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The outcome for metastatic colorectal cancer (mCRC) patients has improved substantially in recent decades. This has chiefly been observed in study populations, and predominantly in left-sided primary tumours, which is why we wanted to study if and how survival has improved in the background population. It has also been seen that certain molecular subtypes are more common in population-based materials, and, thus, we studied the prevalence and effects of different molecular alterations. Paper I is a national population-based material of all 19 566 Swedish patients with a diagnosis of mCRC 2007-2016, 55% were male and 70% had synchronous metastases. Median overall survival (OS) for all patients was 14.0 months. An improvement could be seen over time, also in stratified analyses. OS was influenced by presentation of metastases, age, primary tumour location, and sex. All except sex remained statistically significant in a multivariable analysis. Differences of about one month in median OS were seen between healthcare regions, but these diminished over time. Paper II included all 765 patients from the Uppsala Region with a mCRC diagnosis 2010-2020. Right colon primary tumours were seen in 38%, left colon in 27% and rectum in 34%. BRAF-V600E mutations (mt) and deficient mismatch repair (dMMR) had a poor OS and were more common in right colon primary tumours. Primary tumour location did not affect OS in subgroups according to mutations in RAS or BRAF, nor in a multivariable analysis. Molecular alterations seem to be more important than primary tumour location for prognosis. Paper III studied KRAS-G12Cmt in three population-based and one real-world material. KRAS-G12C was seen in 2-4% of all tested and in 4-8% of all KRASmt. No differences in patient characteristics were observed between KRAS-G12C and other KRASmt. No differences in OS were seen between KRAS-G12C and other KRASmt, neither for all patients, nor in different treatment groups. Paper IV studied atypical BRAFmt (a, https://doi.org/10.33063/diva-522642

OBJECTIVE: This study examined BMI in young men and incident site-specific cancer to estimate population attributable fractions due to BMI based on projected obesity prevalence. METHODS: A population-based cohort study with measured height and weight at age 18. Cox regression models assessed linear associations for BMI and included age, year, and site of conscription as well as parental level of education as covariates. RESULTS: Primary analyses were performed in 1,489,115 men, of whom 78,217 subsequently developed cancer during a mean follow-up of 31 years. BMI was linearly associated with risk of developing all 18 site-specific cancers assessed (malignant melanoma; leukemia; myeloma; Hodgkin lymphoma; non-Hodgkin lymphoma; and cancer in the lungs, head and neck, central nervous system, thyroid, esophagus, stomach, pancreas, liver and gallbladder, colon, rectum, kidney, and bladder), in some instances evident at BMI levels usually defined as normal (20-25 kg/m2 ). Higher BMI was associated with lower risk of prostate cancer. The highest hazard ratios and population attributable fractions were seen for some gastrointestinal cancers. CONCLUSIONS: This study reports linear associations between BMI at age 18 and subsequent site-specific cancers, calling for rapid action to stem the obesity epidemic and to prepare the health care system for steep increases in cancer cases.

BACKGROUND: Magnetic resonance imaging (MRI) is useful in the diagnosis of clinically significant prostate cancer (csPCa). MRI-derived radiomics may support the diagnosis of csPCa. PURPOSE: To investigate whether adding radiomics from biparametric MRI to predictive models based on clinical and MRI parameters improves the prediction of csPCa in a multisite-multivendor setting. MATERIAL AND METHODS: Clinical information (PSA, PSA density, prostate volume, and age), MRI reviews (PI-RADS 2.1), and radiomics (histogram and texture features) were retrieved from prospectively included patients examined at different radiology departments and with different MRI systems, followed by MRI-ultrasound fusion guided biopsies of lesions PI-RADS 3-5. Predictive logistic regression models of csPCa (Gleason score ≥7) for the peripheral (PZ) and transition zone (TZ), including clinical data and PI-RADS only, and combined with radiomics, were built and compared using receiver operating characteristic (ROC) curves. RESULTS: In total, 456 lesions in 350 patients were analyzed. In PZ and TZ, PI-RADS 4-5 and PSA density, and age in PZ, were independent predictors of csPCa in models without radiomics. In models including radiomics, PI-RADS 4-5, PSA density, age, and ADC energy were independent predictors in PZ, and PI-RADS 5, PSA density and ADC mean in TZ. Comparison of areas under the ROC curve (AUC) for the models without radiomics (PZ: AUC = 0.82, TZ: AUC = 0.80) versus with radiomics (PZ: AUC = 0.82, TZ: AUC = 0.82) showed no significant differences (PZ: P = 0.366; TZ: P = 0.171). CONCLUSION: PSA density and PI-RADS are potent predictors of csPCa. Radiomics do not add significant information to our multisite-multivendor dataset.

The rapidly evolving landscape of biomarkers for colorectal cancer (CRC) necessitates an integrative, updated repository. In response, we constructed the Colorectal Cancer Biomarker Database (CBD), which collected and displayed the curated biomedicine information for 870 CRC biomarkers in the previous study. Building on CBD, we have now developed CBD2, which includes information on 1569 newly reported biomarkers derived from different biological sources (DNA, RNA, protein, and others) and clinical applications (diagnosis, treatment, and prognosis). CBD2 also incorporates information on nonbiomarkers that have been identified as unsuitable for use as biomarkers in CRC. A key new feature of CBD2 is its network analysis function, by which users can investigate the visible and topological network between biomarkers and identify their relevant pathways. CBD2 also allows users to query a series of chemicals, drug combinations, or multiple targets, to enable multidrug, multitarget, multipathway analyses, toward facilitating the design of polypharmacological treatments for CRC. CBD2 is freely available at http://www.eyeseeworld.com/cbd., This work was supported by the National Natural Science Foundation of China (Grant numbers: 32200545 and 32271292), and the GDPH Supporting Fund for Talent Program (Grant numbers: KJ012020633 and KJ012019530) from Guangdong Provincial People's Hospital. This work was also supported by the Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (Grant number: 2022B121 2010011).

BACKGROUND AND AIMS: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. METHODS: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression. RESULTS: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6). CONCLUSION: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis.

PURPOSE: Evidence supporting the use of neoadjuvant chemotherapy (NAC) in early breast cancer is based on studies mainly including women, whereas the utilization and effectiveness of NAC in men is less studied. The present study aimed to investigate the utilization and effectiveness of NAC in men and women with early breast cancer. METHODS: Eligible patients were identified through the Swedish National Breast Cancer Quality Register, that includes all newly diagnosed breast cancer cases in Sweden from 2008 and onwards. For the treatment utilization analysis, all patients with stage I-III between 2008 and 2020 were included (n = 82,888), whereas for the effectiveness analysis the cohort was restricted to patients receiving NAC (n = 6487). For both analyses, multivariate logistic regression models were applied to investigate potential sex disparities in NAC utilization and effectiveness, adjusted for patient- and tumor characteristics. RESULTS: In the NAC utilization analysis, 487 men and 82,401 women with stage I-III were included. No statistically significant difference between sexes in terms of NAC utilization was observed (adjusted Odds Ratio (adjOR): 1.135; 95% Confidence Interval (CI) 0.606-2.128) with an overall utilization rate of 4.9% in men compared to 7.8% in women. Among the 24 men and 6463 women who received NAC, the pathologic complete response (pCR) rates were 16.7% and 21.2%, respectively (adjOR: 1.141; 95% CI 0.141-9.238). CONCLUSION: The present study did not find any sex disparities in NAC utilization or effectiveness in terms of pCR. This supports the current recommendations of treating men with breast cancer with the same indications for NAC as women.

