Cardiovascular diseases after high-dose chemotherapy and autologous stem cell transplant for lymphoma: A Danish population-based study.

Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m2 ) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 [1.8-3.8]) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies.

The National Swedish Lymphoma Register - a systematic validation of data quality.

BACKGROUND AND PURPOSE: The Swedish Lymphoma Register (SLR) was initiated in the year 2000 with the aim to monitor quality of care in diagnostics, treatment and outcome of all lymphomas diagnosed nationally among adults. Here, we present the first systematic validation of SLR records as a basis for improved register quality and patient care. PATIENTS AND METHODS: We evaluated timeliness and completeness of register records among patients diagnosed with lymphoma in the SLR (n = 16,905) compared with the National Cancer Register for the period 2013-2020. Comparability was assessed through evaluation of coding routines against national and international guidelines. Accuracy of 42 variables was evaluated through re-abstraction of data from medical records among 600 randomly selected patients diagnosed in 2016-2017 and treated across all six Swedish healthcare regions.  Results: Completeness was high, >95% per year for the period 2013-2018, and >89% for 2019-2020 compared to the National Cancer Register. One in four patients was registered within 3 months, and 89.9% within 2 years of diagnosis. Registration instructions and coding procedures followed the prespecified guidelines. Missingness was generally low (<5%), but high for occasional variables, for example, those describing maintenance and consolidative treatment. Exact agreement of categorical variables was high overall (>80% for 24/34 variables), especially for treatment-related data (>80% for 17/19 variables). INTERPRETATION: Completeness and accuracy are high in the SLR, while timeliness could be improved. Finetuning of variable registration guided by this validation can further improve reliability of register reports and advance service to lymphoma patients and health care in the future.

Reproduction patterns among classical Hodgkin lymphoma survivors treated with BEACOPP and ABVD in Sweden, Denmark and Norway-A population-based matched cohort study.

Childbirth rates in classical Hodgkin lymphoma (cHL) survivors have historically been reduced compared to the general population. Understanding if contemporary treatment protocols are associated with reduced fertility is crucial as treatment guidelines shift toward more liberal use of intensive chemotherapy. We identified 2834 individuals aged 18-40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital diagnosed 1995-2018, who were linked to national medical birth registers. Cox regression adjusted for stage, performance status, year, and age at diagnosis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) contrasting time to first childbirth by treatment groups (ABVD, 2-4 BEACOPP, 6-8 BEACOPP) up to 10 years after diagnosis. Overall, 74.8% of patients were treated with ABVD, 3.1% with 2-4 BEACOPP and 11.2% with 6-8 BEACOPP. Adjusted HRs comparing childbirth rates in individuals treated with 6-8 BEACOPP, and 2-4 BEACOPP to ABVD were 0.53 (CI: 0.36-0.77) and 0.33 (CI: 0.12-0.91) for males, and 0.91 (CI: 0.61-1.34) and 0.38 (CI: 0.12-1.21) for females. Cumulative incidence of childbirths after 10 years was 19.8% (CI: 14.5%-27.0%) for males and 34.3% (CI: 25.8%-45.6%) for females treated with 6-8 BEACOPP. Proportions of children born after assisted reproductive technique (ART) treatments were 77.4% (CI: 60.2-88.6%) for males following 6-8 BEACOPP, and <11% for females. Among ABVD treated patients the corresponding proportions were 12.2% (CI: 8.5%-17.3%) and 10.6% (CI: 7.4%-14.9%). BEACOPP treatment is associated with decreased childbirth rates compared to ABVD in male, but not female, cHL patients, despite widespread access to ART in the Nordics.

Reproduction patterns among non-Hodgkin lymphoma survivors by subtype in Sweden, Denmark and Norway: A population-based matched cohort study.

