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1.	Hemminki, Kari, et al. (författare) Critical survival periods in prostate cancer in Sweden explored by conditional survival analysis 2024 Ingår i: Cancer Medicine. - 2045-7634. ; 13:7 Tidskriftsartikel (refereegranskat)abstract Backround: We wanted to characterize conditional survival in prostate cancer (PC) in Sweden around and after 2005 when the vast increase in incidence due to the opportunistic testing for prostate specific antigen (PSA) culminated. We hypothesize that analyzing survival data during that time period may help interpret survival trends. We focus on stage-specific analysis using conditional survival in order to define the periods when deaths most commonly occurred. Methods: Data on PC patients were obtained from the Swedish cancer registry for analysis of 1-, 2.5- and 5-year relative survival and conditional relative survival between years 2004 and 2018. Tumor-node-metastatic stage classification at diagnosis was used to specify survival. Results: Small improvements were observed in stage- and age-related relative survival duriring the study period. Applying conditional relative survival showed that survival in stage T3 up to 2.5 years was better than survival between years 2.5 and 5. Survival in stage T4 was approximately equal in the first and the subsequent 2.5-year period. For M1, the first 2.5 year survival period was worse than the subsequent one. The proportion of high risk and M1 disease in old patients (80+ years) remained very high and their survival improved only modestly. Conclusions: The data indicate that M1 metastases kill more patients in the first 2.5 years than between years 2.5 and 5 after diagnosis; T4 deaths are equal in the two periods, and in T3 mortality in the first 2.5-year period is lower than between years 2.5 and 5 after diagnosis. Conditional survival could be applied to explore critical survival periods even past 5 years after diagnoses and to monitor success in novel diagnostic and treatment practices. Improvement of survival in elderly patients may require clinical input.
2.	Hemminki, Kari, et al. (författare) Incidence trends in bladder and lung cancers between Denmark, Finland and Sweden may implicate oral tobacco (snuff/snus) as a possible risk factor 2021 Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 21:1 Tidskriftsartikel (refereegranskat)abstract Background: The dominant risk factor for urinary bladder cancer has been cigarette smoking, but, as smoking prevalence is decreasing in many populations, other risk factors may become uncovered. Such new risk factors could be responsible for halting the declining incidence of bladder cancer. We hypothesize that snuff use by Swedish men may increase the rate for bladder cancer, as snuff contains carcinogenic nitrosamines.Methods: We carried out an ecological study by comparing incidence trends in lung and bladder cancers between Danish, Finnish and Swedish men in order to test if the Swedish bladder cancer rate deviates from the Danish and Finnish ones. We used the NORDCAN database for cancer data from 1960 through 2016 to test the hypothesis.Results: In the three countries, the incidence of lung cancer started to decrease after a peak incidence, and this was later followed by declining incidence in bladder cancer in Denmark from 1990 to 2016 by 14.3%, in Finland by 8.3% but not in Sweden (the decline of 1.4% was not significant). The difference in trends can be partly explained by the increasing incidence in Swedish men aged 70 or more years. Sweden differs from the two other countries by low male smoking prevalence but increasing use of snuff recorded by various surveys.Conclusion: The stable bladder cancer trend for Swedish men was opposite to the declining trends in Denmark, Finland and globally. We suggest that this unusual finding may be related to the increasing use of snuff by Swedish men. Average users of snuff are exposed to at least 3 times higher levels of carcinogenic tobacco-specific nitrosamines than a smoker of one daily pack of cigarettes.
3.	Hemminki, Kari, et al. (författare) Incidence trends in lung and bladder cancers in the Nordic Countries before and after the smoking epidemic 2022 Ingår i: European Journal of Cancer Prevention. - : Lippincott Williams & Wilkins. - 0959-8278 .- 1473-5709. ; 31:3, s. 228-234 Tidskriftsartikel (refereegranskat)abstract Cigarette smoking epidemic, which started before the World War II, completely changed the cancer landscape. Reliable incidence data spanning the stepwise spreading epidemic are rare, but the Nordic cancer registries are unique sources in being able to catch the pre-epidemic situation in the female population where smoking became more prevalent after the War. For Swedish men, smoking prevalence has decease early and cancer rates may herald postsmoking rates. We used data from the NORDCAN database, constructed by the cancer registries of Denmark, Finland, Norway and Sweden, for the analysis of incidence changes in lung and bladder cancers from year 1943 (Denmark), from 1953 (Finland and Norway) and from 1960 (Sweden) until year 2016. The analyses revealed four novel observation relevant to the smoking epidemic. (1) The incidence of lung cancer in Norwegian women in the 1950s, when the smoking prevalence was very low, was 1.8/100 000 (world standard rate), which is at the level of lowest global female rates known to-date; (2) the earliest lung-to-bladder incidence ratio among Norwegian women was 0.64, probably benchmarking the incidence rates prior to the smoking epidemic; (3) bladder cancer incidence for Finnish women diagnosed in the 1950s was 1.2/100 000 which is at the level of the lowest rates currently known and (4) Swedish men with the lowest smoking prevalence in Europe, showed an epochal crossing of lung and bladder cancer incidence rates before year 2015. The data suggest that the approaching of the incidence rates for lung and bladder cancer can be expected in the course of the abating smoking epidemic.
4.	Hemminki, Kari, et al. (författare) Progress in survival in renal cell carcinoma through 50 years evaluated in Finland and Sweden 2021 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16 Tidskriftsartikel (refereegranskat)abstract Global survival studies have shown favorable development in renal cell carcinoma (RCC) treatment but few studies have considered extended periods or covered populations for which medical care is essentially free of charge. We analyzed RCC survival in Finland and Sweden over a 50-year period (1967-2016) using data from the NORDCAN database provided by the local cancer registries. While the health care systems are largely similar in the two countries, the economic resources have been stronger in Sweden. In addition to the standard 1- and 5-year relative survival rates, we calculated the difference between these as a measure of how well survival was maintained between years 1 and 5. Relative 1- year survival rates increased almost linearly in both countries and reached 90% in Sweden and 80% in Finland. Although 5-year survival also developed favorably the difference between 1- and 5-year survival rates did not improve in Sweden suggesting that the gains in 5-year survival were entirely due to gains in 1-year survival. In Finland there was a gain in survival between years 1 and 5, but the gain in 1-years survival was the main contributor to the favorable 5-year survival. Age group specific analysis showed large survival differences, particularly among women. Towards the end of the follow-up period the differences narrowed but the disadvantage of the old patients remained in 5-year survival. The limitations of the study were lack of information on performed treatment and clinical stage in the NORDCAN database. In conclusion, the available data suggest that earlier diagnosis and surgical treatment of RCC have been the main driver of the favorable change in survival during the past 50 years. The main challenges are to reduce the age-specific survival gaps, particularly among women, and push survival gains past year 1.
5.	Hemminki, Kari, et al. (författare) Survival in bladder and upper urinary tract cancers in Finland and Sweden through 50 years 2022 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 17:1 Tidskriftsartikel (refereegranskat)abstract Survival has improved in bladder cancer but few studies have considered extended periods or covered populations for which medical care is essentially free of charge. We analyzed survival in urothelial cancer (UC, of which vast majority are bladder cancers) in Finland and Sweden over a 50-year period (1967–2016) using data from the NORDCAN database. Finland and Sweden are neighboring countries with largely similar health care systems but higher economic resources and health care expenditure in Sweden. We present results on 1- and 5-year relative survival rates, and additionally provide a novel measure, the difference between 1- and 5-year relative survival, indicating how well survival was maintained between these two periods. Over the 50-year period the median diagnostic age has increased by several years and the incidence in the very old patients has increased vastly. Relative 1- year survival rates increased until early 1990s in both countries, and with minor gains later reaching about 90% in men and 85% in women. Although 5-year survival also developed favorably until early 1990s, subsequent gains were small. Over time, age specific differences in male 1-year survival narrowed but remained wide in 5-year survival. For women, age differences were larger than for men. The limitations of the study were lack of information on treatment and stage. In conclusion, challenges are to improve 5-year survival, to reduce the gender gap and to target specific care to the most common patient group, those of 70 years at diagnosis. The most effective methods to achieve survival gains are to target control of tobacco use, emphasis on early diagnosis with prompt action at hematuria, upfront curative treatment and awareness of high relapse requiring regular cystoscopy follow up.