Colorectal cancer is one of the most common cancer types worldwide. Since colorectal cancer takes time to develop, its incidence and mortality can be treated effectively if it is detected in its early stages. As a result, non-invasive or invasive biomarkers play an essential role in the early diagnosis of colorectal cancer. Many experimental studies have been carried out to assess genetic, epigenetic, or protein markers in feces, serum, and tissue. It may be possible to find biomarkers that will help with the diagnosis of colorectal cancer by identifying the genes, RNAs, and/or proteins indicative of cancer growth. Recent advancements in the molecular subtypes of colorectal cancer, DNA methylation, microRNAs, long noncoding RNAs, exosomes, and their involvement in colorectal cancer have led to the discovery of numerous new colorectal cancer biomarkers. In small-scale investigations, most biomarkers appear promising. However, large-scale clinical trials are required to validate their effectiveness before routine clinical implementation. Hence, this review focuses on small-scale investigations and results of big data analysis that may provide an overview of the biomarkers for the diagnosis, therapy, and prognosis of colorectal cancer., The authors would like to thank Chettinad Academy of Research and Education, Chennai, India and University Grants Commission (UGC) for providing financial support through Savitribai Jyotirao Phule Fellowship to the first author Nagainallur Ravichandran Shruthi (ID: UGCES-22-GE-TAM-F-SJSGC-9631).

PURPOSE: An increased incidence of hypothyroidism among breast cancer survivors has been observed in earlier studies. The impact of the postoperative treatment modalities and their potential interplay on hypothyroidism development needs to be studied. METHODS: We conducted a population- and registry-based study using the Breast Cancer Data Base Sweden (BCBaSe) including females diagnosed with breast cancer between 2006 and 2012. In total, 21,268 female patients diagnosed with early breast cancer between 2006 and 2012, with no previous prescription of thyroid hormones and no malignant diagnosis during the last ten years before breast cancer diagnosis, were included in the final analysis. RESULTS: During the follow-up (median follow-up time 7.9 years), 1212 patients (5.7%) developed hypothyroidism at a median time of 3.45 years from the index date. No association of the systemic oncological treatment in terms of either chemotherapy or endocrine therapy and hypothyroidism development could be identified. A higher risk (HR 1.68;95% CI 1.42-1.99) of hypothyroidism identified among patients treated with radiation treatment of the regional lymph nodes whereas no increased risk in patients treated only with radiation therapy to the breast/chest wall was found (HR 1.01; 95% CI 0.86-1.19). The risk of hypothyroidism in the cohort treated with radiotherapy of the regional lymph nodes was present irrespective of the use of adjuvant chemotherapy treatment. CONCLUSIONS: Based on the results of our study, the implementation of hypothyroidism surveillance among the breast cancer survivors treated with radiotherapy of the regional lymph nodes can be considered as reasonable in the follow-up program.

Background Digital patient monitoring (DPM) tools can facilitate early symptom management for patients with cancer through systematic symptom reporting; however, low adherence can be a challenge. We assessed patient/healthcare professional (HCP) use of DPM in routine clinical practice.Materials and Methods Patients with locally advanced/metastatic lung cancer or HER2-positive breast cancer received locally approved/reimbursed drugs alongside DPM, with elements tailored by F. Hoffmann-La Roche Ltd, on the Kaiku Health DPM platform. Patient access to the DPM tool was through their own devices (eg, laptops, PCs, smartphones, or tablets), via either a browser or an app on Apple iOS or Android devices. Coprimary endpoints were patient DPM tool adoption (positive threshold: 60%) and week 1-6 adherence to weekly symptom reporting (positive threshold: 70%). Secondary endpoints included experience and clinical impact.Results At data cutoff (June 9, 2022), adoption was 85% and adherence was 76%. Customer satisfaction and effort scores for patients were 76% and 82%, respectively, and 83% and 79% for HCPs. Patients spent approximately 10 minutes using the DPM tool and completed approximately 1.0 symptom questionnaires per week (completion time 1-4 minutes). HCPs spent approximately 1-3 minutes a week using the tool per patient. Median time to HCP review for alerted versus non-alerted symptom questionnaires was 19.6 versus 21.5 hours. Most patients and HCPs felt that the DPM tool covered/mostly covered symptoms experienced (71% and 75%), was educational (65% and 92%), and improved patient-HCP conversations (70% and 83%) and cancer care (51% and 71%).Conclusion The DPM tool demonstrated positive adoption, adherence, and user experience for patients with lung/breast cancer, suggesting that DPM tools may benefit clinical cancer care. Digital patient monitoring tools can facilitate early symptom monitoring and management for cancer through systematic symptom reporting; however, low, Funding Agencies|F. Hoffmann-La Roche Ltd; F. Hoffmann-La Roche Ltd, Basel, Switzerland

Introduction: Observational studies suggest that breast conserving surgery (BCS) and radiotherapy (RT) offers superior survival compared to mastectomy. The aim was to compare patient and tumour characteristics in women with invasive breast cancer <= 30 mm treated with either BCS or mastectomy, and to explore the underlying reason for choosing mastectomy. Methods: Women registered with breast cancer <= 30 mm and <= 4 positive axillary lymph nodes in the Swedish National Breast Cancer Register 2013-2016 were included. Logistic regression analyses were performed to assess the association of tumour and patient characteristics with receiving a mastectomy vs. BCS. Results: Of 1860 breast cancers in 1825 women, 1346 were treated by BCS and 514 by mastectomy. Adjuvant RT was given to 1309 women (97.1 %) after BCS and 146 (27.6 %) after mastectomy. Variables associated with receiving a mastectomy vs. BCS included clinical detection (Odds Ratio (OR) 4.15 (95 % Confidence Interval (CI) 3.35-5.14)) and clinical stage (T2 vs. T1 (OR 3.68 (95 % CI 2.90-4.68)), N1 vs. N0 (OR 2.02 (95 % CI 1.38-2.96)). Women receiving mastectomy more often had oestrogen receptor negative, HER2 positive tumours of higher histological grade. The most common reported reason for mastectomy was large or multifocal tumours (53.5 %), followed by patient preference (34.5 %). Conclusion: Choice of surgery is strongly associated with key prognostic factors among women undergoing BCS with RT compared to mastectomy. Failure to control for all relevant confounders may bias results in outcome studies in favour of BCS.

Background: Childhood cancer impacts the family system and has psychosocial consequences for all family members. For the parents, the ill child, and the siblings to be able to adjust to this challenging situation, the whole family needs access to psychosocial support. However, only a few such family interventions in pediatric oncology have been evaluated. The aim of this study was to explore the potential effects of a family-centered intervention, the Family Talk Intervention (FTI), in pediatric oncology from the parents' perspectives. Methods: A concurrent mixed methods design was used for this study. Data were derived from a pilot study of 26 families recruited from one pediatric oncology center in Sweden. This study focused on questionnaire and interview data from 52 parents. Results: After participation in FTI, the parents felt more satisfied with the conversations within the family about the illness. FTI also contributed to strengthened family togetherness, including more open communication and improved family relations, as described by the parents. Parents further expressed that they felt more empowered in their parenting role following FTI. Conclusions: The findings regarding FTI's ability to improve family communication and family relations, thus strengthening family togetherness in families with childhood cancer, are promising. This provides motivation for a large-scale study of FTIs in pediatric oncology.