Previous studies concerning reproductive patterns among non-Hodgkin lymphoma (NHL) survivors are scarce and those available have reported conflicting results. Treatment regimens vary considerably between aggressive and indolent NHL and studies of reproductive patterns by subtypes are warranted. In this matched cohort study, we identified all NHL patients aged 18-40 years and diagnosed between 2000 and 2018 from the Swedish and Danish lymphoma registers, and the clinical database at Oslo University Hospital (n = 2090). Population comparators were matched on sex, birth year and country (n = 19 427). Hazard ratios (HRs) were estimated using Cox regression. Males and females diagnosed with aggressive lymphoma subtypes had lower childbirth rates (HRfemale : 0.43, 95% CI: 0.31-0.59, HRmale : 0.61, 95% CI: 0.47-0.78) than comparators during the first 3 years after diagnosis. For indolent lymphomas, childbirth rates were not significantly different from comparators (HRfemale : 0.71, 95% CI: 0.48-1.04, HRmale : 0.94, 95% CI: 0.70-1.27) during the same period. Childbirth rates reached those of comparators for all subtypes after 3 years but the cumulative incidence of childbirths was decreased throughout the 10-year follow-up for aggressive NHL. Children of NHL patients were more likely to be born following assisted reproductive technology than those of comparators, except for male indolent lymphoma patients. In conclusion, fertility counselling is particularly important for patients with aggressive NHL.

Patient trajectories after diagnosis of diffuse large B-cell lymphoma-a multistate modelling approach to estimate the chance of lasting remission.

BACKGROUND: Achieving lasting remission for at least 2 years is a good indicator for favourable prognosis long term after Diffuse large B-cell lymphoma (DLBCL). The aim of this study was to provide real-world probabilities, useful in risk communication and clinical decision-making, of the chance for lasting remissions by clinical characteristics. METHODS: DLBCL patients in remission after primary treatment recorded in the Swedish Lymphoma register 2007-2014 (n = 2941) were followed for relapse and death using multistate models to study patient trajectories. Flexible parametric models were used to estimate transition rates. RESULTS: At 2 years, 80.7% (95% CI: 79.0-82.2) of the patients were predicted to remain in remission and 13.2% (95% CI: 11.9-14.6) to have relapsed. The relapse risk peaked at 7 months, and the annual decline of patients in remission stabilised after 2 years. The majority of patients in the second remission transitioned into a new relapse. The probability of a lasting remission was reduced by 20.4% units for patients with IPI 4-5 compared to patients with IPI 0-1, and time in remission was shortened by 3.5 months. CONCLUSION: The long-term prognosis was overall favourable with 80% achieving durable first remissions. However, prognosis varied by clinical subgroups and relapsing patients seldom achieved durable second remissions.

Outcomes of relapsed/refractory diffuse large B-cell lymphoma and influence of chimaeric antigen receptor T trial eligibility criteria in second line-A population-based study of 736 patients.

Several recently published trials investigate novel therapies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). To estimate the benefit of these therapies in the real-world setting, comprehensive data on patients treated in clinical routine are needed. We report outcomes for 736 R/R DLBCL patients identified among all curatively treated DLBCL patients in Sweden in the period 2007-2014. Survival and associations with disease characteristics, second-line treatment and fulfilment of chimaeric antigen receptor (CAR) T-cell trial criteria were assessed. Median overall survival (OS) was 6.6 months (≤70 years 9.6 months, >70 years 4.9 months). Early relapse (≤12 months) was strongly associated with selection of less intensive treatment and poor survival. Among patients of at most 70 years of age, 63% started intensive second-line treatment and 34% received autologous stem cell transplantation (ASCT). Two-year OS among transplanted patients was 56% (early relapse ≤12 months 40%, late relapse >12 months 66%). A minority of patients 76 years (n = 178/506, 35%) fitted CAR T trial criteria. Median progression-free survival (PFS) for patients with early relapse fitting trial criteria was 4.8 months. In conclusion, most R/R DLBCL manifest early and are often ineligible for or cannot complete intensive regimens resulting in dismal survival. Real-world patients eligible for CAR T trials also did poorly, providing a benchmark for efficacy of novel therapies.