6.	Kanerva, Anna, et al. (författare) Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors. 2015 Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 23:2, s. 321-329 Tidskriftsartikel (refereegranskat)abstract Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (From 170 to 208 days, P = 0.0012, N=148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N=90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N=37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.Molecular Therapy (2014); doi:10.1038/mt.2014.218.
7.	Chattopadhyay, Subhayan, et al. (författare) Multiple myeloma : family history and mortality in second primary cancers 2018 Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 8:8 Tidskriftsartikel (refereegranskat)
8.	Chattopadhyay, Subhayan, et al. (författare) Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer : a nationwide, observational follow up study in Sweden 2018 Ingår i: The Lancet Haematology. - 2352-3026. ; 5:8, s. 368-377 Tidskriftsartikel (refereegranskat)abstract Background: Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers—ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer—to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. Methods: Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. Findings: Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1·29, 95% CI 1·17–1·41), chronic myeloid leukaemia (1·52, 1·35–1·69), myelodysplastic syndrome (1·42, 1·26–1·59), and all myeloproliferative neoplasms (1·37, 1·30–1·43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1·57, 1·48–1·65), chronic myeloid leukaemia (1·26, 1·13–1·40), and myelodysplastic syndrome (1·54, 1·42–1·67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5·08 and 10·04). Interpretation: The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. Funding: Deutsche Krebshilfe, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, Swedish Research Council, ALF from Region Skåne, and Bloodwise.
9.	Chattopadhyay, Subhayan, et al. (författare) Second primary cancers in non-Hodgkin lymphoma : Bidirectional analyses suggesting role for immune dysfunction 2018 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 143:10, s. 2449-2457 Tidskriftsartikel (refereegranskat)abstract Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients.
10.	Chattopadhyay, Subhayan, et al. (författare) Second primary cancers in non-Hodgkin lymphoma : Family history and survival 2020 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:4, s. 970-976 Tidskriftsartikel (refereegranskat)abstract Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses and family history of cancer may be a risk factor for SPCs. Using the Swedish Family-Cancer Database on non-Hodgkin lymphoma (NHL), we assessed the influence of family history on risk of SPCs and of SPCs on survival. NHL patients were identified from the years 1958 to 2015 and generalized Poisson models were used to calculate relative risks (RRs) for SPCs and familial SPCs. Among 14,393 NHL patients, a total of 1,866 (13.0%) were diagnosed with SPC. Familial risk of nine particular cancers was associated with risks of these cancers as SPCs, with twofold to fivefold increase in RRs. At the end of a 25-year follow-up period, the survival probability for persons with SPC was only 20% of that for patients without SPC; the hazard ratio for SPC was 1.59 (95% CI: 1.46–1.72). Survival could be predicted by the prognostic groups based on first cancers and HRs increase systematically with worse prognosis yielding a trend of p = 4.6 × 10 −5 . SPCs had deleterious consequences for survival in NHL patients. Family history was associated with increasing numbers of SPCs. Prevention of SPCs and their early detection is an important target in the overall strategy to improve survival in NHL patients. Counseling for avoidance of risk factors and targeted screening based on family history are feasible steps in risk reduction.
11.	Chattopadhyay, Subhayan, et al. (författare) Second Primary Cancers in Patients with Invasive and In Situ Squamous Cell Skin Carcinoma, Kaposi Sarcoma, and Merkel Cell Carcinoma : Role for Immune Mechanisms? 2020 Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X. ; 140:1, s. 48-55 Tidskriftsartikel (refereegranskat)abstract Second primary cancers (SPCs) are becoming a common cancer entity, which may interfere with survival in relatively benign first primary cancers. We examined the hypothesis that immune dysfunction may contribute to SPCs by assessing SPCs associated with known immune responsive skin cancers, invasive and in situ squamous cell carcinoma, Kaposi sarcoma, and Merkel cell carcinoma. Cancers were identified from the Swedish Cancer Registry from the year 1958 to 2015. Standardized relative risks were calculated bidirectionally for any SPC after skin cancer and for skin cancer as SPC. Over 80,000 first primary cancers were identified for each invasive and in situ squamous cell carcinoma of the skin. Bidirectional increased risks were observed for 26 cancers associated with invasive skin cancer; the Spearman rank correlation was 0.72 (P = 4.6 × 10–5). The highest bidirectional relative risks were for invasive and in situ skin cancer as SPCs (14.59 and 16.71, respectively). Remarkably high risks for second in situ squamous cell carcinoma of the skin were found after Kaposi sarcoma (685.68) and Merkel cell carcinoma (117.23). The high systematic bidirectional risks between immune responsive skin cancers and most other cancers suggest that immune suppression is a key mechanism contributing to an increased risk of SPCs.
12.	Frank, Christoph, et al. (författare) Concordant and discordant familial cancer : Familial risks, proportions and population impact 2017 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 140:7, s. 1510-1516 Tidskriftsartikel (refereegranskat)abstract Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown - beyond well characterized hereditary cancer syndromes - but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family-Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge.
13.	Frank, Christoph, et al. (författare) Familial Associations Between Prostate Cancer and Other Cancers 2017 Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 71:2, s. 162-165 Tidskriftsartikel (refereegranskat)abstract Prostate cancer (PCa) has a large familial component, but understanding of its genetic basis is fragmentary. Breast cancers may be associated with PCa, but whether this is true for other tumor types is poorly established. We used a novel approach to study familial associations of any type of cancer with PCa. We assessed the relative risk (RR) for all types of tumors as a function of the number of first-degree relatives diagnosed with PCa. We hypothesized that for a familial association to be real, the RR for a given type of cancer should increase with the number of PCa diagnoses. In families with multiple PCa patients, significantly increased risks were observed for female breast cancer (RR 1.37 for families with three men with PCa), kidney cancer (RR 2.32), nervous system tumors (RR 1.77; RR 2.40 when PCa was diagnosed before age 70 yr), and myeloma (RR 2.44; RR 6.29 when PCa was diagnosed before age 70 yr). Some evidence of association was also found for melanoma (RR 1.82) and endocrine tumors (RR 2.18). The consistency and magnitude of the effects suggest that familial PCa is genetically associated with breast, kidney, and nervous system tumors and myeloma. This suggestion has implications for clinical counseling and design of genetic studies. Patient summary: It is known that prostate cancer runs in families, but it is not known whether other cancers are common in such families. We showed that at least breast, kidney, and nervous system tumors and myeloma occur more often than by chance. The present results demonstrate that prostate cancer (PCa) families show a statistical excess of some defined cancers. The cancers associated with PCa include breast, kidney, and nervous system tumors and myeloma and possibly melanoma and endocrine tumors.
14.	Frank, Christoph, et al. (författare) Risk of other Cancers in Families with Melanoma : Novel Familial Links 2017 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7 Tidskriftsartikel (refereegranskat)abstract A family history of cutaneous melanoma ('melanoma') is a well-established risk factor for melanoma. However, less is known about the possible familial associations of melanoma with other discordant cancers. A risk for discordant cancer may provide useful information about shared genetic and environmental risk factors and it may be relevant background data in clinical genetic counseling. Using the Swedish Family-Cancer Database, we assessed the relative risk (RR) for any cancer in families with increasing numbers of first-degree relatives diagnosed with melanoma, including multiple melanoma, and in reverse order RR for melanoma in families of multiple discordant cancers. Close to 9% of melanoma was familial; among these 92% were in 2-case families and 8% in families with 3 cases or more. Cancers that were associated with melanoma, in at least two independent analyses, included breast, prostate, colorectal, skin and nervous system cancers. Other associations included cancer of unknown primary, acute myeloid leukemia/myelofibrosis and Waldenström macroglobulinemia/myeloma. Significant results, which appear biologically plausible, were also obtained for rare nasal melanoma and mesothelioma. Although small samples sizes and multiple comparisons were of concern, many of the above associations were internally consistent and provide new diverse leads for discordant familial association of melanoma.