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.

Hepatocellular carcinoma (HCC) is characterized by a low and variable response to chemotherapeutic treatments. One contributing factor to the overall pharmacodynamics is the activation of endoplasmic reticulum (ER) stress pathways. This is a cellular stress mechanism that becomes activated when the cell's need for protein synthesis surpasses the ER's capacity to maintain accurate protein folding, and has been implicated in creating drug-resistance in several solid tumors. Objective: To identify the role of ER-stress and lipid metabolism in mediating drug response in HCC. Methods: By using a chemically-induced mouse model for HCC, we administered the ER-stress inhibitor 4m8C and/or doxorubicin (DOX) twice weekly for three weeks post-tumor initiation. Histological analyses were performed alongside comprehensive molecular biology and lipidomics assessments of isolated liver samples. In vitro models, including HCC cells, spheroids, and patient-derived liver organoids were subjected to 4m8C and/or DOX, enabling us to assess their synergistic effects on cellular viability, lipid metabolism, and oxygen consumption rate. Results: We reveal a pivotal synergy between ER-stress modulation and drug response in HCC. The inhibition of ER-stress using 4m8C not only enhances the cytotoxic effect of DOX, but also significantly reduces cellular lipid metabolism. This intricate interplay culminates in the deprivation of energy reserves essential for the sustenance of tumor cells. Conclusions: This study elucidates the interplay between lipid metabolism and ER-stress modulation in enhancing doxorubicin efficacy in HCC. This novel approach not only deepens our understanding of the disease, but also uncovers a promising avenue for therapeutic innovation. The long-term impact of our study could open the possibility of ER-stress inhibitors and/or lipase inhibitors as adjuvant treatments for HCC-patients. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article und

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We analyzed long-term results of the response-adapted trial for adult patients with advanced-stage Hodgkin lymphoma. The aim was to confirm noninferiority of treatment de-escalation by omission of bleomycin from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for interim fluorodeoxyglucose positron emission tomography (iPET)–negative patients and assess efficacy and long-term safety for iPET-positive patients who underwent treatment intensification with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP/BEACOPP14). The median follow-up is 7.3 years. For all patients, the 7-year progression-free survival (PFS) and overall survival (OS) are 78.2% (95% CI, 75.6 to 80.5) and 91.6% (95% CI, 89.7 to 93.2), respectively. The 1.3% difference in 3-year PFS (95% CI, –3.0 to 4.7) between ABVD and doxorubicin, vinblastine, and dacarbazine (AVD) now falls within the predefined noninferiority margin. Among 172 patients with positive iPET, the 7-year PFS was 65.9% (95% CI, 58.1 to 72.6) and the 7-year OS was 83.2% (95% CI, 76.2 to 88.3). The cumulative incidence of second malignancies at 7 years was 5.5% (95% CI, 4.0 to 7.5) for those receiving ABVD/AVD and 2.5% (95% CI, 0.8 to 7.7) for those escalated to BEACOPP. With extended follow-up, these results confirm noninferiority of treatment de-escalation after a negative iPET. Escalation with BEACOPP for iPET-positive patients is effective and safe, with no increase in second malignancies.

Background: In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment. Methods: Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and "other" subtypes of GC were analyzed. Results: In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and "other" subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the "other" subtypes, respectively. Conclusion: Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible.

The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit similar routes for infiltrating the brain parenchyma. In this report, we have examined the migration of GBM cells using three-dimensional high-resolution confocal microscopy in brain tumors derived from eight different human GBM cell lines xenografted into immunodeficient mice. The primary invasion routes identified were long-distance migration along white matter tracts and local migration along blood vessels. We found that GBM cells in the majority of tumors (6 out of 8) did not exhibit association with blood vessels. These tumors, derived from low lamin A/C expressing GBM cells, were comparatively highly diffusive and invasive. Conversely, in 2 out of 8 tumors, we noted perivascular invasion and displacement of astrocyte end-feet. These tumors exhibited less diffusive migration, grew as solid tumors, and were distinguished by elevated expression of lamin A/C. We conclude that the migration pattern of glioblastoma is distinctly tumor cell-specific. Furthermore, the ability to invade the confined spaces within white matter tracts may necessitate low expression of lamin A/C, contributing to increased nuclear plasticity. This study highlights the role of GBM heterogeneity in driving the aggressive growth of glioblastoma.

Background: Turnover of RNA is a regulated process that in part controls gene expression. This process is partly controlled by the scavenger decapping enzyme (DcpS). This study aimed to investigate the expression of DcpS in colorectal cancer (CRC) tissue, to evaluate its prognostic significance in patients with CRC and to investigate potentially targeted genes by DcpS. Methods: Immunohistochemical analysis was used to determine localization of DcpS in normal and CRC tissue, western blot analysis for quantification of protein expression and qPCR for mRNA expression in normal and CRC tissue and expression in cell lines after silencing using siRNA. Gene array analysis was used to study regulation of genes after silencing of DcpS. Proliferation was studied using BRDU. Results: DcpS expression was localized to the epithelial cells of both control and cancer tissue. Tumor and paired control tissue samples from 100 patients who underwent surgical resection for primary colorectal adenocarcinomas were utilized. mRNA and protein of DcpS was significantly up-regulated in the patients with CRC and the mRNA level was higher in rectal cancer tissue compared to colon cancer tissue (p < 0.05). Lowest tertile levels of DcpS mRNA in cancer tissue was associated with a decreased cancer-specific survival rate with a hazard ratio (HR) of 4.7 (95% CI=1.02-12.3), independent of disease stage. The low level of DcpS mRNA was a predictor of poorer survival in patients with rectal and disseminated cancer and in patients receiving adjuvant treatment (p < 0.05). After silencing DcpS in Caco-2 cancer cells, altered expression of several genes associated with RNA, cell cycle regulation, alternative splicing and microRNA was observed and resulted in 23% increase in proliferation. Conclusions: These results indicate that DcpS has potential as a prognostic factor for CRC but further studies in a broader cohort are warranted to evaluate the significance of the findings in the clinic.

Purpose: This study aimed to investigate whether malnutrition or nutrition impact symptoms (NIS) affect the possibility of returning to work after treatment for head and neck cancer. Methods: Patients of working age with head and neck cancer were followed up from treatment initiation to 3 months (n = 238), 1 year (n = 182), and 2 years (n = 130) after treatment completion. The observed decrease in the number of patients over time was due to retirement, lack of follow-up, or death. Returning to work was dichotomised as yes or no. Malnutrition was diagnosed 7 weeks after treatment initiation using the Global Leadership Initiative on Malnutrition (GLIM) criteria. This time-point corresponds to the end of chemoradiotherapy or radiotherapy (with or without prior surgery), except for patients who underwent exclusive surgery. NIS were scored on a Likert scale (1-5) at each follow-up using the Head and Neck Patient Symptom Checklist (c) (HNSC (c)). Nonparametric tests were used to analyse the ability of patients with/without malnutrition and high/low NIS scores to return to work. Results: At 3 months, 1 year, and 2 years after treatment completion, 135/238 (56.7%), 49/182 (26.9%), and 23/130 (17.7%) patients had not returned to work. Patients with malnutrition at 7 weeks after treatment initiation were more likely to not return to work at 3 months than those without malnutrition, 70.5% compared to 47.1% (p < 0.001). At all three follow-up time-points, patients reporting high scores for a number of NIS had more often not returned to work, with this pattern being most distinct at 2 years. Conclusion: Malnutrition according to the GLIM criteria at 7 weeks after treatment initiation and NIS assessed by the HNSC (c) at subsequent follow-ups were predictors of the return-to-work process after treatment for up to 2 years.

