| 1. |
- Ekedahl, Henrik, et al.
(författare)
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Low-grade inflammation in survivors of childhood cancer and testicular cancer and its association with hypogonadism and metabolic risk factors
- 2022
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 22, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In childhood (CCS) and testicular cancer (TCS) survivors, low-grade inflammation may represent a link between testosterone deficiency (hypogonadism) and risk of metabolic syndrome. We aimed to study levels of inflammatory markers in CCS and TCS and the association with hypogonadism and future cardio-metabolic risk factors.METHODS: Serum levels of inflammatory markers and testosterone were analyzed in CCS (n = 90), and TCS (n = 64, median time from diagnosis: 20 and 2.0 years, respectively), and in controls (n = 44). Differences in levels between patients and controls were calculated using univariate analysis of variance. T-test and logistic regression were applied to compare levels of cardio-metabolic risk factors and odds ratio (OR) of hypogonadism and metabolic syndrome in low and high inflammatory marker groups after 4-12 years of follow up. Adjustment for age, smoking, and active cancer was made.RESULTS: TCS and CCS, as compared to controls, had 1.44 (95%CI 1.06-1.96) and 1.25 (95 CI 1.02-1.53) times higher levels of IL-8, respectively. High IL-6 levels were associated with hypogonadism at baseline (OR 2.83, 95%CI 1.25-6.43) and the association was stronger for high IL-6 combined with low IL-10 levels (OR 3.10, 95%CI 1.37-7.01). High IL-6 levels were also associated with higher BMI, waist circumference, insulin, and HbA1c at follow up. High TNF-α was associated with higher diastolic blood pressure. No individual inflammatory marker was significantly associated with risk of metabolic syndrome at follow up. High IL-6 combined with low IL-10 levels were associated with risk of metabolic syndrome (OR 3.83, 95%CI 1.07-13.75), however not statistically significantly after adjustment.CONCLUSION: TCS and CCS present with low-grade inflammation. High IL-6 levels were associated with hypogonadism and cardio-metabolic risk factors. Low IL-10 levels might reinforce the IL-6 mediated risk of developing metabolic syndrome.
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| 2. |
- Kurek, Magdalena, et al.
(författare)
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Spermatogonia Loss Correlates with LAMA 1 Expression in Human Prepubertal Testes Stored for Fertility Preservation
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.
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| 3. |
- Lahtinen, Atte K., et al.
(författare)
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Decreased spermatogonial numbers in boys with severe haematological diseases
- 2024
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 205:1, s. 229-235
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Tidskriftsartikel (refereegranskat)abstract
- This study examines spermatogonial numbers in testicular samples from 43 prepubertal patients undergoing haematopoietic stem cell transplantation (HSCT). High-dose chemotherapy and/or radiation during HSCT can impact spermatogenesis requiring fertility preservation. Results show that 49% of patients have decreased and 19% severely depleted spermatogonial pool prior to HSCT. Patients with Fanconi anaemia exhibit significantly reduced spermatogonial numbers. Patients with immunodeficiency or aplastic anaemia generally present within the normal range, while results in patients with myelodysplastic syndrome or myeloproliferative neoplasm vary. The study emphasizes the importance of assessing spermatogonial numbers in patients with severe haematological diseases for informed fertility preservation decisions.
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| 4. |
- Rastegar, Bahar, et al.
(författare)
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Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution
- 2023
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 29:14, s. 2668-2677
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
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| 5. |
- Romerius, Patrik, et al.
(författare)
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Estrogen receptor alpha single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors
- 2011
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872. ; 21:5, s. 263-269
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cancer treatment in childhood leads to permanent azoospermia in a significant number of boys and those who are diagnosed with cancer before puberty do not have the option of pretreatment cryopreservation of spermatozoa. However, there is an interindividual variation in the sensitivity to gonadotoxic effects of cancer therapy, which probably is due to genetic factors. Identification of genetic markers for the risk of azoospermia in childhood cancer survivors may help in identifying boys to whom testicular cryopreservation should be offered. METHODS: Fifty-one single nucleotide polymorphisms (SNPs) being markers of 12 different haplotype blocks in the androgen receptor, estrogen receptor (ER) α and ER β genes were examined in 127 adult childhood cancer survivors. RESULTS: In ERα, markers of one specific haplotype block (rs2207396, rs9340958, rs9340978) were associated with an increased risk of azoospermia. Compared with those with the GG genotype, patients being heterozygous for the A allele in rs2207396 had a significantly increased risk of azoospermia [odds ratio (OR): 3.8; 95% confidence interval: 1.5-9.5; P=0.008], this OR being even higher in the subgroup treated with alkylating drugs (OR: 8.8; 95% confidence interval: 2.1-36; P=0.004). In this subgroup, 48% of the patients carried the A allele of rs2207396, this proportion being 70% among the azoospermic patients. CONCLUSION: Use of genetic markers of high risk of posttreatment azoospermia may, in the future, prove an important clinical tool in selection of boys to whom preservation of testicular tissue before cancer therapy should be offered.