15.	Hemminki, Kari, et al. (författare) Autoimmune diseases as comorbidities for liver, gallbladder, and biliary duct cancers in Sweden 2023 Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:8, s. 1227-1236 Tidskriftsartikel (refereegranskat)abstract Background: Autoimmune diseases are associated with many cancers but there is a lack of population-based studies with different autoimmune diseases that have a long follow-up. This is also true of hepatobiliary cancers, which include hepatocellular cancer (HCC) and rarer entities of gallbladder cancer (GBC), intra- and extrahepatic cholangiocarcinoma (iCCA and eCCA), and ampullary cancer. Methods: Diagnostic data on 43 autoimmune diseases were collected from the Swedish Inpatient Register from 1987 to 2018, and cancer data were derived from the national cancer registry from 1997 onward. Relative risks were expressed as standardized incidence ratios (SIRs). Results: In a population of 13.6 million, 1.1 million autoimmune diseases were diagnosed and subsequent hepatobiliary cancer was diagnosed in 3191 patients (17.2% of cancers). SIRs for HCC were 2.73 (men) and 2.86 (women), 3.74/1.96 for iCCA, 2.65/1.37 for GBC, 2.38/1.64 for eCCA, and 1.80/1.85 for ampullary cancer. Significant associations between autoimmune disease and HCC were observed for 13 autoimmune diseases, with the highest risks being for autoimmune hepatitis (48.92/73.53, men/women) and primary biliary cirrhosis (38.03/54.48). GBC was increased after six autoimmune diseases, with high SIRs for ulcerative colitis (12.22/3.24) and men with Crohn disease (9.16). These autoimmune diseases were also associated with a high risk of iCCA, which had seven other associations, and eCCA, which had five other associations. Ampullary cancer occurrence was increased after four autoimmune diseases. Conclusion: An autoimmune disease is a common precursor condition for hepatobiliary cancers. This calls for careful control of autoimmune disease symptoms in each patient and encouragement to practice a healthy lifestyle.
16.	Hemminki, Kari, et al. (författare) Collection and Use of Family History in Oncology Clinics. 2014 Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 32:29, s. 3344-3344 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
17.	Hemminki, Kari, et al. (författare) Familial risks and proportions describing population landscape of familial cancer 2021 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:17 Tidskriftsartikel (refereegranskat)abstract Background: Familial cancer can be defined through the occurrence of the same cancer in two or more family members. We describe a nationwide landscape of familial cancer, including its frequency and the risk that it conveys, by using the largest family database in the world with complete family structures and medically confirmed cancers. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for concordant cancer among first-degree relatives using the Swedish Cancer Registry from years 1958 through 2016. Results: Cancer risks in a 20–84 year old population conferred by affected parents or siblings were about two-fold compared to the risk for individuals with unaffected relatives. For small intestinal, testicular, thyroid and bone cancers and Hodgkin disease, risks were higher, five-to-eight-fold. Novel familial associations included adult bone, lip, pharyngeal, and connective tissue cancers. Familial cancers were found in 13.2% of families with cancer; for prostate cancer, the proportion was 26.4%. High-risk families accounted for 6.6% of all cancer families. Discussion/Conclusion: High-risk family history should be exceedingly considered for management, including targeted genetic testing. For the major proportion of familial clustering, where genetic testing may not be feasible, medical and behavioral intervention should be indicated for the patient and their family members, including screening recommendations and avoidance of carcinogenic exposure.
18.	Hemminki, Kari, et al. (författare) Familial Risks for Liver, Gallbladder and Bile Duct Cancers and for Their Risk Factors in Sweden, a Low-Incidence Country 2022 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:8 Tidskriftsartikel (refereegranskat)abstract We used the Swedish Cancer Registry data to address familial risks for concordant (same) and discordant (different) hepatobiliary cancers, including their associations with any other cancers and with known risk factors. Risks were also assessed between spouses. The analysis covered Swedish families and their cancers between years 1958 and 2018. Adjusted familial risks were expressed as standardized incidence ratios (SIRs). Familial SIRs for concordant hepatocellular carcinoma (HCC) were 2.60, and for gallbladder cancer they were at the same level (2.76). Familial risk was also found for intrahepatic bile duct cancer and for female extrahepatic bile duct cancer. HCC was associated with lung and cervical cancers; extrahepatic bile duct and ampullary cancers were associated with colon and pancreatic cancers, suggesting Lynch syndrome. Among spouses, hepatobiliary cancer was associated with HCC, stomach, pancreatic, cervical and upper aerodigestive tract cancers. Among risk factors, family members diagnosed with alcohol-related disease showed association with HCC. The observed familial risks for hepatobiliary cancers were relatively high, and considering the poor prognosis of these cancers, prevention is of the utmost importance and should focus on moderation of alcohol consumption, vaccination/treatment of hepatitis viral infections and avoidance of overweight and other risk factors of type 2 diabetes.
19.	Hemminki, Kari, et al. (författare) Genetics of gallbladder cancer 2017 Ingår i: The Lancet Oncology. - 1470-2045. ; 18:6, s. 296-296 Tidskriftsartikel (refereegranskat)
20.	Hemminki, Kari, et al. (författare) Location of metastases in cancer of unknown primary are not random and signal familial clustering. 2016 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6 Tidskriftsartikel (refereegranskat)abstract Cancer of unknown primary (CUP) is a fatal disease diagnosed through metastases. It shows intriguing familial clustering with certain defined primary cancers. Here we examine whether metastatic location in CUP patients is related to primary non-CUP cancers in relatives based on the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP patients defined by metastatic location depending on cancer in their first degree relatives. SIRs for CUP were high in association with liver (3.94), ovarian (3.41), lung (2.43) and colorectal cancers (1.83) in relatives. The SIR was 1.63 for CUP with metastases in the abdomen when a relative was diagnosed with ovarian cancer. CUP with liver metastases associated with liver (1.44) cancer in relatives. CUP with head and neck region metastases associated with relatives' esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative's cancers in the upper aerodigestive tract (2.14) and lung (1.74). The findings, matching metastatic location in CUP and primary cancer in relatives, could be reconciled if these cases of CUP constitute a phenotypically modified primary lacking tissue identification, resulting from epitope immunoediting. Alternatively, CUP metastases arise in a genetically favored tissue environment (soil) promoting growth of both primary cancers and metastases (seeds).
21.	Hemminki, Kari, et al. (författare) Personal comorbidities and their subsequent risks for liver, gallbladder and bile duct cancers 2023 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 152:6, s. 1107-1114 Tidskriftsartikel (refereegranskat)abstract Many environmental risk factors for hepatobiliary cancers are known but whether they are associated with specific cancer types is unclear. We present here a novel approach of assessing standardized incidence ratios (SIRs) of previously diagnosed comorbidities for hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cholangiocarcinoma (CCA) and ampullary cancer. The 13 comorbidities included alcohol and nonalcohol related liver disease, chronic obstructive pulmonary disease, gallstone disease, viral and other kinds of hepatitis, infection of bile ducts, hepatic and other autoimmune diseases, obesity and diabetes. Patients were identified from the Swedish Inpatient Register from 1987 to 2018, and their cancers were followed from 1997 onwards. SIRs for HCC were 80 to 100 in men and women diagnosed with hepatitis C virus and they were also >10 in patients diagnosed with hepatitis B virus, other kind of hepatitis, hepatic autoimmune disease and nonalcohol related liver disease. Many of these risks, as well as alcohol related liver disease, were either specific to HCC or were shared with intrahepatic CCA. For GBC, CCA and ampullary cancer infection of bile ducts was the main risk factor. Gallstone disease, nonhepatic autoimmune diseases and diabetes were associated with all hepatobiliary cancers. The limitations of the study include inability to cover some rare risk factors and limited follow-up time. Many of the considered comorbidities are characterized by chronic inflammation and/or overt immune disturbance in autoimmune diseases. The results suggest that local chronic inflammation and a related immune disturbance is the carcinogenic trigger for all these cancers.