Purpose To examine differences in health-related quality of life (HRQoL) between native and foreign-born gynaecological cancer patients in Sweden, taking into account clinical, demographic, and socioeconomic factors. Methods The 30-item European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30) and a study-specific questionnaire covering demographic and socioeconomic factors were answered by 684 women aged ≥ 18 years old, diagnosed in 2014, 2016, or 2018 with gynaecological cancer in the Stockholm-Gotland health care region, Sweden. Clinical data were obtained from the Swedish Cancer Register. Data were analysed using the Kruskal–Wallis test and linear regression. Results The women had a mean age of 65.4 years, with 555 (81.1%) born in Sweden, 54 (7.9%) in other Nordic countries (ONC), 43 (6.3%) in other European countries (OEC), and 32 (4.7%) in non-European countries (NEC). HRQoL differed significantly between the four groups for 14 of the 15 QLQ-C30 scales/items. On average, Swedish-born women scored 2.0, 15.2, and 16.7 points higher for QoL/functioning scales/items and 2.2, 14.1, and 18.7 points lower for symptom scales/items, compared with ONC-, OEC-, and NEC-born women, respectively. In adjusted analyses, none of the differences between Swedish-born and ONC-born women were significant, while for OEC- and NEC-born women the differences were significant for most QLQ-C30 scales/items. Conclusion HRQoL differs between native and foreign-born gynaecological cancer patients in Sweden, with lower HRQoL the further from Sweden the women are born. A more individualised cancer care, with tailored support to optimize HRQoL is needed for this vulnerable group of patients.

IntroductionPublic contribution in research can facilitate the design and conduct of meaningful research, resulting in feasible and sustainable solutions to healthcare challenges. However, the evidence concerning the acceptability, feasibility, and impact of public contribution in research is limited. We will embed a mixed-method examination of public contribution activities into the CHANGE trial. The overall aim of the CHANGE trial is to evaluate the efficacy and cost-effectiveness of an internet-administered, guided, low-intensity cognitive behavioral therapy-based self-help intervention (EJDeR) plus treatment as usual (TAU) versus TAU for symptoms of depression and/or Generalized Anxiety Disorder in a superiority randomized controlled trial with an internal pilot phase. In this protocol we describe how we aim to: (1) involve parents of children treated for cancer in the managing and undertaking, analysis and interpretation, and dissemination phases of the CHANGE trial; and (2) examine the acceptability, feasibility, and perceived impact of Parent Advisory Board contribution to the trial from the perspective of board members and public contribution coordinators. Methods We will recruit around six parents of children treated for cancer to the Parent Advisory Board. Board members will contribute throughout the trial during online workshops and steering group meetings. An impact log will be used during workshops to record activities and examine the perceived impact of activities according to board members and public contribution coordinators, including anticipated and unanticipated changes to the research process and potential benefits and harms. Activities will be reported using the Guidance for Reporting Involvement of Patients and the Public checklist. We will conduct semi-structured interviews with board members and public contribution coordinators 6 months after the board is established and at the end of the trial to examine the acceptability, feasibility, and p

INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease. METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index). RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005). CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.

One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, −1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, −1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P =.01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.

Background: Insulin resistance is a hypothesised biological mechanism linking obesity with prostate cancer (PCa) death. Data in support of this hypothesis is limited. Methods: We included 259,884 men from eight European cohorts, with 11,760 incident PCa’s and 1784 PCa deaths during follow-up. We used the triglyceride-glucose (TyG) index as indicator of insulin resistance. We analysed PCa cases with follow-up from PCa diagnosis, and the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index. Results: In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01–1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14–1.35, of which 28%; 4%–52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death. Conclusions: Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death.

Background: The immune response has important clinical value in colorectal cancer (CRC) in both prognosis and response to immunotherapy. This study aims to explore tumour immune cell infiltration in relation to clinically well-established molecular markers of CRC. Methods: Multiplex immunohistochemistry and multispectral imaging was used to evaluate tumour infiltration of cytotoxic T cells (CD8+), Th1 cells (T-bet+), T regulatory cells (FoxP3+), B cells (CD20+), and macrophages (CD68+) in a cohort of 257 CRC patients. Results: We found the expected association between higher immune-cell infiltration and microsatellite instability. Also, whereas BRAF-mutated tumours displayed increased immune-cell infiltration compared to BRAF wild-type tumours, the opposite was seen for KRAS-mutated tumours, differences that were most prominent for cytotoxic T cells and Th1 cells. The opposing relationships of BRAF and KRAS mutations with tumour infiltration of cytotoxic T cells was validated in an independent cohort of 608 CRC patients. A positive prognostic importance of cytotoxic T cells was found in wild-type as well as KRAS and BRAF-mutated CRCs in both cohorts. Conclusion: A combined evaluation of MSI status, KRAS and BRAF mutational status, and immune infiltration (cytotoxic T cells) may provide important insights to prognosis and response to immunotherapy in CRC.

Background: The association of fitness with cancer risk is not clear. Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

The current medical standard for setting an oral cancer (OC) diagnosis is histological examination of a tissue sample taken from the oral cavity. This process is time-consuming and more invasive than an alternative approach of acquiring a brush sample followed by cytological analysis. Using a microscope, skilled cytotechnologists are able to detect changes due to malignancy; however, introducing this approach into clinical routine is associated with challenges such as a lack of resources and experts. To design a trustworthy OC detection system that can assist cytotechnologists, we are interested in deep learning based methods that can reliably detect cancer, given only per-patient labels (thereby minimizing annotation bias), and also provide information regarding which cells are most relevant for the diagnosis (thereby enabling supervision and understanding). In this study, we perform a comparison of two approaches suitable for OC detection and interpretation: (i) conventional single instance learning (SIL) approach and (ii) a modern multiple instance learning (MIL) method. To facilitate systematic evaluation of the considered approaches, we, in addition to a real OC dataset with patient-level ground truth annotations, also introduce a synthetic dataset—PAP-QMNIST. This dataset shares several properties of OC data, such as image size and large and varied number of instances per bag, and may therefore act as a proxy model of a real OC dataset, while, in contrast to OC data, it offers reliable per-instance ground truth, as defined by design. PAP-QMNIST has the additional advantage of being visually interpretable for non-experts, which simplifies analysis of the behavior of methods. For both OC and PAP-QMNIST data, we evaluate performance of the methods utilizing three different neural network architectures. Our study indicates, somewhat surprisingly, that on both synthetic and real data, the performance of the SIL approach is better or equal to the performance of the