Predictive models for clinical decision making: Deep dives in practical machine learning.

The deployment of machine learning for tasks relevant to complementing standard of care and advancing tools for precision health has gained much attention in the clinical community, thus meriting further investigations into its broader use. In an introduction to predictive modelling using machine learning, we conducted a review of the recent literature that explains standard taxonomies, terminology and central concepts to a broad clinical readership. Articles aimed at readers with little or no prior experience of commonly used methods or typical workflows were summarised and key references are highlighted. Continual interdisciplinary developments in data science, biostatistics and epidemiology also motivated us to further discuss emerging topics in predictive and data-driven (hypothesis-less) analytics with machine learning. Through two methodological deep dives using examples from precision psychiatry and outcome prediction after lymphoma, we highlight how the use of, for example, natural language processing can outperform established clinical risk scores and aid dynamic prediction and adaptive care strategies. Such realistic and detailed examples allow for critical analysis of the importance of new technological advances in artificial intelligence for clinical decision-making. New clinical decision support systems can assist in prevention and care by leveraging precision medicine.

Reproductive history, as measured by parity, age at first birth and sex of offspring, and cancer-specific survival after a haematological malignancy.

BACKGROUND: Overall, women have better cancer-specific survival than men following haematological malignancies. The effect of reproductive factors on prognosis in women remains unknown and population-based studies are needed. MATERIAL AND METHODS: A nationwide cohort of 21,237 Swedish women with a recorded haematological malignancy at ages 18-69 years was identified in the Swedish Cancer Register 1970-2018. Pre-diagnosis childbirths for each woman were linked to the Swedish Multigeneration Register. Net survival and excess hazard ratios for parity, age at first birth, time since the latest birth, and sex of offspring were estimated using flexible parametric models adjusted for age, year, and educational level. RESULTS: In unadjusted analyses, parity (p = 0.0012) and high age at first birth (p < 0.0001) were associated with better survival. After co-adjustments for reproductive factors and confounders, the associations were attenuated. The adjusted association with parity was mainly observed among women aged above 40 years at diagnosis (p = 0.0033). The associations with reproductive factors were non-significant across subtypes of haematological malignancy. There was a tendency of higher excess mortality for an increasing number of boys compared to girls, although only significant for women with three or more children (p = 0.0126). CONCLUSION: Reproductive factors were in part associated with survival following diagnosis of a haematological malignancy. However, the effect sizes were small with inconsistent association patterns, and thus reproductive factors may only partly contribute to the survival advantage of women over men.

Cardiovascular, bone, and metabolic health in men with castrate-resistant prostate cancer treated with androgen deprivation: a matched cohort study.

BACKGROUND: Descriptive data on late effects associated with castrate-resistant prostate cancer (CRPC) are sparse. We aimed to define the timing and incidence of cardiovascular disease (CVD), fractures, and diabetes in a patient population with CRPC. METHODS: In the population-based STHLM0 cohort 1464 men with CRPC were identified and matched with three men free from prostate cancer (PC) in the Stockholm region of Sweden. Kaplan-Meier estimates of net survival were used to describe time to CVD, fracture, and diabetes. Cox regression was used to compare incidence rates (IRRs) for the respective late effects. Cumulative incidence analyses of late effects in the presence of the competing risk of death were performed to estimate absolute risks. RESULTS: The Kaplan Meier estimates demonstrated a higher net probability for CVD, fracture, and diabetes among men diagnosed with CRPC compared to the matched comparators. The IRRs were 1.94 (95% CI: 1.79-2.12) for CVD, 2.08 (95% CI: 1.70-2.53) for fracture, and 2.00 (95% CI: 1.31-3.05) for diabetes, respectively, comparing men diagnosed with CRPC to men free from PC. The cumulative incidence of CVD at 12 months of follow-up was higher in men diagnosed with CRPC compared to healthy controls regardless of age with a difference in cumulative incidence being 0.20 for men aged <65 and 0.11 for men aged >84. CONCLUSIONS: In this cohort, the incidence of CVD was significantly higher among men with CRPC compared to healthy controls. Despite having this end-stage disease this finding proves that clinicians must recognize this late effect in men diagnosed with CRPC to improve preventive actions. These men did not have a higher absolute risk of fractures and diabetes after accounting for deaths due to any cause compared to healthy controls.