22.	Hemminki, Kari, et al. (författare) Population-Attributable Fractions of Personal Comorbidities for Liver, Gallbladder, and Bile Duct Cancers 2023 Ingår i: Cancers. - 2072-6694. ; 15:12 Tidskriftsartikel (refereegranskat)abstract Background: We aim to estimate population-attributable fractions (PAF) for 13 comorbidities potentially predisposing to hepatobiliary cancer of hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cancers of the intrahepatic and extrahepatic bile ducts (ICC and ECC), and ampullary cancer. Methods: Patients were identified from the Swedish Inpatient Register from 1987 to 2018 and cancers from the Swedish Cancer Registry from 1997 through 2018. PAFs were calculated for each comorbidity-associated cancer using a cohort study design. Results: For male HCC, the major individual comorbidities (PAF > 10) were diabetes, alcohol-related liver disease, and hepatitis C virus infection. For female HCC, diabetes and autoimmune diseases were important contributors. For female GBC, gallstone disease was an overwhelming contributor, with a PAF of 30.57%, which was also important for men. The overall PAF for male ICC was almost two times higher than the female one. For ECC and ampullary cancer, infection of bile ducts was associated with the highest PAF. Conclusions: The 13 comorbidities accounted for 50% or more of the potential etiological pathways of each hepatobiliary cancer except female ICC. The underlying convergent mechanism for these cancers may be chronic inflammation lasting for decades and thus offering possibilities for intervention and disease monitoring.
23.	Hemminki, Kari, et al. (författare) Smoking and body mass index as risk factors for subtypes of cancer of unknown primary. 2015 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:1, s. 246-247 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
24.	Riihimäki, Matias, et al. (författare) Causes of death in patients with extranodal cancer of unknown primary: searching for the primary site 2014 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14 Tidskriftsartikel (refereegranskat)abstract Background: Cancer of unknown primary (CUP) is a fatal cancer, accounting for 3-5% of all diagnosed cancers. Finding the primary site is important for therapeutic choices and we believe that the organ which is designated as the cause of death may give clues about the primary site. Methods: A total of 20,570 patients with CUP were identified from the Swedish Family-Cancer Database. Causes of death - as reported in the death certificate - were investigated, analyzing reported metastatic sites and histological subtypes separately. Survival was compared with metastatic cancer with a known primary tumor. Results: An organ-specific cancer could be identified as a cause of death in approximately 60% of all CUP patients with adenocarcinoma or undifferentiated histology. In adenocarcinoma, lung cancer was the most frequent cause of death (20%), followed by pancreatic cancer (14%), and ovarian cancer (11%). Lung cancer was the most common cause of death in patients with CUP metastases diagnosed in the nervous system (69%), respiratory system (53%), and bone (47%), whereas ovarian cancer was the most common cause of death when CUP was diagnosed in the pelvis (47%) or the peritoneum (32%). In CUP diagnosed in the liver, liver and pancreatic cancers accounted for 26% and 22% of deaths, respectively. Also in squamous cell CUP, lung cancer was the most common cause of death (45%). Conclusions: According to the causes of death, the primary site appeared frequently to be either the organ where CUP metastases were diagnosed or an organ which may be traced through the known metastatic patterns of different cancer types.
25.	Riihimäki, Matias, et al. (författare) Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer 2013 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13 Tidskriftsartikel (refereegranskat)abstract Background: Cancer of unknown primary site (CUP) is considered an aggressive metastatic disease but whether the prognosis differs from metastatic cancers of known primary site is not known. Such data may give insight into the biology of CUP and the metastatic process in general. Methods: 6,745 cancer patients, with primary metastatic cancer at diagnosis, were identified from the Swedish Cancer Registry, and were compared with 2,881 patients with CUP. Patients were diagnosed and died between 2002 and 2008. The influence of the primary site, known or unknown, on survival in patients with metastases at specific locations was investigated. Hazard ratios (HRs) of death were estimated for several sites of metastasis, where patients with known primary sites were compared with CUP patients. Results: Overall, patients with metastatic cancers with known primary sites had decreased hazards of death compared to CUP patients (HR = 0.69 [95% CI = 0.66-0.72]). The exceptions were cancer of the pancreas (1.71 [1.54-1.90]), liver (1.58 [1.36-1.85]), and stomach (1.16 [1.02-1.31]). For individual metastatic sites, patients with liver or bone metastases of known origin had better survival than those with CUP of the liver and bone. Patients with liver metastases of pancreatic origin had an increased risk of death compared with patients with CUP of the liver (1.25 [1.06-1.46]). The median survival time of CUP patients was three months. Conclusions: Patients with CUP have poorer survival than patients with known primaries, except those with brain and respiratory system metastases. Of CUP sites, liver metastases had the worst prognosis. Survival in CUP was comparable to that in metastatic lung cancer. The aggressive behavior of CUP may be due to initial immunosuppression and immunoediting which may allow accumulation of mutations. Upon escape from the suppressed state an unstoppable tumor spread ensues. These novel data on the epidemiology of the metastatic process at the population level demonstrated large survival differences in organ defined metastases depending on the original cancer.
26.	Riihimäki, Matias, et al. (författare) Metastatic spread in patients with gastric cancer 2016 Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:32, s. 52307-52316 Tidskriftsartikel (refereegranskat)abstract Background: The epidemiology of metastatic gastric cancer is unexplored because cancer registries seldom cover metastatic involvement apart from "present or not". We used a novel approach by utilizing Swedish registers to assess metastatic spread in gastric cancer. To our knowledge, this is the first nationwide description of metastases in gastric cancer. Results: The most common sites of metastasis were liver (in 48% of metastatic cancer patients), peritoneum (32%), lung (15%), and bone (12%). Metastases to the lung, nervous system, and bone were more frequent in cardia cancer and men, whereas non-cardia cancer more frequently metastasized within the peritoneum. Signet ring adenocarcinomas more frequently metastasized within the peritoneum, bone and ovaries, and less frequently to the lungs and liver compared with generic adenocarcinoma. The liver and the peritoneum were commonly single metastases while lung metastases occurred frequently together with liver metastases. The median survival in metastatic gastric cancer was 3 months, worst among those with bone and liver metastases (2 months). Methods: A total of 7,559 patients with gastric cancer were identified. Metastatic patterns and survival depending on sex, age, stage, anatomical location (cardia and non-cardia), and histological type were assessed. Conclusions: The patterns of metastasis differ notably depending on histological type. Cardia cancer exhibits a completely different metastatic behavior than noncardia cancer. Awareness of the differing patterns may guide in tailored diagnosis of metastases. Survivors from cardia cancer would benefit from increased surveillance of extraperitoneal metastases. Bone metastases should be considered in patients with signet ring adenocarcinoma if symptoms emerge.
27.	Riihimäki, Matias, et al. (författare) Patterns of metastasis in colon and rectal cancer 2016 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6 Tidskriftsartikel (refereegranskat)abstract Investigating epidemiology of metastatic colon and rectal cancer is challenging, because cancer registries seldom record metastatic sites. We used a population based approach to assess metastatic spread in colon and rectal cancers. 49,096 patients with colorectal cancer were identified from the nationwide Swedish Cancer Registry. Metastatic sites were identified from the National Patient Register and Cause of Death Register. Rectal cancer more frequently metastasized into thoracic organs (OR = 2.4) and the nervous system (1.5) and less frequently within the peritoneum (0.3). Mucinous and signet ring adenocarcinomas more frequently metastasized within the peritoneum compared with generic adenocarcinoma (3.8 [colon]/3.2 [rectum]), and less frequently into the liver (0.5/0.6). Lung metastases occurred frequently together with nervous system metastases, whereas peritoneal metastases were often listed with ovarian and pleural metastases. Thoracic metastases are almost as common as liver metastases in rectal cancer patients with a low stage at diagnosis. In colorectal cancer patients with solitary metastases the survival differed between 5 and 19 months depending on T or N stage. Metastatic patterns differ notably between colon and rectal cancers. This knowledge should help clinicians to identify patients in need for extra surveillance and gives insight to further studies on the mechanisms of metastasis.