Chimeric Antigen Receptor (CAR) T cell therapy has produced revolutionary success in hematological cancers such as leukemia and lymphoma. Nonetheless, its translation to solid tumors faces challenges due to manufacturing complexities, short-lived in vivo persistence, and transient therapeutic impact. We introduce 'Drydux' - an innovative macroporous biomaterial scaffold designed for rapid, efficient in-situ generation of tumor-specific CAR T cells. Drydux expedites CAR T cell preparation with a mere three-day turnaround from patient blood collection, presenting a cost-effective, streamlined alternative to conventional methodologies. Notably, Drydux-enabled CAR T cells provide prolonged in vivo release, functionality, and enhanced persistence exceeding 150 days, with cells transitioning to memory phenotypes. Unlike conventional CAR T cell therapy, which offered only temporary tumor control, equivalent Drydux cell doses induced lasting tumor remission in various animal tumor models, including systemic lymphoma, peritoneal ovarian cancer, metastatic lung cancer, and orthotopic pancreatic cancer. Drydux's approach holds promise in revolutionizing solid tumor CAR T cell therapy by delivering durable, rapid, and cost-effective treatments and broadening patient accessibility to this groundbreaking therapy.

Cancer is the second leading cause of death globally and is one of the most pressing health issues today. While significant advances have been made in cancer treatment, drug resistance and toxicity remain formidable obstacles to successful therapy. Thus, there is a need to find novel targets that pave the way for new cancer therapeutics. Ubiquitination, the process of tagging substrate proteins with ubiquitin molecules, regulates many of the pathways that underlie cancer progression. This thesis aims to explore innovative strategies for combating cancer by focusing on crucial elements within the ubiquitination machinery, specifically the Ubiquitin-Proteasome System (UPS) and deubiquitinases (DUBs). In Paper I, we employed the Connectivity Map to discern UPS inhibitors by analyzing the gene expression patterns of various compounds in comparison to those induced by proteasome perturbation. In Paper II, we employed orthogonal methods to identify the primary mechanism for the cytotoxicity of b-AP15. Here, we showed that pharmacologic doses of b-AP15 resulted in strong proteasome inhibition and that cytotoxicity is mediated through the mitochondria and influenced by the proteasome-associated DUB, USP14. In Paper III, we explored the role of USP14 in colorectal cancer cells and evaluated its potential as a cancer target. We found that the genetic deletion of USP14 confers a quiescent phenotype to cancer cells. In Paper IV, we used CRISPR-based screens to search for new deubiquitinase targets. We identified deubiquitinase interactions essential for cancer and explored the possibility of combinatorial deubiquitinase targeting. We pinpointed highly-networked deubiquitinases (PSMD14, USP9X, USP39, and USP7) and deubiquitinase pairs represent promising drug targets. This thesis underscores the importance of the ubiquitination process in the search for novel cancer therapeutics and provides new avenues to explore in developing therapies based on the inhibition of deubiquitinase

Purpose: To examine the role of RhoB expression in relation to chemotherapy response, clinical outcomes and associated signaling pathways in colorectal cancer patients. Materials and methods: The study included 5 colon cancer cell lines, zebrafish embryos and 260 colorectal cancer patients treated with 5-fluorouracil (5-FU) and oxaliplatin (OXL). The methods consisted of CRISPR/Cas9, reactive oxygen species (ROS), caspase-3 activity, autophagy flux, in-silico RNA sequencing and immunohistochemistry. Gene expression analysis and pathway analysis were conducted using RNA-seq data. Results: All cancer lines tested, including SW480, SW480-KO13 (RhoB knockout), SW480-KO55 (RhoB knockout), HCT116 and HCT116-OE (RhoB overexpressed), exhibited cytotoxicity to 5-FU and OXL. RhoB knockout cell lines demonstrated significantly reduced migration compared to the control cell lines. Furthermore, RhoB played a role in caspase-3-dependent apoptosis, regulation of ROS production and autophagic flux. The mRNA sequencing data indicated lower expression levels of oncogenes in RhoB knockout cell lines. The zebrafish model bearing SW480-KO showed a light trend toward tumor regression. RhoB expression by immunohistochemistry in patients was increased from normal mucosa to tumor samples. In patients who received chemotherapy, high RhoB expression was related to worse survival compared to low RhoB expression. Furthermore, the molecular docking analysis revealed that OXL had a higher binding affinity for RhoB than 5-FU, with a binding affinity of -7.8 kcal/mol and HADDOCK predicted molecular interactions between RhoB and caspase 3 protein. Gene-set enrichment analysis supported these findings, showing that enrichment of DNA damage response pathway and p53 signaling in RhoB overexpression treatment group, while the RhoB knockout treatment group exhibited enrichment in the negative regulation pathway of cell migration. Conclusion: RhoB was negatively associated with chemotherapy response and s

Background Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer is notable for its aggressive behavior, however with the introduction of trastuzumab in the early 2000’s, prognosis has improved. This thesis investigates the efficacy of trastuzumab in real-world settings after its introduction and evaluates the prognostic value of molecular biomarkers, aiming to optimize treatment approaches and improve patient outcomes. Material and Methods HER2-positive patients treated in the advanced and early stages of breast cancer were retrospectively identified using Swedish patient registries and through the review of medical records. Study I included 46 patients with advanced breast cancer treated with trastuzumab between 2000 and 2007. Immunohistochemical analysis of several proteins hypothesized to be involved in trastuzumab resistance were evaluated. Additionally, gene copy number variations were analyzed using droplet digital PCR. Study II include 599 patients who received adjuvant trastuzumab between 2006 and 2014 in the Southeastern health care region, in order to evaluate the implementation of trastuzumab after its approval and to evaluate patient outcomes with regard to clinicopathological variables. Study III conducted quantitative analyses of stromal tumor-infiltrating lymphocytes (sTILs) in patients with available tumor material from the same cohort identified in study II. Additionally, a case-control study of 21 cases with 21 matched controls treated with trastuzumab were analyzed with RNA-sequencing in order to identify important differentially expressed genes. Results Study I demonstrated that trastuzumab treatment in a real-world setting had similar survival as in pivotal clinical trials. Additionally, high amplification of HER2 correlated with improved progression-free survival (PFS) and overall survival (OS) in advanced breast cancer patients and PTPN2 gain was correlated with reduced PFS and OS. Study II confirmed trastuzumab's efficacy in

Introduction: Neuroendocrine neoplasms (SI-NEN) are the commonest malignancies of the small intestine. Traditionally, surgical treatment for SI-NEN has been open surgery. Purpose: The purpose of this study was to compare minimally invasive surgery (MIS) with the traditional open surgery approach for treating SI-NEN in a Swedish population. Methods: Patients with histopathological confirmed SI-NEN who underwent open surgery or MIS resection within 2009-2021 were extracted from the hospital's medical records. Results: 65 patients were included in this study, with 35 (54 %) undergoing MIS and 30 (46 %) undergoing open surgery. We found no statistically significant difference (p = 0.173) in the frequency of R0 resections (MIS group n = 34 (97 %), open surgery group n = 26 (87 %)). Nor was there a significant difference (p = 0.101) when comparing the median number of resected lymph nodes (MIS group n = 13.5, open surgery group n = 10). A post-operative paralytic ileus was more often reported (p = 0.052) in the MIS group (n = 9, 26 %) compared to the open surgery group (n = 2, 7 %). In light of this, the days of hospital stay did not differ significantly (MIS group median = 6, IQR (5-8), open surgery group median = 6, IQR (5-9)). The Kaplan-Meier analysis did not reveal differences concerning cancer-related deaths (p = 0.109). Conclusion: The results from this study support that a MIS approach for the treatment of SI-NEN may not be inferior to open surgery. The higher number of resected lymph nodes and R0 resections may even speak in favor for a MIS approach. More studies with a longer time of observation are needed to further support this conclusion.

