Cancer and male reproductive function- the effect on sperm DNA integrity and on birth outcomes in the offspring

Male cancer survivors (MCS) are at risk of suffering from impaired fertility. Male fertility is dependant on sperm DNA quality. The Sperm Chromatin Structure Assay (SCSA) reflects the proportion of sperm with poor DNA, the DNA fragmentation index, DFI. A high DFI indicates reduced in vivo fertility and the need of ICSI (Intracytoplasmic sperm injection) to achieve pregnancy. A concern with ICSI, in which a single spermatozoon is injected into the oocyte, is the risk of transmitting defect DNA to the offspring. For MCS, due to the potential mutagenicity of radiotherapy (RT) and chemotherapy (CT), demonstrated in animal studies, this concern is even more pronounced. The aims of my thesis were to investigate the impact of cancer disease and its treatment on sperm DNA integrity and to study birth outcomes in the offspring of MCS. In papers 1 and II DFI was investigated in 96 testicular cancer patients (TC) and related to treatment and follow-up time. In paper III sperm DFI was investigated in pretreatment semen from 121 cancer patients in which 58 were analyzed also posttreatment. Cancer disease per se was associated with a moderate increase in DFI, especially TC and Hodgkin’s lymphoma (mean DFI 17.5 and 16.5% respectively) compared to controls (mean DFI 11.5%), but for the majority of patients DFI was not at levels associated with reduced fertility. In TC patients adjuvant RT induced a transient increase in DFI, normalizing within 3-5 years, whereas intense CT induced a persisting decrease in DFI, DFIpost 9.1 vs. DFIpre 12% (median values, p = 0.02). In paper III, in a group with varying diagnoses, the analysis of cryopreserved pre- vs. posttreatment semen demonstrated no change in DFI, regardless of therapy (median follow-up 3 years). Study IV was a Danish-Swedish register study investigating the impact of paternal cancer and mode of conception on birth outcomes, including 1.8 million singleton children, born 1994-2005. A moderate increase in malformation rate, 3.7 %, was seen in the 8879 children fathered by MCS, with a RR of 1.17 (95% CI 1.05, 1.31) compared to non-MCS, of having an infant with a malformation. IVF/ICSI was associated with an equivalent increased malformation rate, but did not constitute an additional risk for MCS. Treatment data was not available, but analyses of specific diagnoses, in which treatment can be anticipated, did not indicate that the increased malformation rate was treatment-induced

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD):a multicentre, open-label, phase 2 trial

Background: Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods: In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings: Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation: Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations. Funding: Janssen Research & Development

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer.

Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Produktutveckling och outsourcing – en studie bland skånska livsmedelsföretag

Livsmedelsindustrin utgör en viktig del av svensk industri och är den fjärde största branschen i Sverige mätt i omsättning. Syftet var att kartlägga hur stora och medelstora svenska producerande livsmedelsföretag i Skåne arbetar med produktutveckling samt hur de arbetar med och vilken inställning de har till outsourcing. Undersökningens resultat grundas på halvstrukturerade kvalitativa intervjuer på intervjupersonernas företag vid nio livsmedelsproducerande företag i Skåne. I resultatdelen visas en kartläggning över hur företagen i stora drag arbetar med produktutveckling från idé till färdig produkt, samt hur företagen arbetar med uppföljning av existerande produkter. Resultatdelens kärna ligger vid outsourcing av produktutveckling och företagens inställning till detta, samt vilka delar och i vilken utsträckning företagen arbetar med outsourcing i dagsläget. Resultatet visar en övervägande positiv inställning till outsourcing. Beroende på var när och hur är externa tjänster mer eller mindre intressant för företagen att köpa in. Slutsatsen är att de stora och medelstora företagen är positivt inställda till outsourcing och ser ljust på framtiden när det gäller produktutveckling

Tillgänglighet, användbarhet och universell utformning

När ett barn föds är det mycket i samhället som det ännu inte har träffat på. Ja, faktiskt det mesta. Vem barnet blir och vilka vägar det väljer genom livet kommer att påverkas av många faktorer, däribland utformningen av alla de produkter och miljöer det över tid möter och interagerar med. I detta kapitel ägnar vi oss åt fysiska aspekter av interaktionen mellan individ och samhälle, med fokus på hur tillgänglighet, användbarhet och universell utformning (UU) formar förutsättningarna för delaktighet. Vi argumenterar för att de tre begreppen kan och bör ses som delar i en helhet och att de kompletterar varandra med avseende på underliggande tankemodeller och fokus. I kapitlet går vi igenom begreppen och hur de förhåller sig till varandra, för att därefter ge vår syn på hur de hänger ihop

Sperm DNA integrity in testicular cancer patients.

BACKGROUND: We evaluated the impact of testicular germ cell cancer (TGCC), its treatment and length of follow-up on sperm DNA integrity. METHODS: In 96 TGCC patients, semen was collected at specific intervals until 5 years after treatment. Sperm DNA integrity was assessed by the sperm chromatin structure assay (SCSA, n = 193) and by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL, n = 159) assay. Results were expressed as DNA fragmentation index (DFI). Controls comprised of 278 military conscripts. RESULTS: Post-surgery testicular cancer (TC) patients did not differ from controls. Compared with pretreatment values, radiotherapy induced a transient increase in SCSA(DFI) (medians: 12 versus 19%; P = 0.03), normalizing after 3-5 years. One year or more after therapy, 5/13 (38%) of normozoospermic, irradiated patients had SCSA(DFI) > 27% compared with 7% of normozoospermic controls (P = 0.002). More than two cycles of chemotherapy decreased DFI 3-5 years post-therapy (median SCSA(DFI): 12 versus 9.1%, P = 0.02; median TUNELDFI: 11 versus 7.5%, P = 0.03). CONCLUSION: Irradiation increases sperm DNA damage 1-2 years after treatment, and 38% of irradiated patients with normozoospermia had high (> 27%) DNA damage, which may affect the sperm-fertilizing ability. TC per se is not associated with an increase of DFI, and DFI is reduced by three or more cycles of chemotherapy

The impact of testicular carcinoma and its treatment on sperm DNA integrity

BACKGROUND: In patients with testicular germ cell carcinoma (TGCC), spermatogenesis and fertility are impaired. Intracytoplasmic sperm injection has improved their possibility of fatherhood, but might also impose a risk of transmitting DNA defects to the offspring. The aim of the current study was to evaluate the impact of chemotherapy and irradiation on sperm DNA integrity.METHODS: The study included 74 patients with TGCC. Semen samples were collected before and at specific time points after patients received therapy. Sperm DNA integrity was assessed by the sperm chromatin structure assay. Controls comprised 278 military conscripts.RESULTS: There was no significant difference in the fraction of sperm with fragmented DNA (DNA fragmentation index [DFI]) between controls and patients with TGCC before postoperative cancer treatment (11% vs. 13%). Men treated with adjuvant radiotherapy had a transiently (up to 2 years) higher DFI than nontreated patients (18% vs. 13%; P = 0.03). Patients who received 1-2 cycles of adjuvant chemotherapy had a significantly lower DFI 6 months after treatment than after 1-2 years (9.1% vs. 13%; P = 0.004). Higher doses of chemotherapy among patients resulted in a significantly lower DFI compared with controls (7.3% vs. 11%; P = 0.028), which persisted throughout the 5 years of follow-up.CONCLUSIONS: Postorchiectomy, the DFI in sperm samples from patients with testicular carcinoma was at the level of controls. Radiotherapy caused a transient increase in the proportion of DFI, whereas this value decreased after chemotherapy. The biologic implications of such changes in sperm DNA after cancer therapy need to be elucidated