28.	Riihimäki, Matias, et al. (författare) The epidemiology of metastases in neuroendocrine tumors 2016 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 139:12, s. 2679-2686 Tidskriftsartikel (refereegranskat)abstract The epidemiology of metastases in neuroendocrine tumors (NETs) is virtually unknown. The present novel approach took use of two nationwide Swedish registers to assess the distribution of metastatic sites in comparison to adenocarcinoma. 7,334 patients with NET were identified from the Swedish Cancer Registry. Metastatic sites were identified from the National Patient and Cause of Death Registries. Sites of metastasis were investigated depending on the primary site of NET. The metastatic potential of NET was assessed. The liver was the most common site of metastasis (82% of patients with metastases), and the small intestine was the most common source of NET metastases. Of all patients with metastatic lung NETs, 66% had liver metastases, whereas the corresponding number for adenocarcinoma of lung was only 20%. The risk of metastasis was highest if the primary was in the small intestine or pancreatohepatobiliary tract, whereas it was lower with appendiceal and rectal NET. Men had more bone metastases compared to women. Patients with metastatic NET had worse prognosis if the primary site was unknown (11 months, 9% of NET patients) compared to those whose primary was known (19 months). The metastatic potential of NETs varies profoundly depending on the primary site. NETs show a clear preference to metastasize to the liver. Surveillance of liver metastases may enable earlier diagnosis and treatment. In liver metastases from NET, the small intestine should be suspected as the primary site, whereas the lung should be suspected in nervous system metastases of NET origin.
29.	Yu, Hongyao, et al. (författare) Common cancers share familial susceptibility : Implications for cancer genetics and counselling 2017 Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 54, s. 248-253 Tidskriftsartikel (refereegranskat)abstract Background It has been proposed that cancer is more common in some families than in others, but the hypothesis lacks population level support. We use a novel approach by studying any cancers in large threegeneration families and thus are able to find risks even though penetrance is low. Methods Individuals in the nation-wide Swedish Family- Cancer Database were organised in three generations and the relative risk (RR) of cancer was calculated to the persons in the third generation by the numbers of patients with cancer in generations 1, 2 and 3. Results The RRs for any cancer in generation 3 increased by the numbers of affected relatives, reaching 1.61 when at least seven relatives were diagnosed. The median patient had two affected relatives, and 7.0% had five or more affected relatives with an RR of 1.46, which translated to an absolute risk of 21.5% compared with 14.7% in population by age 65 years. For prostate cancer, the RR was 2.85 with four or more affected family members with any cancer, and it increased to 14.42 with four or more concordant cancers in family members. RRs for prostate cancer were approximately equal (2.70 vs 2.85) if a man had one relative with prostate cancer or four or more relatives diagnosed with any cancer. Conclusions A strong family history of cancer, regardless of tumour type, increases cancer risk of family members and calls for mechanistic explanations. Our data provide tools for counselling of patients with cancer with both low and high familiar risks.
30.	Yu, Hongyao, et al. (författare) Familial Associations of Colon and Rectal Cancers With Other Cancers 2019 Ingår i: Diseases of the Colon and Rectum. - 0012-3706. ; 62:2, s. 189-195 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Many studies have indicated that colon and rectal cancers differ in etiology and histology. OBJECTIVE: The aim of this study was to investigate whether the associations of colon and rectal cancers with any other (discordant) cancer were site specific. DESIGN: A novel approach was implemented in which cancer risks were analyzed in families with increasing numbers of family members diagnosed with defined cancers. The novel assumption was that, for a true familial association, the risk should increase by the number of affected family members. In separate analyses, familial risks were calculated after the exclusion of putative families with hereditary nonpolyposis colorectal cancer. SETTINGS: The study was conducted using the Swedish Family-Cancer Database. MAIN OUTCOME MEASURES: The outcome measure was relative risk. RESULTS: Relative risks of colorectal cancer and colon cancer were higher when family members were diagnosed with colon cancer than when family members were diagnosed with rectal cancer (incidence rate ratio for colorectal: 1.82 (95% CI, 1.74-1.90) vs 1.61 (95% CI, 1.51-1.71); incidence rate ratio for colon: 1.92 (95% CI, 1.83-2.02) vs 1.56 (95% CI, 1.45-1.69)). Relative risks for 10 discordant cancers were increased in colon or rectal cancer families, whereas none of the relative risks differed significantly between colon and rectal cancers. After deleting hereditary nonpolyposis colorectal cancer families, the relative risks of endometrial and ovarian cancers were no longer significant. LIMITATIONS: Genetic data are unavailable in the database. CONCLUSIONS: Our results suggested that familial risks for colon cancer were higher than risks for rectal cancer in families of patients with colorectal cancer and colon cancer. The relationships of lung cancer and nervous system cancer with colorectal cancer were site specific. The associations of colon and rectal cancers with lung cancer, myeloma, and cancer of unknown primary appeared not to point out known syndromes and may suggest involvement of a novel predisposition. See Video Abstract at http://links.lww.com/DCR/A791.
31.	Yu, Hongyao, et al. (författare) Familial associations of colorectal cancer with other cancers 2017 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1 Tidskriftsartikel (refereegranskat)abstract Colorectal cancer (CRC) has a strong familial component which extends to discordant cancers (ie non-CRC tumors). This is best seen in cancer syndromes such as hereditary non-polyposis colorectal cancer (HNPCC) which predisposes to several tumor types. Population-based family studies have also found discordant associations for CRC but they have included cancers which manifest in HNPCC, and there is no convincing evidence of discordant associations beyond the known syndromes. We address familial associations of non-CRC tumors with CRC using the resources of the Swedish Family-Cancer Database and applying a powerful approach of assessing familial relative risks in families of increasing numbers of patients with discordant cancers. Among 1.8 million cancer patients and over 200,000 CRC cases consistent familial associations of CRC was observed for several HNPCC related cancers. However, for small intestinal, pancreatic and nervous system cancers RRs remained essentially unchanged when potential HNPCC families were excluded, suggesting involvement of genes not related to HNPCC. Two independent associations of CRC were found for melanoma, thyroid and eye cancers and these appeared not to be related to known syndromes. A number of other cancers associated with CRC in single analyses and independent studies are required to assess the relevance of such findings.
32.	Yu, Hongyao, et al. (författare) Other cancers in lung cancer families are overwhelmingly smoking-related cancers 2017 Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 3:2 Tidskriftsartikel (refereegranskat)abstract Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology. We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking. The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found. Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor.
33.	Zheng, Guoqiao, et al. (författare) Association between tumor characteristics and second primary cancers with cutaneous melanoma survival : A nationwide cohort study 2020 Ingår i: Pigment Cell and Melanoma Research. - : Wiley. - 1755-1471 .- 1755-148X. ; 33:4, s. 625-632 Tidskriftsartikel (refereegranskat)abstract The increased survival in malignant cutaneous melanoma (melanoma) is probably due to early diagnosis combined with improved treatment most recently. National health campaigns and screening programs for melanoma detection were started in Sweden several decades ago. We want to assess the influence of tumor characteristics, based on the TNM classification, and of second primary cancers on overall survival in melanoma. We used the Swedish Cancer Registry to assess all-cause survival in melanoma from 2003 to 2015. Hazard ratios (HRs) were estimated using multivariable Cox regression models. A total of 19,773 melanoma patients were diagnosed with TNM data. Survival showed a strong improving trend over time (p-trend <.001). T1a was the most common classification (48.0% of all), while higher T class was associated systematically with worse survival (p-trend <.001). For distant metastases, the HR was 3.17, accounting for 0.9% of the patients. Any types of second primary cancers, other than melanoma, were associated with an HR of 2.00, accounted for 6.7% of all cases. Even if melanoma survival in Sweden ranks among the best national rates, the large percentage of patients with advanced tumors (T3b, T4a, and T4b, 17%) and 21% of deaths with T1a call for improved preventive and follow-up strategies.