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| 6. |
- Romerius, Patrik, et al.
(författare)
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Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors
- 2011
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 21:5, s. 263-269
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cancer treatment in childhood leads to permanent azoospermia in a significant number of boys and those who are diagnosed with cancer before puberty do not have the option of pretreatment cryopreservation of spermatozoa. However, there is an interindividual variation in the sensitivity to gonadotoxic effects of cancer therapy, which probably is due to genetic factors. Identification of genetic markers for the risk of azoospermia in childhood cancer survivors may help in identifying boys to whom testicular cryopreservation should be offered. METHODS: Fifty-one single nucleotide polymorphisms (SNPs) being markers of 12 different haplotype blocks in the androgen receptor, estrogen receptor (ER) α and ER β genes were examined in 127 adult childhood cancer survivors. RESULTS: In ERα, markers of one specific haplotype block (rs2207396, rs9340958, rs9340978) were associated with an increased risk of azoospermia. Compared with those with the GG genotype, patients being heterozygous for the A allele in rs2207396 had a significantly increased risk of azoospermia [odds ratio (OR): 3.8; 95% confidence interval: 1.5-9.5; P=0.008], this OR being even higher in the subgroup treated with alkylating drugs (OR: 8.8; 95% confidence interval: 2.1-36; P=0.004). In this subgroup, 48% of the patients carried the A allele of rs2207396, this proportion being 70% among the azoospermic patients. CONCLUSION: Use of genetic markers of high risk of posttreatment azoospermia may, in the future, prove an important clinical tool in selection of boys to whom preservation of testicular tissue before cancer therapy should be offered.
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| 7. |
- Romerius, Patrik, et al.
(författare)
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High risk of azoospermia in men treated for childhood cancer.
- 2011
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Ingår i: International Journal of Andrology. - : Wiley. - 1365-2605 .- 0105-6263. ; 34, s. 69-76
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Tidskriftsartikel (refereegranskat)abstract
- Summary Childhood cancer survivors (CCS) have an increased risk of impaired spermatogenesis, but data regarding the disease- and treatment-related risk factors of azoospermia are scarce. Such information is crucial both for counselling CCS and for selecting patients for testicular tissue cryopreservation. The proportion of azoospermic men in CCS was 18% [95% confidence interval (CI): 12-26], specifically for leukaemias (19%; 95% CI: 5.5-42), Hodgkin's disease (53%; 95% CI: 29-76), non-Hodgkin's lymphoma (11%; 95% CI: 0.28-48) and testicular cancer (11%; 95% CI: 0.28-48). In CCS treated with high doses of alkylating agents, the proportion of azoospermic men was 80% (95% CI: 28-99) and if radiotherapy was used additionally, the proportion was 64% (95% CI: 35-87). In CCS with subnormal Inhibin B levels, the proportion of azoospermic men was 66% (95% CI: 47-81) and for those with elevated follicle-stimulating hormone (FSH) levels, the proportion was 50% (95% CI: 35-67). Among CCS with subnormal testicular volume (
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| 8. |
- Romerius, Patrik, et al.
(författare)
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Hypogonadism Risk in Men Treated for Childhood Cancer.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94, s. 4180-4186
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Tidskriftsartikel (refereegranskat)abstract
- Context: Pediatric cancer treatment may imply an increased risk of hypogonadism, leading to metabolic disorders and osteoporosis. Such complications are potentially preventable. Objective: The aim of this study was to assess diagnosis- and treatment-dependent risk of hypogonadism in male childhood cancer survivors (CCS). Design: Male CCS who were treated during the period 1970-2002 and who in 2004 were 18-45 yr of age were eligible. Setting: The study was conducted in a university hospital clinic. Patients: A consecutive group of CCS treated at Lund University Hospital was selected for the study, of whom 151 (38%) agreed to participate. Furthermore, 141 healthy fertile men served as controls. Interventions: We measured serum levels of free and total testosterone, SHBG, and LH. Main Outcome Measures: Odds ratios (OR) for biochemical hypogonadism, defined as total testosterone less than 10 nmol/liter and/or LH above 10 IU/liter, were calculated and related to type of cancer, treatment received, as well as testicular volume. Results: Hypogonadism was more commonly detected in CCS than in controls (OR, 6.7; 95% CI, 2.7, 17). The increased presence of hypogonadism was noted in the following treatment groups: brain surgery, chemotherapy (with and without radiotherapy), and testicular irradiation. Low total testicular volume (
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| 9. |
- Romerius, Patrik
(författare)
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Reproductive function in male childhood cancer survivors
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Childhood cancer (CC) survival rate has increased over the last couple of decades, today approaching 80%. Therefore more attention has been paid to late effects. One important issue for CC survivors (CCS) is impaired reproductive function. CC per se and/or its treatment can impair the reproductive ability by affecting sperm production, as well as by damaging sperm DNA. This is a matter of concern, since subsequent use of assisted reproduction can cause transmission of genetic abnormalities to the offspring. Another, relatively uncovered issue is the question of androgen deficiency in CCS. To improve the counselling and management of CCS, the aim of this thesis was to investigate reproductive function in a group of male CCS (n=151). The specific aims were: • to investigate the magnitude of risk for hypogonadism in relation to diagnosis- and treatment; • to determine to which extent CC treatment is associated with the risk of azoospermia and to whether genetic polymorphisms, hormonal levels and ⁄ or testicular size could predict its risk; • to assess the impact of the disease, or the treatment, on sperm DNA integrity. We found that: • hypogonadism was almost 7 times more common in CCS than in controls, which should be acknowledged in the long-term follow up of CCS. None of the clinical predictors, except hormone analysis was sufficiently reliable in diagnosing androgen deficiency; • most childhood cancer diagnoses are associated with an increased risk of azoospermia, especially in CCS receiving testicular irradiation, high doses of alkylating drugs, and other types of cytotoxic treatment, if combined with irradiation. Inhibin B, FSH and testicular volume can, to a limited degree be used as predictors for the risk of azoospermia; • sperm DNA integrity is slightly impaired in CCS, not treated with chemotherapy. This sperm DNA damage may be associated with the disease per se rather than the treatment and may have negative consequences in relation to fertility and health of the offspring; • a genetic variant of the Estrogen Receptor α was associated with an increased risk of azoospermia, a finding demonstrating the potential of genetic analysis in future selection of boys to whom preservation of testicular tissue prior to cancer therapy should be offered.