Palliativ vård av barn är en aktiv, multidimensionell vårdform som inkluderar familjen och bedrivs av interdisciplinära team. En nationell studie med frågeformulär har undersökt om vårdnadshavare till barn med cancer uppfattade att deras barn fick palliativ vård innan barnet dog och deras syn på den vård barnet fick den sista månaden. Majoriteten av vårdnadshavarna rapporterar att barnet har fått palliativ vård och att personalen var kompetent. Många vårdnadshavare uppfattade att deras barn upplevde smärta den sista tiden i livet. Geografiska skillnader föreligger, och färre vårdnadshavare i glesbygd rapporterar att barnet fått palliativ vård. Studien visar på behovet av tillgång till nationell jämlik palliativ vård., [Palliative care in paediatric oncology - a national parental perspective] The WHO definition of paediatric palliative care (PPC) emphasises the role of active multidimensional care, carried out with interdisciplinary competence, and providing support to the entire family. The aim of the current national study was to investigate whether parents perceived that their child received palliative care (PC) before the child died of cancer and the parent's view of the care during the child's last month of life. In 2016, parents (n=226) completed a study-specific survey, and a majority reported that their child had received PC with good professional competence. However, many parents reported that the child was greatly affected by pain in the last month of life. Geographical differences indicated that parents who live in sparsely populated areas to a lesser extent reported that their child received PC. Lastly, our conclusion is that access to equal PPC and improved symptom control is crucial for children and their families.

Aim: The aim of this systematic review and meta-analysis was to explore and evaluate the effect of psychosocial interventions in improving sexual health outcomes among post-treatment patients with pelvic cancer. Methods: Inclusion and exclusion criteria were pelvic cancer survivors; psychosocial interventions; studies with a control group and measures of sexual health. Five databases were searched for literature along with an inspection of the included studies' reference lists to extend the search. Risk of bias was assessed with the RoB2 tool. Standardised mean difference (SMD) with a random effects model was used to determine the effect size of psychosocial interventions for sexual health in patients with pelvic cancers. Results: Thirteen studies were included, with a total number of 1,541 participants. There was a large heterogeneity regarding the type of psychosocial intervention used with the source found in a leave one out analysis. Six studies showed statistically significant improvements in sexual health, while three showed positive but non-significant effects. The summary effect size estimate was small SMD = 0.24 (95% confidence interval [CI]: 0.05 to 0.42, p = 0.01). Discussion: There is limited research on psychosocial interventions for sexual health in pelvic cancer patients. There are also limitations in the different pelvic cancer diagnoses examined. Commonly, the included articles examined physical function rather than the whole sexual health spectrum. The small effect sizes may in part be due to evaluation of psychosocial interventions by measuring physical dysfunction. Future research should broaden sexual health assessment tools and expand investigations to more cancer types.

Background Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors. Methods gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease -causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients. Findings The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second -hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non -cancer related features (23%, 20/88), and >= 2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet con fi rmed de novo in 64% (18/28). The 35 ChiCaP fi ndings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35). Interpretation Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients., Funding Agencies|Swedish Childhood Cancer Fund; Ministry of Health and Social Affairs

Evolution of brain tumours backwards in time is studied using well-established brain tumour growth models being semilinear parabolic equations of reaction-diffusion type. To run the models backwards, the tumour cell density data at a fixed (final) time is used, rendering an inverse ill-posed problem. This problem is recast as the minimisation of a cost functional matching the data against the solution at a final time of a forward parabolic model having the initial cell density as a control function. Regularisation is incorporated via penalising terms involving Sobolev norms. Mathematical properties of the semilinear parabolic equations are shown in Sobolev-Bochner spaces including uniqueness of a solution to the inverse problem. Differentiability of the control-to-state map is established rendering a sensitivity problem. The derivative of the cost functional is calculated and the adjoint state is derived via the Lagrange formalism. A non-linear conjugate gradient method (NCG) is presented for the minimisation. Numerical realisation of the minimisation on the BraTS'20 dataset is included using a standard finite difference discretisation of the space and time derivatives, showing that tumour evolution backwards in time can be accomplished and that the initial tumour cell density can be reconstructed. Comparison is done with a non-linear Landweber method.

Persistent taxane-induced peripheral neuropathy (TIPN) is highly prevalent among early-stage breast cancer survivors (ESBCS) and has detrimental effect on quality of life. We leveraged logistic regression models to develop and validate polygenic prediction models to estimate the risk of persistent PN symptoms in a training cohort and validation cohort taking clinical risk factors into account. Based on 337 whole-exome sequenced ESBCS two of five prediction models for individual PN symptoms obtained AUC results above 60% when validated. Using the model for numbness in feet (35 SNVs) in the test cohort, 73% survivors were correctly predicted. For tingling in feet (55 SNVs) 70% were correctly predicted. Both models included SNVs from the ADAMTS20, APT6V0A2, CCDC88C, CYP2C8, EPHA5, NR1H3, PSKH2/APTV0D2, and SCN10A genes. For cramps in feet, difficulty climbing stairs and difficulty opening a jar the validation was unsuccessful. Polygenic prediction models including clinical risk factors can estimate the risk of persistent taxane-induced numbness in feet and tingling in feet in ESBCS., Funding Agencies|Swedish Research Council; Knut and Alice Wallenberg Foundation; Swedish Cancer Society [22 2202]; Swedish governmental funding of clinical research (ALF) [ROE-975072]; Medical Research Council of Southeast Sweden [FORSS 941224]; Futurum-the academy for health and care, Region Jonkoping County [FUTURUM-975687]

Simple Summary: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with almost half of all patients diagnosed with non-metastatic disease (stage IA-IIIC). The treatment options for patients with NSCLC are evolving rapidly, and survival outcomes have improved since the introduction of immunotherapies and targeted treatments in the non-metastatic setting. In this study, we explored treatment patterns and outcomes for patients with non-metastatic NSCLC in Sweden prior to the availability of these treatments. Patient outcomes were comparable with those reported in other real-world studies; however, the prognosis for patients with NSCLC, particularly at higher disease stages, remained poor. These results provide a baseline upon which to evaluate the effectiveness of immunotherapies and targeted treatments as they are introduced into routine clinical practice, including for patients in the non-metastatic setting. Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with similar to 40-50% of patients diagnosed with non-metastatic disease (stages IA-IIIC). The treatment landscape is evolving rapidly as immunotherapies and targeted therapy are introduced in the non-metastatic setting, creating a need to assess patient outcomes prior to their introduction. This real-world study using Swedish National Lung Cancer Registry data examined outcomes (overall survival (OS) and time to next treatment or death (TTNTD)) and treatment patterns for adults diagnosed with non-metastatic NSCLC. Baseline characteristics and OS from diagnosis were described for all patients; OS, treatment patterns, and TTNTD from treatment start were described for the treatment subgroup (patients diagnosed from 2014 onwards), stratified by disease stage and initial treatment. OS and TTNTD were described using the Kaplan-Meier estimator. The overall population (2008-2019) included 17,433 patients; the treatment subgroup included 5147, Funding Agencies|Bristol Myers Squibb