Statin use and survival in 16 098 patients with non-Hodgkin lymphoma or chronic lymphocytic leukaemia treated in the rituximab era.

Statin use has been associated with reduced mortality from several cancers but also suggested, in vitro, to diminish the effectiveness of lymphoma treatments including rituximab. The present study aimed to assess the association of statin use with mortality in patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). We identified all incident NHLs and CLLs in Sweden from 2007 to 2013 with subtype information in the Swedish Lymphoma and Cancer Registers. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of pre- or post-diagnosis statin use (yes/no, intensity) with lymphoma-specific, cardiovascular, or all-cause mortality; and for follicular lymphoma (FL) by initial treatment strategy (active/watch-and-wait). Among 16 098 incident NHL/CLL patients, 20% used statins at diagnosis. Pre- and post-diagnosis statin use, and statin intensity were not consistently associated with any mortality outcome in patients with NHL, overall or for any subtype. For actively treated patients with FL, statin use did not appear to increase lymphoma-specific mortality (vs. non-users, HR [95% CI]after diagnosis 0·87 [0·45-1·67]). For CLL, statin use was associated with all-cause and cardiovascular but not consistently with lymphoma-specific mortality. In conclusion, statin use was not associated with improved lymphoma survival but appears safe to use during lymphoma treatment.

Clinical characteristics and outcomes among 2347 patients aged ≥85 years with major lymphoma subtypes: a Nordic Lymphoma Group study.

There is a lack of data regarding treatment and prognosis for the growing group of oldest old patients with lymphoma. Therefore, we studied 2347 patients aged ≥85 years from the Danish and Swedish lymphoma registers 2000-2016 (Denmark) and 2007-2013 (Sweden). Outcome was assessed using relative survival (RS). The 2-year RS overall for patients with aggressive lymphomas was 38% [95% confidence interval (CI) 35-42%], of whom 845 (66%) patients received active treatment (chemotherapy, radiotherapy, immunotherapy, other). For aggressive lymphomas, not receiving active treatment was associated with an inferior 2-year RS of 12% (95% CI 9-17%) compared to 49% (95% CI 45-53%) for patients who received active treatment (excess mortality rate ratio 2·84, 95% CI 2·3-3·5; P < 0·0001). For patients with indolent lymphoma, the 2-year RS was 77% (95% CI 72-82%). Here, 383 (46%) patients received active treatment at diagnosis, but did not have better 2-year RS (75%, 95% CI 67-81%) compared to those who did not receive active treatment (83%, 95% CI 74-89%). We conclude that outcomes for the oldest old patients with lymphoma are encouraging for several subtypes and that active treatment is associated with improved outcome amongst the oldest old patients with aggressive lymphomas, indicating that age itself should not be a contraindication to treatment.

A multistate model incorporating estimation of excess hazards and multiple time scales.

As cancer patient survival improves, late effects from treatment are becoming the next clinical challenge. Chemotherapy and radiotherapy, for example, potentially increase the risk of both morbidity and mortality from second malignancies and cardiovascular disease. To provide clinically relevant population-level measures of late effects, it is of importance to (1) simultaneously estimate the risks of both morbidity and mortality, (2) partition these risks into the component expected in the absence of cancer and the component due to the cancer and its treatment, and (3) incorporate the multiple time scales of attained age, calendar time, and time since diagnosis. Multistate models provide a framework for simultaneously studying morbidity and mortality, but do not solve the problem of partitioning the risks. However, this partitioning can be achieved by applying a relative survival framework, allowing us to directly quantify the excess risk. This article proposes a combination of these two frameworks, providing one approach to address (1) to (3). Using recently developed methods in multistate modeling, we incorporate estimation of excess hazards into a multistate model. Both intermediate and absorbing state risks can be partitioned and different transitions are allowed to have different and/or multiple time scales. We illustrate our approach using data on Hodgkin lymphoma patients and excess risk of diseases of the circulatory system, and provide user-friendly Stata software with accompanying example code.