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| 10. |
- Romerius, Patrik, et al.
(författare)
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Sperm DNA Integrity in Men Treated for Childhood Cancer.
- 2010
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Ingår i: Clinical Cancer Research. - 1078-0432. ; Jul 1, s. 3843-3850
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: It is unknown whether childhood cancer and its treatment are associated with sperm DNA damage, which subsequently affects fertility and might be transmitted to the offspring. The aim of this study was to assess DNA fragmentation index (DFI) as an indicator of sperm DNA integrity in childhood cancer survivors (CCS), treatment regimen taken into account.EXPERIMENTAL DESIGN: In 99 CCS and 193 age-matched healthy controls, the DFI was assessed by the use of Sperm Chromatin Structure Assay.RESULTS: In the whole group of CCS DFI was increased as compared to the controls with borderline statistical significance (mean difference=0.94%; 95%CI: -0.0088; 3.7%). Those treated with radiotherapy only (mean difference=6.0%; 95%CI: 1.6; 10%) or surgery only (mean difference=2.9%; 95%CI: 0.083; 3.7%) had statistically significantly higher DFI than the controls. The odds ratio (OR) for having DFI >20%, which is associated with reduced fertility, was significantly increased in CCS as compared to the control group (OR=2.2, 95%CI: 1.1; 4.4). For the radiotherapy only group the OR was even higher (OR=4.9, 95%CI 1.3; 18). The DFI was not associated to the dose of scattered testicular irradiation or the type of chemotherapy given.CONCLUSIONS: The DFI is increased in CCS, those treated with chemotherapy being the only exception. This sperm DNA impairment may be associated with the disease per se rather than due to the treatment and may have negative consequences in terms of fertility and risk of transmission to the offspring.
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| 11. |
- Yasui, Hiroaki, et al.
(författare)
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A dynamic mutational landscape associated with an inter-regionally diverse immune response in malignant rhabdoid tumour
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 252:1, s. 22-28
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Tidskriftsartikel (refereegranskat)abstract
- Malignant rhabdoid tumour (MRT) is a childhood neoplasm of high malignancy characterised by biallelic mutation and/or loss of the epigenetic master regulator SMARCB1, accompanied by no or few other oncogenic drivers. In spite of their generally low mutational burden, an intratumoural T-cell response has been reported in a subset of MRTs, indicating that immune checkpoint inhibition may be considered a viable therapy option for some patients. We assess here the evolution over time and space of predicted neoantigens and indicators of immune checkpoint status in two MRT patients who progressed under treatment. Both patients showed an accumulation of novel clonal and subclonal mutations, including predicted neoantigens, in metastases compared to their inferred ancestral clones in the primary tumours. The first patient had peritoneal metastases from an MRT of the liver. Clonal deconvolution revealed polyclonal seeding from the primary tumour to a single metastatic site, followed by a local subclonal burst of mutations. The second patient had a renal MRT with multiple pulmonary metastases, each of which could be traced back to a single genetically unique founder cell, with formation of novel subclones in two metastases. Both patients showed a regionally heterogeneous landscape of predicted neoantigens and of tumour-infiltrating lymphocytes expressing CD8 and PD1. In both patients, some tumour regions fulfilled established criteria for PD-L1 positivity (> 1% of tumour cells), while others did not. This suggests that even in a tumour type like MRT, with a single driver mutation, there can be heterogeneity in neoantigen repertoire, immune response, and biomarkers for checkpoint blockade among sampled locations. This must be taken into account when assessing progressed MRT patients for checkpoint inhibition therapy.
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