34.	Zheng, Guoqiao, et al. (författare) Familial associations of female breast cancer with other cancers 2017 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 141:11, s. 2253-2259 Tidskriftsartikel (refereegranskat)abstract Familial risks of breast cancer (BC) are well established but whether BC clusters with other, i.e. discordant, cancers is less certain but of interest for the identification of common genetic and possible environmental factors contributing to a general cancer susceptibility. We apply a novel approach to search for familial associations of BC with other (discordant) cancers based on the Swedish Family-Cancer Database. Relative risks (RRs) were calculated for BC in families with increasing numbers of patients with discordant cancer X, and conversely, familial RRs for cancer X in families with increasing numbers of BC patients. Joint p-values were calculated from independent analyses. The total number of familial BCs was 12,266, 14.9% with one first-degree relative with BC and 1.2% with at least 2 affected relatives. Ovarian and prostate cancers showed the strongest associations with BC (p-value <10−11). The p-value for melanoma was <10−6, for stomach and male colorectal cancer <2.5 × 10−6, for cancer of unknown primary <2.5 × 10−5 and for lung cancer <5 × 10−5. Significance level <5 × 10−4 was reached with pancreatic cancer. The remaining associations (p < 0.0025) included thyroid, endometrial, testicular, eye cancers (uveal melanoma), nervous system and endocrine tumors and non-Hodgkin lymphoma. The RR for BC increased by increasing numbers of patients with any cancer in family members and it reached 1.62 when three or more family members were affected. The results suggest that BC shares susceptibility with a number of other cancers. This might alert genetic counselors and challenge approaches for gene and gene–environment identification.
35.	Zheng, Guoqiao, et al. (författare) Familial associations of male breast cancer with other cancers 2017 Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 166:3, s. 897-902 Tidskriftsartikel (refereegranskat)abstract Purpose: Male breast cancer is associated with female breast cancer in families but whether male breast cancer clusters with other discordant cancers has not been studied. As concordant male breast cancers are utterly rare, discordant associations of male breast cancer with other cancers may reveal genetic and possible environmental risk factors contributing to male breast cancer susceptibility. Methods: We calculated relative risks (RRs) for male breast cancer in families with discordant cancers, and conversely, for discordant cancers in families of male breast cancer patients, based on 15.7 million individuals in the Swedish Family-Cancer Database. Results: Among 1428 male breast cancer patients, 16.2% had a female relative diagnosed with breast cancer. Ovarian and female anal cancers showed the strongest associations with male breast cancer (p value < 0.0005). The other significant associations included colorectal, small intestinal, and thyroid cancers, cancer of unknown primary and non-Hodgkin lymphoma but these were each based on a single positive association with male breast cancer. The RRs for male breast cancer were increased in families in which multiple patients were diagnosed with diverse cancers, reaching an RR of 2.58 when three or more family members were affected. Conclusions: The results suggest that male breast cancer shares susceptibility with a number of other cancers but confirmation is needed in other datasets.
36.	Zheng, Guoqiao, et al. (författare) Incidence differences between first primary cancers and second primary cancers following skin squamous cell carcinoma as etiological clues 2020 Ingår i: Clinical Epidemiology. - 1179-1349. ; 12, s. 857-864 Tidskriftsartikel (refereegranskat)abstract Background: Most literature on second primary cancers (SPCs) focuses on possible factors, which may increase the risk of these cancers, and little attention has been paid for the overall incidence differences between first primary cancers (FPCs) and same SPCs. We wanted to compare the incidence rates for all common cancers when these were diagnosed as FPCs and SPCs after invasive and in situ squamous cell carcinoma (SCC) of the skin, which are usually treated by surgery only. Methods: Cancers were identified from the Swedish Cancer Registry from the years 1990 through to 2015, and they included, in addition to skin cancers, 20 male cancers totaling 484,850 patients and 22 female cancers totaling 452,909 patients. Standardized incidence rates and relative risks (RRs) were calculated for sex-specific common cancers as FPC and as SPC after skin SCC. Spearman rank correlations were used in the analysis of incidence ranking of FPC and SPC. Results: Of total, 29,061 men and 23,533 women developed invasive SCC and 27,842 men and 36,383 women in situ SCC. The total number of 20 other male cancers was 484,850 and of 22 female cancers it was 452,909. Rank correlations ranged from 0.90 to 0.96 (P~5×10−6), indicating that overall skin SCC did not interfere with SPC formation. The exceptions were increased SPC risks for melanoma, sharing risk factors with skin SCC, and non-Hodgkin and Hodgkin lymphoma, and cancers of the upper aerodigestive tract, connective tissue, and male and female genitals suggesting contribution by skin cancer initiated immune dysfunction. Conclusion: The incidence ranking of SPCs after skin cancers largely follows the incidence ranking of FPCs indicating that overall skin SCC does not greatly interfere with the intrinsic carcinogenic process. The main deviations in incidence between FPC and SPC appeared to be due to shared risk factors or immunological processes promoting immune responsive cancer types.
37.	Zheng, Guoqiao, et al. (författare) Rate differences between first and second primary cancers may outline immune dysfunction as a key risk factor 2020 Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:21, s. 8258-8265 Tidskriftsartikel (refereegranskat)abstract Background: Many cancers are increased in immunosuppressed patients and evidence is accumulating that immune dysfunction may be a contributing risk factor for second primary cancers (SPCs). The aim of this study was to explore the potential influence of immune mechanisms in SPC. Methods: We used the Swedish Cancer Registry (1990-2015) to select 13 male and 14 female first primary cancers (FPCs) that are known to be related to immune suppression. We assessed relative risks (RRs) for any of these as concordant (same first and second cancer) and discordant FPC-SPC pairs. Hierarchical clustering of significant RRs was performed for cancers as FPC and SPC. Results: Concordant risks for SPCs were excessive in men and women for nasal (RRs 59.3 for men and 150.6 for women), tongue/mouth (51.7 and 100.8), and lip (32.4 and 61.2) cancers. Heatmaps showed that some cancers, such as skin cancer, tongue/mouth cancers, and non-Hodgkin lymphoma had multiple bidirectional associations as FPC and SPC. Nasal cancer and chronic lymphocytic leukemia had associations mainly as FPC while liver and kidney cancers showed most associations as SPC. Conclusions: Immune dysfunction may be a plausible contributing factor for most of the associations, which calls for experimental verification.
38.	Zheng, Guoqiao, et al. (författare) Second primary cancer after female breast cancer : Familial risks and cause of death 2019 Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 8:1, s. 400-407 Tidskriftsartikel (refereegranskat)abstract Background: With continuous increases in survival rates following breast cancer (BC) diagnosis, the challenge of multiple primary cancers has become an issue. The data on familial risk of SPCs after BC diagnosis and the related mortality in BC patients are scarce. Methods: A total of 87 752 female BC patients were followed for SPC diagnoses and records of death. Relative risks (RRs) of SPC in BC patients who had first-degree relatives (parents or siblings) affected by the same cancer were compared to the patients without family history. Causes of death were compared between patients with and without SPC. Results: After a median follow-up of 5 years, 14 952 BC patients developed SPCs, among which 10 280 (68.8%) had first-degree relatives diagnosed with cancer. Familial risks were significant for 14 site-specific SPCs, and the highest risk was for second ovarian cancer (RR = 6.28, 95%CI: 4.50-8.75), compared to those without family history (1.49, 1.34-1.65). In patients with SPC, SPC was the main cause of death, including diverse cancers and BC in approximately equal proportions. Conclusions: Family history contributed to the excess number of patients with SPCs, and SPC was the leading cause of death in patients with SPC. Taking family history at diagnosis of BC may provide warning signs with regard to possible subsequent SPCs and may offer possibilities for counseling, intervention and management.
