Survivorship in Hodgkin lymphoma : childbearing and treatment-related disease

Cancer is often considered a disease with, historically, poor survival that affects middle-aged and elderly individuals. Hodgkin lymphoma (HL) is a lymphatic malignancy that affects both young and old individuals, with the age-specific incidence curve having its first peak at ages 20-30 years. As survival has improved substantially over the last decades, there is an increasing number of survivors – some still at a young age. The primary purpose of this thesis was to address issues related to childbearing and treatment-associated disease among HL survivors. As a means to investigate these issues, novel statistical methods were developed and applied. Childbearing in relation to HL Some HL survivors will be at the beginning, or in the midst, of their childbearing years. Both pregnancy and HL are associated with changes to the immune system, making it plausible that pregnancy could affect the progression of the disease. Study I in this thesis aimed to answer if pregnancy affects the risk of relapse among female patients in remission from HL. Ever since the introduction of radio- and chemotherapy with the possibility to cure HL, the negative effects of therapy on fertility have been a concern. Contemporary treatments are believed to be less gonadotoxic than those previously used, but few studies have compared childbearing potential between the main treatment regimens administered today (ABVD and BEACOPP) in a real-world setting. In Study II, temporal trends in childbearing among female HL patients (of childbearing ages) were investigated, within groups of treatments, and in comparison with the general population. Both studies utilized a cohort of women diagnosed between 1992 and 2009, at ages 18-40 years, for whom detailed information on relapse as well as patient and disease characteristics was available. For the purpose of comparing childbirth rates with the general population, HL patients were individually matched to HL-free comparators. Childbirth rates were studied separately within two time windows during follow-up: 0-3 years and 3-7 years, and cumulative probability of childbirth was calculated in the presence of the competing risks of death and relapse. No evidence to support the hypothesis of pregnancy-associated relapse was found. However, since the absolute risk of relapse is at its highest levels during the first 2-3 years after diagnosis, female HL patients could, if possible, be advised to delay childbearing to avoid co-occurence. Childbearing potential improved over calendar time, reflecting reduced toxicity and changes in counseling. Women treated during recent years had childbirth potential in line with that of matched comparators three years after diagnosis. Even women treated with BEACOPP, the most gonadotoxic chemotherapy, had an increasing cumulative probability of having children after HL. Importantly, no women had children after a relapse within the first seven years af- ter diagnosis, which motivates a need for fertility advice and counseling at time of HL diagnosis. Treatment-related disease Late effects from cancer therapy are becoming increasingly important to quantify as the number of cancer survivors grows. Chemo- and radiotherapy used to treat HL increases the risk of cardio- and cerebrovascular diseases, and secondary malignancies (SMs). In Study III, excess incidence of diseases of the circulatory system (DCS) among HL patients was investigated to describe temporal trends in DCS morbidity attributable to HL and its treatment. Data on patients diagnosed with HL between 1985 and 2013 at ages 18-80 years, for whom information on inpatient DCS records was available, was used. Relative survival methods were applied to estimate excess incidence rates indirectly from the observed and expected rates of DCS. Cumulative excess incidence of DCS was calculated in the presence of competing risks. The treatment-related incidence of DCS declined between the mid-1980s and mid-1990s, after which no substantial improvements were observed. The risk of a treatment-related DCS persists for up to 10 years among patients who completed their treatment in the new millennium. When studying late effects it is important to attempt to capture the additional disease incidence associated with cancer treatment. Additionally, to gain insight in real-life risks, it is of interest to study not only time to first event, but continue to follow patients as they experience different types of late effects before reaching an absorbing state. Doing both of these simultaneously requires estimating excess transition rates to transient states in a multi-state model framework, for which no methods have existed. Study IV suggested a way to achieve this, using a recently developed simulation strategy to predict transition probabilities. As an illustrative example, data from Study III on HL patients and DCS incidence was used. Combining methods from relative survival with the multi-state framework enables investigation of complex patient pathways and can be useful for several applications related to survivorship among cancer patients

Exposure to oestrogen and risk of anastomotic leakage after colorectal cancer surgery - A clue to the different leak rates in men and women

Background Colorectal anastomotic leakage is consistently more common in men, regardless of tumour location. This fact is largely unexplained but might be a consequence of biological differences including hormonal exposure and not only related to anatomy. Methods This was a retrospective, nationwide registry-based observational study of post-menopausal women operated for colorectal cancer with an anastomosis between 2007 and 2016. Hormonal exposure before surgery, as defined by prescribed drugs affecting oestrogen levels, was related to postoperative anastomotic leakage, using mixed-effects logistic regression models with adjustment for confounding. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were derived. In addition, separate estimates according to tumour location were computed, and a sensitivity analysis excluding topical oestrogen hormone exposure was conducted. Results Some 16,535 post-menopausal women were included, of which 16.2% were exposed to drugs increasing oestrogen levels before surgery. In this exposed group compared to the unexposed, leak rates were 3.1 and 3.8%, respectively. After adjustment, a reduction of anastomotic leakage in the exposed group was detected (OR: 0.77; 95% CI: 0.59-0.99). This finding was largely attributed to the rectal cancer subgroup (OR: 0.55; 95% CI: 0.36-0.85), while the exclusion of topical oestrogen drugs further reduced the estimates of the main analysis (OR: 0.63; 95% CI: 0.38-1.02). Conclusions Anastomotic leakage rates are lower in women exposed to hormone replacement therapy before surgery for colorectal cancer, which might explain some of the difference in leak rates between men and women, especially regarding rectal cancer.Peer reviewe