Tubulin beta-3 staining pattern and staining intensity of 5-hydroxymethyl cytosine (5-hmC) are potential diagnostic and prognostic markers in melanocytic lesions that need further evaluation. Melanocytic nevi and primary cutaneous melanomas were immunohistochemically stained for tubulin-beta-3 and 5-hmC. Immunoreactivity and staining patterns were correlated with Breslow-thickness, clinical and pathological characteristics, and progression-free survival. Melanocytes showed positive tubulin beta-3 staining. However, in most nevi, tubulin beta-3 staining appeared as a gradient with intense cytoplasmic staining in cells of the superficial part of the lesion that faded to weak staining in the deep dermal part, while no gradient was found in deep penetrating nevi and melanomas. In 53 % of the melanomas, areas with loss of tubulin beta-3 staining were found. 5-hmC staining intensity was significantly higher in melanocytic nevi compared to melanomas. Breslow thickness in combination with low 5-hmC score and loss of tubulin-beta-3 staining was predictive for poor prognosis. As single markers, tubulin-beta-3 and 5-hmC can be useful to distinguish between melanocytic nevi and melanoma, but staining variability limits the use of 5-hmC. In melanomas measuring >1.5 mm, combination of low 5-hmC score and loss of tubulin-beta-3 staining may have prognostic value., Funding Agencies|Swedish Cancer Society; Hudfonden (Welander-Finsen Foundation); Ostgotaregionens Cancer Foundation; County Council of Ostergotland; Olle Engkvist Foundation

Background and purpose: Tamoxifen remains an important adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Thus, determination of hormone receptors is important. Here, we compare cytosol-based methods, immunohistochemistry (IHC), and gene expression (GEX) analysis for determining hormone receptor status in premenopausal breast cancer patients from a randomised tamoxifen trial, to evaluate their performance in identifying patients that benefit from tamoxifen. Patients and Methods: Premenopausal patients (n=564) were randomised to 2 years of tamoxifen or no measured by cytosol-based methods and IHC, and mRNA by GEX analysis were compared in 313 patients with available data from all methods. Kaplan Meier estimates and Cox regression were used to evaluate the treatment-predictive value for recurrence-free interval (RFi) and overall survival (OS). Median follow-up for event-free patients was 26 (RFi) and 33 (OS) years. Results: The mRNA data of ESR1 and PGR distributed bimodally, patterns confirmed in an independent cohort. Kappa-values between all methods were 0.76 and 0.79 for ER and PR, respectively. Tamoxifen improved RFi in patients with ER-positive (ER+) or PR-positive (PR+) tumours (Hazard Ratio [HR] and 95% confidence interval [CI]), cytosol-ER+ 0.53 [0.36-0.79]; IHC-ER+ 0.55 [0.38-0.79]; GEX-ER+ 0.54 [0.37-0.77]; cytosol-PR+ 0.49 [0.34-0.72]; IHC-PR+ 0.58 [0.40-0.85]; GEX-PR+ 0.55 [0.38-0.80]). Results were similar for OS. Interpretation: These methods can all identify patients that benefit from 2 years of tamoxifen with equal performance, indicating that GEX data might be used to guide adjuvant tamoxifen therapy., Funding Agencies|Swedish Cancer Society [19 0388 Pj, 22 2137]; Anna and Edwin Berger Foundation [2019-2022]; Governmental Funding of Clinical Research within the Swedish National Health Service [2022-40304]; Berta Kamprad Foundation [FBKS-2021-11]

Introduction Traditionally, cancer pain has often been viewed as an independent third major category in pain medicine alongside acute pain and chronic non-cancer pain. However, the new chronic pain category MG30 in the eleventh version of International Classification of Diseases (ICD-11) includes cancer-related pain as one of its seven subgroups. In light of this, the aim of the paper is to investigate whether the traditional trichotomy should be replaced by a dichotomy between acute pain and chronic pain, cancer-related pain being part of both groups depending on the duration of pain.Methods The rationale for viewing cancer pain as a separate category is reviewed.Results Cancer being a deadly disease, cancer pain has a life-and-death and existential dimension that is different from non-cancer pain. It seems sensible to believe that this is an additional dimension to the suffering caused by cancer pain, and that clinicians should therefore take this existential dimension into consideration when assessing pain.Conclusion Without challenging the place of chronic cancer-related pain under the MG30 heading, it is concluded that while using ICD-11 in the future, pain clinicians should continue being mindful of the fact that the reality of death shapes the experience of cancer pain. The traditional trichotomy is therefore still valid and mirrors the fact that human beings are vulnerable (acute pain), temporal (chronic pain) and mortal (cancer pain)., Funding Agencies|ALF Grants, Region Ostergotland

Background Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. Methods We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, <= 20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. Results Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.

Background Characterization of shared cancer mechanisms have been proposed to improve therapy strategies and prognosis. Here, we aimed to identify shared cell-cell interactions (CCIs) within the tumor microenvironment across multiple solid cancers and assess their association with cancer mortality.Methods CCIs of each cancer were identified by NicheNet analysis of single-cell RNA sequencing data from breast, colon, liver, lung, and ovarian cancers. These CCIs were used to construct a shared multi-cellular tumor model (shared-MCTM) representing common CCIs across cancers. A gene signature was identified from the shared-MCTM and tested on the mRNA and protein level in two large independent cohorts: The Cancer Genome Atlas (TCGA, 9185 tumor samples and 727 controls across 22 cancers) and UK biobank (UKBB, 10,384 cancer patients and 5063 controls with proteomics data across 17 cancers). Cox proportional hazards models were used to evaluate the association of the signature with 10-year all-cause mortality, including sex-specific analysis.Results A shared-MCTM was derived from five individual cancers. A shared gene signature was extracted from this shared-MCTM and the most prominent regulatory cell type, matrix cancer-associated fibroblast (mCAF). The signature exhibited significant expression changes in multiple cancers compared to controls at both mRNA and protein levels in two independent cohorts. Importantly, it was significantly associated with mortality in cancer patients in both cohorts. The highest hazard ratios were observed for brain cancer in TCGA (HR [95%CI] = 6.90[4.64-10.25]) and ovarian cancer in UKBB (5.53[2.08-8.80]). Sex-specific analysis revealed distinct risks, with a higher mortality risk associated with the protein signature score in males (2.41[1.97-2.96]) compared to females (1.84[1.44-2.37]).Conclusion We identified a gene signature from a comprehensive shared-MCTM representing common CCIs across different cancers and revealed the regulatory role, Funding Agencies|Cancerfonden