Survival among solid organ transplant recipients diagnosed with cancer compared to nontransplanted cancer patients-A nationwide study.

Solid organ transplant recipients (OTRs) have an increased cancer risk but their survival once diagnosed with cancer has seldom been assessed. We therefore investigated cancer-specific survival among OTRs with a wide range of cancer forms nationally in Sweden. The study included 2,143 OTRs with cancer, and 946,089 nontransplanted cancer patients diagnosed 1992-2013. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models adjusted for age, sex and calendar year. Median follow-up was 3.1 (range 0-22) years. Overall, OTRs diagnosed with any cancer had a 35% higher rate of cancer death compared to nontransplanted cancer patients (HR: 1.35, 95% CI: 1.24-1.47). Specifically, higher rates of cancer-specific death were observed among OTRs diagnosed with Hodgkin lymphoma (HR: 15.0, 95% CI: 5.56-40.6), high-grade non-Hodgkin lymphoma (HR: 2.68, 95% CI: 1.90-3.77), malignant melanoma (HR: 2.80, 95% CI: 1.74-4.52) and urothelial (HR: 2.56, 95% CI: 1.65-3.97), breast (HR: 2.12, 95% CI: 1.38-3.25), head/neck (HR: 1.55, 95% CI: 1.02-2.36) and colorectal (HR: 1.42, 95% CI: 1.07-1.88) cancer. The worse outcomes were not explained by differences in distribution of cancer stage or histologic subtypes. For other common cancer forms such as prostate, lung and kidney cancer, the prognosis was similar to that in nontransplanted cancer patients. In conclusion, several but not all types of posttransplantation cancer diagnoses are associated with worse outcomes than in the general population. Reasons for this should be further explored to optimize posttransplantation cancer management.

Comorbidities and sex differences in causes of death among mantle cell lymphoma patients - A nationwide population-based cohort study.

The prognosis for mantle cell lymphoma (MCL) remains poor. Our aim was to assess the impact of comorbidities on survival and causes of death. For 1,385 MCL patients (1,009 males, 376 females) diagnosed in 2000-2014 (median age 71 years, range 22-96) comorbidities ≤ 10 years of diagnosis were classified according to the Charlson comorbidity index (CCI; 0, 1, 2+). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to compare lymphoma-specific and all-cause mortality rates. Model-based predictions were used to obtain probabilities of death. Overall, 44% had any comorbidity (CCI 1+) and 28% severe comorbidity (CCI 2+). Over a median follow-up of 3·7 years (range 0-16), 633 (46%) died, the majority (76%) from lymphoma. Severe comorbidity was independently associated with higher all-cause [hazard ratio (HR) = 1·52; 95% CI: 1·24-1·85) and lymphoma-specific mortality (HR = 1·31; 95% CI: 1·04-1·65). Particularly among patients with connective tissue, renal and psychiatric diseases, and dementia. Among females with any comorbidity, non-lymphoma deaths represented a larger proportion of all deaths, compared to males with any comorbidity. In general, more efficient lymphoma treatments need to be considered also for patients with severe comorbidity. However, among females with any comorbidity, the likelihood of non-lymphoma death was still considerable, perhaps favouring a more liberal use of a "wait and watch" approach.

Trends in the prevalence, incidence and survival of non-Hodgkin lymphoma subtypes during the 21st century - a Swedish lymphoma register study.

