 1990 to 2020 from the nationwide, population-based Swedish Melanoma Registry. Analyses on acral melanoma melanoma-specific survival rates were adjusted for age, sex, histopathological subtype, and tumour thickness. Clinicopathological features and melanoma-specific survival rates were compared between diagnostic periods: 1990-1999, 2000-2009, and 2010-2020, respectively. Changes in standardized incidence rates in 1996-2020 were evaluated separately for males and females. In total, 1,000 acral melanomas in 999 patients were included in the study. No significant yearly change in standardized incidence rates for either males or females was observed, even though the absolute number of cases increased. Factors such as male sex, age ≥ 70 years, and Breslow thickness > 1.0 were independently linked to lower melanoma-specific survival. The 5-year melanoma-specific survival across the studied period ranged from 75.8% to 77.9% for females, and from 62.4% to 71.7% for males.

Purpose: The Obesity and Disease Development Sweden (ODDS) study was designed to create a large cohort to study body mass index (BMI), waist circumference (WC) and changes in weight and WC, in relation to morbidity and mortality., Participants: ODDS includes 4 295 859 individuals, 2 165 048 men and 2 130 811 women, in Swedish cohorts and national registers with information on weight assessed once (2 555 098 individuals) or more (1 740 761 individuals), in total constituting 7 733 901 weight assessments at the age of 17-103 years in 1963-2020 (recalled weight as of 1911). Information on WC is available in 152 089 men and 212 658 women, out of whom 108 795 have repeated information on WC (in total 512 273 assessments). Information on morbidity and mortality was retrieved from national registers, with follow-up until the end of 2019-2021, varying between the registers., Findings to Date: Among all weight assessments (of which 85% are objectively measured), the median year, age and BMI (IQR) is 1985 (1977-1994) in men and 2001 (1991-2010) in women, age 19 (18-40) years in men and 30 (26-36) years in women and BMI 22.9 (20.9-25.4) kg/m 2 in men and 23.2 (21.2-26.1) kg/m 2 in women. Normal weight (BMI 18.5-24.9 kg/m 2 ) is present in 67% of assessments in men and 64% in women and obesity (BMI≥30 kg/m 2 ) in 5% of assessments in men and 10% in women. The median (IQR) follow-up time from the first objectively measured or self-reported current weight assessment until emigration, death or end of follow-up is 31.4 (21.8-40.8) years in men and 19.6 (9.3-29.0) years in women. During follow-up, 283 244 men and 123 457 women died., Future Plans: The large sample size and long follow-up of the ODDS Study will provide robust results on anthropometric measures in relation to risk of common diseases and causes of deaths, and novel findings in subgroups and rarer outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We investigated time trends of the obesity-mortality association, accounting for age, sex, and cause-specific deaths., Methods: We analysed pooled nationwide data in Sweden for 3,472,310 individuals aged 17-39 years at baseline in 1963-2016. Cox regression and flexible parametric survival models investigated BMI-mortality associations in sub-groups of sex and baseline calendar years (men: <1975, 1975-1985, ≥1985 and women: <1985, 1985-1994, ≥1995)., Results: Comparing men with obesity vs. normal weight, all-cause and "other-cause" mortality associations decreased over periods; HR (95% CI) 1.92 (1.83-2.01) and 1.70 (1.58-1.82) for all-cause and 1.72 (1.58-1.87) and 1.40 (1.28-1.53) for "other-cause" mortality in <1975 and ≥1985, but increased for CVD mortality; HR 2.71 (2.51-2.94) and 3.91 (3.37-4.53). Higher age at death before 1975 coincided with more obesity-related deaths at higher ages. Furthermore, the all-cause mortality association for different ages in men showed no clear differences between periods (p-interaction=0.09), suggesting no calendar effect after accounting for attained age. Similar, but less pronounced, results were observed in women. Associations with cancer mortality showed no clear trends in men or in women., Conclusions: Accounting for differences in age and death causes between calendar periods when investigating BMI-mortality time trends may avoid misinterpreting the risks associated with obesity over time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC., Methods: CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells., Results: In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12-2.81) and 2.20 (95% CI 1.39-3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression., Conclusion: CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target., Competing Interests: Ana Bosch has received institutional honoraria from Pfizer, Roche and Lilly for consultation and lectures. She has participated in Advisory Board meetings for Pfizer and Novartis. Co-founder and chair of the board for SACRA therapeutics. Karolin Isaksson has received speaker honorarium from Pierre Fabre. The other authors declare no conflict of interest., (Copyright: © 2024 Godina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Vitamin D has some anticancer properties that may decrease breast cancer risk and improve prognosis. The aim was to investigate associations between four previously studied VDR SNPs (Taq1, Tru91, Bsm1, and Fok1) and prognosis in different groups of breast cancer patients., Methods: VDR genotyping of 1,017 breast cancer patients included 2002-2012 in Lund, Sweden, was performed using Oncoarray. Follow-up was until June 30, 2019. Clinical data and patient information were collected from medical records and questionnaires. Cox regression was used for survival analyses., Results: Genotype frequencies were as follows: Fok1 (AA 15.7%, AG 49.1%, GG 35.1%), Bsm1 (CC 37.2%, CT 46.1%, TT 16.7%), Tru91 (CC 77.8%, CT 20.7%, TT 1.5%), and Taq1 (AA 37.2%, AG 46.2%, GG 16.6%). During follow-up there were 195 breast cancer events. The homozygous variants of Taq1 and Bsm1 were associated with reduced risk of breast cancer events (adjusted HR = 0.59, 95% CI 0.38-0.92 for Taq1 and adjusted HR = 0.61, 95% CI 0.40-0.94 for Bsm1). The G allele of the Fok1 was associated with increased risk of breast cancer events in small tumors (pT1, adjusted HR = 1.83, 95% CI 1.04-3.23) but not in large tumors (pT2/3/4, adjusted HR = 0.80, 95% CI 0.41-1.59) with a borderline interaction (P interaction  = 0.058). No interactions between VDR genotypes and adjuvant treatments regarding breast cancer prognosis were detected., Conclusion: VDR genotypes were associated with breast cancer prognosis and the association might be modified by tumor size. Further research is needed to confirm the findings and elucidate their potential clinical implications., (© 2024. The Author(s).)

Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1 + CD8 + T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination., (© 2024. The Author(s).)

Background: Cancer patients often use antioxidants that may interact with adjuvant treatments. The purpose was to investigate pre- and postoperative antioxidant use in relation to clinicopathological characteristics and prognosis in different breast cancer treatment groups., Methods and Patients: Pre- and postoperative antioxidant (vitamin A, C, E, carotenoids, or Q10) or multivitamin use was self-reported by patients from Lund (n = 1855) and Helsingborg (n=478), Sweden. Patients were followed for up to 15 years. Clinical data were obtained from patient charts. The aryl hydrocarbon receptor (AhR) was evaluated in tumor tissue arrays from 915 patients from Lund and with Western blot in MCF-7 and MDA-MB-231 cells., Results: About 10% of patients used antioxidants. Nuclear AhR (AhR nuc ) positivity was twice as common in preoperative antioxidant users compared to non-users. In mechanistic studies vitamin C increased AhR levels and its downstream target CYP1B1, indicating AhR activation. There were significant interactions between tumor AhR nuc status and preoperative antioxidant use in relation to clinical outcome. In all patients, antioxidant use (other than multivitamins) at both visits was associated with poorer prognosis, while use only at the follow-up visit was associated with better prognosis, compared with no use at either visit., Conclusion: The clinical impact of antioxidants depended on antioxidant type, timing of use, and tumor AhR activation. Antioxidants may influence clinical outcome by activation of the master regulator AhR in addition to interference with free radicals. Further studies are needed to identify breast patients that might improve or worsen their prognosis when using antioxidants postoperatively., Competing Interests: Disclosure KI has received speaker honorarium from Pierre Fabre. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Previous research has indicated an association between the presence of the vitamin D receptor (VDR) in breast cancer tissue and a favorable prognosis. This study aimed to further evaluate the prognostic potential of VDR located in the nuclear membrane or nucleus (liganded). The VDR protein levels were analyzed using immunohistochemistry in tumor samples from 878 breast cancer patients from Lund, Sweden, included in the Breast Cancer and Blood Study (BCBlood) from October 2002 to June 2012. The follow-up for breast cancer events and overall survival was recorded until 30 June 2019. Univariable and multivariable survival analyses were conducted, both with complete case data and with missing data imputed using multiple imputation by chained equations (MICE). Tumor-specific positive nuclear membrane VDR (num) staining was associated with favorable tumor characteristics and a longer breast cancer free interval (BCFI; HR: 0.64; 95% CI: 0.44-0.95) and overall survival (OS; HR: 0.52; 95% CI: 0.34-0.78). Further analyses indicated that VDR num status also was predictive of overall survival when investigated in relation to ER status. There were significant interactions between VDR and invasive tumor size (P interaction = 0.047), as well as mode of detection (P interaction = 0.049). VDR num was associated with a longer BCFI in patients with larger tumors (HR: 0.36; 95% CI: 0.14-0.93) or clinically detected tumors (HR: 0.28; 95% CI: 0.09-0.83), while no association was found for smaller tumors and screening-detected tumors. Further studies are suggested to confirm our results and to evaluate whether VDR should and could be used as a prognostic and targetable marker in breast cancer diagnostics.

Combining information from the tumor microenvironment (TME) with PAM50 Risk of Recurrence (ROR) score could improve breast cancer prognostication. Caveolin-1 (CAV1) is a marker of an active TME. CAV1 is a membrane protein involved in cell signaling, extracellular matrix organization, and tumor-stroma interactions. We sought to investigate CAV1 gene expression in relation to PAM50 subtypes, ROR score, and their joint prognostic impact. CAV1 expression was compared between PAM50 subtypes and ROR categories in two cohorts (SCAN-B, n = 5326 and METABRIC, n = 1980). CAV1 expression was assessed in relation to clinical outcomes using Cox regression and adjusted for clinicopathological predictors. Effect modifications between CAV1 expression and ROR categories on clinical outcome were investigated using multiplicative and additive two-way interaction analyses. Differential gene expression and gene set enrichment analyses were applied to compare high and low expressing CAV1 tumors. All samples expressed CAV1 with the highest expression in the Normal-like subtype. Gene modules consistent with epithelial-mesenchymal transition (EMT), hypoxia, and stromal activation were associated with high CAV1 expression. CAV1 expression was inversely associated with ROR category. Interactions between CAV1 expression and ROR categories were observed in both cohorts. High expressing CAV1 tumors conferred worse prognosis only within the group classified as ROR high. ROR gave markedly different prognostic information depending on the underlying CAV1 expression. CAV1, a potential mediator between the malignant cells and TME, could be a useful biomarker that enhances and further refines PAM50 ROR risk stratification in patients with ROR high tumors and a potential therapeutic target., (© 2024. The Author(s).)