39.	Zheng, Guoqiao, et al. (författare) Second primary cancers after gastric cancer, and gastric cancer as second primary cancer 2021 Ingår i: Clinical Epidemiology. - 1179-1349. ; 13, s. 515-525 Tidskriftsartikel (refereegranskat)abstract Background: Second primary cancers (SPCs) are increasing, which may negatively influ-ence patient survival. Gastric cancer (GC) has poor survival and when it is diagnosed as SPC it is often the cause of death. We wanted to analyze the risk of SPCs after GC and the risk of GC as SPC after any cancer. Such bidirectional analysis is important in relation to fatal cancers because SPCs may be under-reported in the short-term survival period. Methods: Cancers were obtained from the Swedish Cancer Registry from years 1990 through 2015. Standardized incidence ratios (SIRs) were used to estimate bidirectional relative. Results: We identified 23,137 GC patients who developed 1042 SPCs (4.5%); 2158 patients had GC as SPC. While the risk for three SPCs was increased after GC, seven first primary cancers were followed by an increased risk of GC as SPC, including esophageal, colorectal, bladder, squamous cell skin and breast cancers and non-Hodgkin lymphoma. Breast cancer, which was followed by a diagnosis of second GC, showed an excess of lobular histology. Conclusion: Multiple primary cancers in the same individuals may signal genetic predis-position. Accordingly, the association of GC with breast cancer may be related to mutations in the CDH1 gene, and clustering of colorectal, small intestinal and bladder cancers could be related to Lynch syndrome. The third line of findings supports a contribution of immune dysfunction on the increased risk of GC as SPC after skin cancer and non-Hodgkin lymphoma. Early detection of GC in the risk groups could save lives.
40.	Zheng, Guoqiao, et al. (författare) Second primary cancers after liver, gallbladder and bile duct cancers, and these cancers as second primary cancers 2021 Ingår i: Clinical Epidemiology. - 1179-1349. ; 13, s. 683-691 Tidskriftsartikel (refereegranskat)abstract Background: Second primary cancers (SPCs) are important clinically as they may negatively influence patient survival and they may tell about therapeutic side effects and general causes of cancer. Population-based literature concerning SPCs after hepatobiliary cancers is limited and here we assess risks of SPCs after hepatocellular cancer (HCC), and cancers of the gallbladder, bile ducts and ampulla of Vater. In reverse order, we consider the risk of hepatobiliary cancers as SPCs after any cancer. Methods: We used standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancers associated with hepatobiliary cancers. Cancer diagnoses were obtained from the Swedish Cancer Registry from years 1990 through 2015. Results: We identified 9997 primary HCCs, 1365 gallbladder cancers and 4721 bile duct cancers. After HCC, risks of four SPCs were increased: gallbladder (SIR = 4.38; 95% confidence interval 1.87–8.67), thyroid (4.13; 1.30–9.70), kidney (2.92; 1.66–4.47) and squamous cell skin (1.55; 1.02–2.26) cancers. In reverse order, HCC as SPC, in addition to the above cancers, associations included upper aerodigestive tract, esophageal, small intestinal and bladder cancers and non-Hodgkin lymphoma. For gallbladder and bile duct cancers, associations were found with small intestinal and pancreatic cancers. Conclusion: The results suggested that HCC is associated with two types of SPC, one related to shared environmental risk factors, such as alcohol, exemplified by upper aero-digestive tract and esophageal cancer, and the other related to immune dysfunction, exemplified by squamous cell skin cancer. SPCs associated with gallbladder and bile duct cancers suggest predisposition to mutations in the mismatch repair gene MLH1.
41.	Zheng, Guoqiao, et al. (författare) Second primary cancers in melanoma patients critically shorten survival 2020 Ingår i: Clinical Epidemiology. - 1179-1349. ; 12, s. 105-112 Tidskriftsartikel (refereegranskat)abstract Background: Survival in malignant cutaneous melanoma has improved but increasing survival will result in an increased likelihood of the occurrence of second primary cancers (SPCs). SPCs may adversely interfere with survival. We quantified survival in patients with different types of SPCs, in comparison to known poor prognostic indicators of metastatic disease. Methods: Data for melanoma and any SPCs were obtained from the Swedish Cancer Registry for years 2003 through 2015, including clinical TNM classification. SPCs were grouped into three ‘prognostic groups’ based on 5-year relative survival of these cancers as first primary cancer. Kaplan-Meier survival curves were generated and hazard ratios were estimated using Cox regression, adjusted for a number of variables and treating diagnosis of SPC as a time-dependent variable. Results: The total number of first melanoma patients was 28,716 followed by 3,202 (11.1%) SPCs, 1/3 of which had a second melanoma while 2/3 had other SPCs. Among men diagnosed at age over 70 years, who survived at least 10 years, 31.4% had SPC. HRs (95% CI) for survival increased systematically from the reference rate of 1.00 (no SPC) to 1.59 (1.35–1.87) with SPC of good prognosis (78.6% of SPCs) to 3.49 (2.58–4.72) of moderate prognosis (12.0%) and to 7.93 (5.50–11.44) of poor prognosis (9.4%). In patients without SPC, the HRs increased to 2.62 (2.02–3.39) with any nodal metastases and to 5.88 (4.57–7.57) with any distant metastases compared to patients without local or distant metastases. Conclusion: The data showed that SPCs are an increasingly common negative prognostic factor for melanoma. Future attempts to improve melanoma survival need to target SPCs.
42.	Zheng, Guoqiao, et al. (författare) Second primary cancers in patients with acute lymphoblastic, chronic lymphocytic and hairy cell leukaemia 2019 Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 185:2, s. 232-239 Tidskriftsartikel (refereegranskat)abstract Improvement of survival in lymphocytic leukaemia has been accompanied by the occurrence of second primary cancer (SPCs). Based on Swedish Family Cancer Database, we applied bi-directional analyses in which relative risks (RRs) were calculated for any SPCs in patients with chronic lymphocytic leukaemia (CLL), acute lymphoblastic leukaemia (ALL) and hairy cell leukaemia (HCL) and the risks of these leukaemias as SPCs. After CLL, RRs were significant for 20 SPCs, and high for skin squamous cell cancer (24·58 for in situ and 7·63 for invasive), Merkel cell carcinoma (14·36), Hodgkin lymphoma (7·16) and Kaposi sarcoma (6·76). Conversely, 15 CLL cancer pairs were reciprocally increased. The increased risks were reciprocal for ALL and four cancers. RR for ALL was 15·35 after myeloid neoplasia. HCL showed reciprocally increased RRs with non-Hodgkin lymphoma and melanoma. The concordance between RRs for bi-directional associations between CLL and different cancers, and HCL and different cancers was highly significant. For CLL (also for HCL), the bi-directional risks with skin cancers and other immune-related cancers suggest the probable involvement of immune dysfunction. For ALL, treatment may contribute to risks of multiple SPCs. Increased risk of ALL after haematological neoplasms may indicate bone marrow dysfunction. These findings may help guide treatment decisions and prognostic assessment.