Non-Hodgkin lymphoma (NHL) prognosis has improved in recent years, yet the number of patients living with the diagnosis, i.e. the prevalence, has seldom been reported. The prevalence provides a measure of the burden of disease, useful for healthcare planning and to optimise resource allocation. We provide a systematic presentation of temporal trends in absolute numbers of prevalent patients by NHL subtypes, linking them to trends in incidence, survival and mortality. Patients diagnosed 2000-2016 were identified in the national Swedish lymphoma register. Incidence and mortality rates, relative survival and prevalence were estimated for NHL overall and for major clinical and morphological subtypes. Poisson regression was used to test for temporal trends. Increasing incidence and improved survival have led to a 47% increase in the five-year prevalence of NHL overall in 2016 compared to 2004. An increasing prevalence was observed for all investigated subtypes during the study period, but most notably for diffuse large B cell lymphomas among aggressive subtypes (66%), and marginal zone lymphomas among indolent subtypes (135%). This dramatic increase in NHL prevalence underscores the need to develop and evaluate alternative follow-up schemes to use resources efficiently and still ensure optimal care of lymphoma survivors.

Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer-a prospective nationwide Swedish multicenter study.

STUDY QUESTION: How efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)? SUMMARY ANSWER: In women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not. WHAT IS KNOWN ALREADY: Cryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population. STUDY DESIGN, SIZE, DURATION: A prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs. PARTICIPANTS/MATERIALS, SETTING, METHODS: After counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Using letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes = 9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P < 0.05) and embryos cryopreserved (P < 0.005), compared with conventional hCG trigger. Of 99 women who returned to fertility clinics after cancer treatment, 32 proceeded to thawing of oocytes or embryos and 10 of them had live births. The all-cause survival between the women that underwent COS and those who did not was similar and did not differ between the two groups. LIMITATIONS, REASONS FOR CAUTION: Data on tumor characteristics and estrogen receptor (ER) status were not known for all women at the time of FP counseling and planning of COS, thus protocols with letrozole have been used for both estrogen-sensitive and non-estrogen-sensitive BC. For the same reason, subsequent adjustment for ERs in the BC or tumor characteristics as potential confounders were not performed as these parameters were not available and did not influence the provision of FP through COS. WIDER IMPLICATIONS OF THE FINDINGS: The results of our study support the premise that recently introduced potential improvements to COS protocols for FP in women with BC are efficacious and safe. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Swedish Cancer Society, the Stockholm County Council, the Percy Falk Stiftelsen, Radiumhemmets Forskningsfonder, The Swedish Breast Cancer Association and Karolinska Institutet to K.A.R.W. J.B. reports grants from Amgen, AstraZeneca, Pfizer, Roche, Sanofi-Aventis and Merck, outside the submitted work, and payment from UpToDate to Asklepios Medicine HB for a chapter on BC prediction and prognostication. All the other authors have no competing interests to report.

Concordance in survival among first-degree relatives diagnosed with indolent lymphoid malignancies including chronic lymphocytic leukemia.

OBJECTIVES: To investigate concordance in survival time among first-degree relatives with lymphoid malignancies. METHODS: By linkage of national Swedish registers, we identified 66 430 patients diagnosed with a lymphoid malignancy 1958-2016 with information on first-degree relationships and follow-up until 2017. Among these, we identified pairs of first-degree relatives with any (N = 3326) or a similar (N = 690) lymphoid malignancy subtype. We defined survival in the first-degree relative as good, expected, or poor based on tertiles of deviance residuals from a multivariable Cox regression model. Next, we used Cox regression to estimate hazard ratios (HR) of death with 95% confidence intervals (CI) among patients, using the survival of their first-degree relative as exposure and adjusting for confounders. RESULTS: There was no concordance in survival among first-degree relatives with any lymphoid malignancy (HRgood  = 1.00 (reference), HRExpected  = 1.02, 95% CI: 0.89-1.17, HRPoor  = 1.12, 95% CI: 0.98-1.27, Ptrend  = .08). Among first-degree relatives with indolent lymphoma, including chronic lymphocytic leukemia, those with a first-degree relative to an expected or poor survival had worse outcome compared to those with a first-degree relative with good survival (HRExpected  = 1.44, 95% CI: 0.82-2.53, HRPoor  = 1.79, 95% CI: 1.07-3.00, Ptrend  = .03). CONCLUSION: Our results support a role of inherited factors in the outcome of indolent lymphoma, including chronic lymphocytic leukemia.