Background: Multiple myeloma (MM), an incurable disease characterized by frequent relapses and a need for multiple treatments, often progresses to a relapse/refractory status resistant to all available drugs and drug classes. Bispecific antibodies, specifically BCMA T-cell engagers, have emerged as effective treatments for MM, demonstrating impressive efficacy. However, these treatments can adversely affect the immune system, increasing vulnerability to infections. Methods/Results: This study evaluated the efficacy and safety of BCMA T-cell engagers in 58 Swedish patients with poor MM prognosis. The patients exhibited a 69% overall response rate, with 69% survival and 60% progression-free survival at 15 months. Conclusions: Despite the risk of infectious complications, the prognosis of MM patients can be significantly improved with vigilant monitoring and proactive management of infections. This real-world data highlight the potential of BCMA T-cell engagers in treating MM, emphasizing the need for careful patient monitoring to mitigate infection risks., Funding Agencies|Cancerfonden; [4-2528/2019]

Purpose Tumor-infiltrating lymphocytes (TILs) can predict complete pathological response (pCR) of tumor in the breast but not so well-defined in the axilla after neoadjuvant chemotherapy. Since axillary surgery is being increasingly de-escalated after NACT, we aimed to investigate the relationship between TILs and pCR in the axilla and breast, as well as survival amongst NACT patients.Methods Clinicopathological data on patients who underwent NACT between 2013 and 2020 were retrospectively examined. Specifically, pre-TILs (before NACT), post-TILs (after NACT) and Delta TIL (changes in TILs) were assessed. Primary endpoint was pCR and secondary endpoints were breast cancer-free interval (BCFI) and overall survival (OS).Results Two hundred and twenty patients with nodal metastases were included. Overall axillary and breast pCR rates were 42.7% (94/220) and 39.1% (86/220), respectively, whereas the combined pCR rate was 32.7% (72/220). High pre-TILs (OR 2.03, 95% CI 1.02-4.05; p = 0.04) predicted axillary pCR whereas, high post-TILs (OR 0.33, 95% CI 0.14-0.76; p = 0.009) and increased Delta TILs (OR 0.25, 95% CI 0.08-0.79; p = 0.02) predicted non-axillary pCR. TILs were not a significant predictor for BCFI and OS.Conclusions This study supports the potential use of pre-TILs to select initially node-positive patients for axillary surgical de-escalation after NACT., Funding Agencies|Stiftelsen Assar Gabrielssons Fond

Background: Data on the incidence and comorbidity of Lichen sclerosus (LS), based on validated nationwide population-based registries, remains scarce. Objective: To explore the incidence and association of comorbidities with LS in Sweden, emphasizing its potential links to malignancies and autoimmune disorders. Methods: A population-based retrospective open cohort study was conducted using the National Patient Register to identify all individuals diagnosed with LS (ICD-10 code L90.0) from 1 January 2001 to 1 January 2021. The study included 154,424 LS patients and a sex and age matched control group of 463,273 individuals to assess the incidence and odds ratios for various cancers and premalignant conditions. Results: The incidence of LS in Sweden was 80.9 per 100,000 person per year, with higher incidence in females (114.4) than in males (47.2). LS patients showed an increased odds ratio for vulvar cancer (OR = 8.3; 95% CI = 7.5-9.0), penile cancer (OR = 8.9; 95% CI = 7.3-11.0), prostate cancer (OR = 1.2; 95% CI = 1.1-1.2), testicular cancer (OR = 1.4; 95% CI = 1.1-1.7), bladder cancer (OR = 1.1; 95% CI = 1.1-1.2), breast cancer (OR = 1.4; 95% CI = 1.3-1.4), leukoplakia of the vulva (OR = 253.5; 95% CI = 221.9-289.6), and leukoplakia of the penis (OR = 5.1; 95% CI = 4.9-5.4). Conclusions: This study underscores the significantly increased association of various cancers and premalignant conditions in LS patients, highlighting the critical need for efficacious treatment and diligent follow-up. The association between LS and autoimmune diseases further necessitates comprehensive investigation to understand the underlying mechanisms and clinical management implications. Future research is essential to confirm these findings and elucidate the role of LS in cancer development., Funding Agencies|Futurum-The Academy for Healthcare, Region Jnkping County

Objective. The aim of the study was to investigate if time to start chemotherapy (TTC) after primary debulking surgery (PDS) impacted relative survival (RS) in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer (EOC). Methods. Nationwide population-based study of women with EOC FIGO stages IIIC-IV, registered 2008-2018 in the Swedish Quality Register for Gynecologic Cancer, treated with PDS and chemotherapy. TTC was categorized into; <= 21 days, 22-28 days, 29-35 days, 36-42 days and > 42 days. Relative survival (RS) was estimated using the Pohar-Perme estimate of net survival. Multivariable analyses of excess mortality rate ratios (EMRRs) were estimated by Poisson regression models. Results. In total, 1694 women were included. The median age was 65.0 years. Older age and no residual disease were more common in TTC >42 days than 0-21 days. The RS at 5-years was 37.9% and did not differ between TTC groups. In the R0 (no residual disease) cohort (n = 806), 2-year RS was higher in TTC <= 21 days (91.6%) and 22-28 days (91.4%) than TTC >42 days (79.1%). TTC >42 days (EMRR 2.33, p = 0.026), FIGO stage IV (EMRR 1.83, p = 0.007) and non-serous histology (EMRR 4.20, p < 0.001) were associated with 2-year worse excess mortality compared to TTC 0-21 days, in the R0 cohort. TTC was associated with 2-year survival in the R0 cohort in FIGO stage IV but not in stage IIIC. TTC was not associated with RS in patients with residual disease. Conclusions. For the entire cohort, stage IV, non-serous morphology and residual disease, but not TTC, influenced 5-year relative survival. However, longer TTC was associated with a poorer 2-year survival for those without residual disease after PDS. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., Funding Agencies|Swedish Cancer Society; Cancera Foundation; Cancer Society in Stockholm; Swedish Quality Registry for Gynecologic Cancer (SQRGC); Swedish Association of Local Authorities and Regions (SKR)

Objective. To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS). Methods. We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially-platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC >= 3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS. Results. The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001). Conclusion. Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC >= 3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http, Funding Agencies|NHMRC [1063012, 570893]; Target Ovarian Cancer [UCL-P001AL]; Cancer Research UK and UCL Cancer Trials Centre [C444/A15953]; Australian Government through Cancer Australia; Department of Health

The pathophysiological mechanism behind complications associated with postmastectomy radiotherapy (PMRT) and subsequent implant-based breast reconstruction are not completely understood. The aim of this study was to examine if there is a relationship between PMRT and microvascular perfusion and saturation in the skin after mastectomy and assess if there is impaired responsiveness to a topically applied vasodilator (Methyl nicotinate - MN). Skin microvascular perfusion and oxygenation >2 years after PMRT were measured using white light diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) in the irradiated chest wall of 31 women with the contralateral breast as a control. In the non-irradiated breast, the perfusion after application of MN (median 0.84, 25th-75th centile 0.59-1.02 % RBC × mm/s) was higher compared to the irradiated chest wall (median 0.51, 25th-75th centile 0.21-0.68 % RBC × mm/s, p < 0.001). The same phenomenon was noted for saturation (median 91 %, 25th-75th centile 89-94 % compared to 89 % 25th-75th centile 77-93 %, p = 0.001). Eight of the women (26%) had a ≥10 % difference in skin oxygenation between the non-irradiated breast and the irradiated chest wall. These results indicate that late microvascular changes caused by radiotherapy of the chest wall significantly affect skin perfusion and oxygenation.