43.	Zheng, Guoqiao, et al. (författare) Types of second primary cancer influence overall survival in cutaneous melanoma 2021 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1 Tidskriftsartikel (refereegranskat)abstract Background: Favorable survival in malignant cutaneous melanoma (melanoma) has increased the likelihood of second primary cancer (SPC). We assess the influence of patient characteristics at diagnosis of first melanoma and the type of SPC (second melanoma and other SPC) on overall survival. Methods: We used the Swedish Cancer Registry data to assess overall survival in melanoma for the period 1990 to 2015. Kaplan-Meier curves were plotted and hazard ratios (HRs) were estimated with Cox regression models by considering SPC diagnosis as a time-dependent variable. Results: A total of 46,726 patients were diagnosed with melanoma, and 15.3% of them developed SPC, among which, two thirds were other SPCs. Second melanomas were diagnosed early (31% during the first year) compared to non-melanoma SPCs (9.5%). Survival for women with second melanoma or other SPC (56 and 21% alive after 25 years of follow-up, respectively) exceeded the male rates (21 and 10%, respectively) but all these figures were lower than for females (60% alive) or males (48%) without SPC. Time dependent analysis showed vastly increased HRs for cancer types that are fatal also as first cancers, but SPC-specific HRs remained relatively uniform, irrespective of SPC diagnosed soon or late after first melanoma. In early-onset melanoma, SPC diagnosis after 10 years may not negatively influence overall survival. Conclusions: As the overall survival of patients with many types of SPCs is unfavorable, advice about health lifestyle should benefit smoking patients and early detection methods may be recommended for SPCs of the breast, prostate and colorectum.
44.	Zheng, Guoqiao, et al. (författare) Types of second primary cancers influence survival in chronic lymphocytic and hairy cell leukemia patients 2019 Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:4 Tidskriftsartikel (refereegranskat)
45.	Diaconu, Iulia, et al. (författare) Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus 2012 Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72:9, s. 2327-2338 Tidskriftsartikel (refereegranskat)abstract Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines.
46.	Joensuu, Heikki, et al. (författare) Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer : an open-label, randomised controlled trial 2009 Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 10:12, s. 1145-1151 Tidskriftsartikel (refereegranskat)abstract Background Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of capecitabine into such a regimen enhances outcome. Methods In this open-label trial, we randomly assigned (centrally by computer; stratified by node status, HER2 status, and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done after 3 years' median follow-tip. Efficacy analyses were by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT00114816. Findings Two patients in each group were excluded from efficacy analyses because of wthdrawal of consent or distant metastases. After a median follow-up of 35 months (IQR 25.5-43-6), recurrence-free survival at 3 years was better with the capecitabine regimen than with control (93% vs 89%; hazard ratio 0.66, 95% CI 0.47-0-94; p=0.020). The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and hand-foot syndrome (83/741 [11%] vs 2/741 [<1%]) and the control regimen with more occurrences of grade 3 or 4 neutropenia (368/375 198%] vs 325/378 186%]) and febrile neutropenia (65/741[9%] vs 33/742 [4%]). More patients discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). Four patients in the capecitabine group and two in the control group died from potentially treatment-related causes. Interpretation The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse effects. Funding Roche, Sanofi-Aventis, AstraZeneca, Cancer Society of Finland.
47.	Leja, Justyna, 1982- (författare) Oncolytic Adenovirus Therapy of Neuroendocrine Tumors 2011 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Neuroendocrine tumors (NETs), originally described as carcinoids, represent a rare and heterogeneous group of neoplasms associated with intensive secretion of hormones, bioactive peptides and amines. Most of the patients are diagnosed at a late stage of disease, often with liver metastases. Surgery remains the main treatment to control metastatic disease, but is not curative. Oncolytic virotherapy represents a promising approach to treat cancer and different strategies have been exploited to restrict viral replication to tumor cells. We developed an oncolytic adenovirus based on serotype 5, Ad5[CgA-E1A], where the chromogranin A (CgA) promoter controls expression of the E1A gene and thereby virus replication. We found that Ad5[CgA-E1A], selectively replicates in NET cells and it is able to suppress fast-growing human BON carcinoid tumors in nude mice. The activity of Ad5[CgA-E1A] was not completely blocked in liver cells. We further repressed virus replication in hepatocytes by targeting E1A with miR122, an miRNA specifically expressed in the liver. miRNAs bind to mRNA and induce its cleavage or translational blockage. By insertion of tandem repeats of miR122 target sequences in 3’UTR of E1A gene, we observed reduced E1A protein expression and replication arrest in miR122 expressing liver cells. The oncolytic potency of the miR122-targeted virus was not affected in NET cells. Since some NET and neuroblastoma cells express high levels of somatostatin receptors (SSTRs), we introduced in the virus fiber knob cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site of somatostatin for SSTRs. The FWKT-modified Ad5 transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to a greater extent than Ad5, indicating that the fiber knob modification may prolong the systemic circulation time. NETs represent a huge therapeutic challenge and novel diagnostic markers are needed for early detection and effective treatment of NETs. We have profiled primary tumors and liver metastases of ileocaceal NETs, using Affymetrix microarrays and advanced bioinformatics. We have identified six novel marker genes and show high similarity between primary lesions and liver metastases transcriptome by hierarchical clustering analysis.
48.	Paju, Annukka, et al. (författare) Increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells 2007 Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 52:6, s. 1670-1681 Tidskriftsartikel (refereegranskat)abstract Objectives: Tumor-associated-trypsin inhibitor (TATI) is frequently coexpressed with trypsinogen in tumors. Recently, we found expression of trypsinogens in prostate cancer. We have now studied whether TATI is also expressed in prostate cancer and if TATI expression is associated with Gleason grade, proliferation, and neuroendocrine differentiation. Methods: Expression of TATI and prostate-specific antigen (PSA) was studied by immunohistochemistryand in situ hybridization, and that of chromogranin A (CgA) and Ki-67 by immunohistochemistry. Immunofluorometric assays were used to quantify TATI and PSA in serum from prostate cancer patients and in medium of 22Rv1 prostate cancer cells. Results: TATI expression was weak in benign prostatic epithelium and moderate to strong in prostate cancer and high-grade prostatic intraepithelial neoplasia. There was no correlation between TATI and Ki-67 immunostaining in a tissue microarray of 115 prostate cancer cores, but strong expression of TATI was associated with higher Gleason grade (p = 0.002) and CgA immunostaining intensity (p = 0.012). Serum TATI was elevated in 44% (29 of 66) of patients with prostate cancer, and the levels correlated with serum PSA (p < 0.0001, r = 0.306). DU145, PC-3, LNCaP, and 22Rv1 cells contained TATI mRNA as determined by RT-PCR, but only 22Rv1 cells produced detectable TATI protein. The synthetic androgen R1881 decreased secretion of TATI from 22Rv1 cells. Conclusions: We demonstrate for the first time that TATI is expressed in the benign and malignant prostate. Increased TATI protein expression is found in high-grade tumors and in 22Rv1 cells in which it is regulated by androgens. (c) 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
49.	Saellström, Sara, et al. (författare) Adenoviral CD40 Ligand Immunotherapy in 32 Canine Malignant Melanomas-Long-Term Follow Up 2021 Ingår i: Frontiers in Veterinary Science. - : Frontiers Media S.A.. - 2297-1769. ; 8 Tidskriftsartikel (refereegranskat)abstract Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. Gene therapy using adenoviruses encoding the immunostimulatory gene CD40L (AdCD40L) has shown promise in initial clinical trials enrolling human patients with various malignancies including melanoma. We report a study of local AdCD40L treatment in 32 cases of canine melanoma (23 oral, 5 cutaneous, 3 ungual and 1 conjunctival). Eight patients were World Health Organization (WHO) stage I, 9 were stage II, 12 stage III, and 3 stage IV. One to six intratumoral injections of AdCD40L were given every seven days, combined with cytoreductive surgery in 20 cases and only immunotherapy in 12 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response based on result of immunotherapy included 7 complete responses, 5 partial responses, 5 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 285 days (range 20-3435 d). Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is ongoing.
50.	Tyynismaa, Henna, et al. (författare) Mitochondrial myopathy induces a starvation-like response 2010 Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 19:20, s. 3948-3958 Tidskriftsartikel (refereegranskat)abstract Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.

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