Statin use is associated with improved survival in multiple myeloma: A Swedish population-based study of 4315 patients.

Statin use has been associated with reduced cancer-specific mortality among patients with several cancer types, including multiple myeloma (MM). We aimed to further elucidate the association of statin use and dose intensity with MM survival. Using Swedish population-based national health registers, we identified all incident MM diagnoses occurring January 1, 2007 to December 31, 2013 and their drug dispensations and comorbidities. We assessed statin exposure in 6-month periods pre- and post-diagnosis, treated diagnosis as baseline for calculating survival time, and calculated hazard ratios (HR) and 95% confidence intervals (CI) of exposure-related MM-specific and all-cause mortality using Cox regression. We assessed statin exposure during the entire follow-up and risk of MM-specific mortality in a nested case-control analysis. We classified dose intensity according to American College of Cardiology/American Heart Association recommendations. We ascertained 4315 MM cases during follow-up. Statin use was associated with reduced MM-specific mortality (pre-diagnosis use multivariate-adjusted HR, 95% CI: 0.83, 0.71-0.96; 6 months post-diagnosis: 0.73, 0.60-0.89; entire follow-up: 0.65, 0.52-0.80) and (more weakly) with all-cause mortality. Intensity analyses suggested a dose-response; MM-specific mortality decreased with increasing statin intensity in all time windows (eg, 6 months post-diagnosis: low [0.76 (0.56-1.03)], medium [0.73 (0.58-0.92)], high [0.33 (0.08-1.32)] intensity). However, relatively few patients received high intensity treatment, and the trend was statistically significant only for unadjusted pre-diagnosis use. In this large population-based MM cohort, statin use was associated with improved MM-specific survival in both sexes. Randomized prospective studies are warranted to evaluate statins as adjuvant treatment in MM.

Outcome and determinants of failure to complete primary R-CHOP treatment for reasons other than non-response among patients with diffuse large B-cell lymphoma.

Patients with diffuse large B-cell lymphoma (DLBCL) who fail to complete planned treatment with R-CHOP due to toxicity are sparsely described. We investigated the extent of failure to complete treatment (six cycles or more, or three cycles + RT for patients with stage I disease) with R-CHOP for reasons unrelated to non-response, the determinants of such failure and the outcome among these patients. Three thousand one hundred and forty nine adult DLBCL patients who started primary treatment with R-CHOP were identified through the Swedish lymphoma register 2007-2014. Of these, 147 (5%) stopped prematurely after 1-3 cycles of R-CHOP for reasons unrelated to non-response, 168 (5%) after 4-5 cycles and 2639 patients (84%) completed planned treatment. Additionally, 195 (6%) patients did not complete treatment due to non-response or death before treatment end. In a multivariable logistic regression model, age > 75 years, poor performance status, extranodal disease and Charlson Comorbidity Index ≥1 were significantly associated with failure to complete planned R-CHOP treatment for other reasons than non-response. Non-completion of treatment strongly correlated with survival. Five-year overall survival for patients who received 1-3 cycles was 26% (95% CI: 19%-33%), 49% (95% CI: 41%-57%) for 4-5 cycles and 76% (74%-77%) for patients who completed treatment. Failure to complete planned R-CHOP treatment is an important clinical issue associated with inferior survival. Old age and poor performance status most strongly predict such failure. These results indicate a need for improved treatment tailoring for patients with certain baseline demographics to improve tolerability and chance for treatment completion.

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study.

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.