A multi-state 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. Multi-state 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, by allowing is to directly quantify the excess risk. This paper proposes a combination of these two frameworks, providing one approach to address (1)-(3). Using recently developed methods in multi-state modeling, we incorporate estimation of excess hazards into a multi-state 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

Infiltration of CD163-, PD-L1-and FoxP3-positive cells adversely affects outcome in patients with mantle cell lymphoma independent of established risk factors

We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3(+) T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1 center dot 97, 95% confidence interval (CI) 1 center dot 18-3 center dot 25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163(+) cells (continuously, HR 1 center dot 51, 95% CI 1 center dot 03-2 center dot 23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3(+) cells (HR 3 center dot 22, 95% CI 1 center dot 40-7 center dot 43) and CD163(+) cells (HR 6 center dot 09, 95% CI 1 center dot 84-20 center dot 21), independent of sex and MIPI. When combined a higher frequency of CD163(+) macrophages and PD-L1(+) cells or high CD163(+) macrophages and FoxP3(+) regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age.Peer reviewe

Маркетинг инноваций как инструмент активизации трансфера знаний

Модель «Тройная спираль» (Triple Helix Model (THM)), основанная на исследовании сложного взаимодействия университетов, бизнеса и власти, является современной моделью развития инновационных систем. В модели ТНМ ведущее значение отводится университетам, которые превращаются в предпринимательские университеты и через собственные каналы для трансфера знаний применяют знания на практике и вкладывают результаты в новые образовательные дисциплины. Университеты все чаще становятся залогом успешного экономического развития региона

Exposure to oestrogen and risk of anastomotic leakage after colorectal cancer surgery - A clue to the different leak rates in men and women

Background Colorectal anastomotic leakage is consistently more common in men, regardless of tumour location. This fact is largely unexplained but might be a consequence of biological differences including hormonal exposure and not only related to anatomy. Methods This was a retrospective, nationwide registry-based observational study of post-menopausal women operated for colorectal cancer with an anastomosis between 2007 and 2016. Hormonal exposure before surgery, as defined by prescribed drugs affecting oestrogen levels, was related to postoperative anastomotic leakage, using mixed-effects logistic regression models with adjustment for confounding. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were derived. In addition, separate estimates according to tumour location were computed, and a sensitivity analysis excluding topical oestrogen hormone exposure was conducted. Results Some 16,535 post-menopausal women were included, of which 16.2% were exposed to drugs increasing oestrogen levels before surgery. In this exposed group compared to the unexposed, leak rates were 3.1 and 3.8%, respectively. After adjustment, a reduction of anastomotic leakage in the exposed group was detected (OR: 0.77; 95% CI: 0.59-0.99). This finding was largely attributed to the rectal cancer subgroup (OR: 0.55; 95% CI: 0.36-0.85), while the exclusion of topical oestrogen drugs further reduced the estimates of the main analysis (OR: 0.63; 95% CI: 0.38-1.02). Conclusions Anastomotic leakage rates are lower in women exposed to hormone replacement therapy before surgery for colorectal cancer, which might explain some of the difference in leak rates between men and women, especially regarding rectal cancer.Peer reviewe

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

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

Sex differences in metastatic surgery following diagnosis of synchronous metastatic colorectal cancer

The aim was to investigate gender differences in the likelihood to receive metastatic surgery, and to compare overall survival between men and women, among patients with synchronous metastatic colorectal cancer (mCRC) in a population-based setting. All Swedish adult patients diagnosed with synchronous mCRC in 2007-2016 were identified using the nationwide colorectal cancer database (CRCBaSe). Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression, comparing the odds of receiving treatment. The Kaplan-Meier method was used to calculate survival proportions and Cox regression models to estimate hazard ratios (HRs) and 95% CIs of all-cause mortality rates. All multivariable models were adjusted for age, ASA score, Charlson comorbidity index, year of diagnosis, location of primary tumor and single or multiple metastatic locations. A total of 12 201 patients met the study criteria. Women received 23% less metastatic surgery for mCRC (adjusted OR = 0.77, CI:0.69-0.86) and experienced a slightly higher mortality following diagnosis (adjusted HR = 1.09, CI:1.05-1.14). In analyses restricted to patients who received metastatic surgery, no significant differences in mortality were found. In conclusion, this population-based study showed that women less often received metastatic surgery of mCRC and experienced slightly higher all-cause mortality compared with men. The differences persisted despite adjustments of patient and cancer characteristics. Gender differences in receiving treatment are unacceptable if the underlying explanation cannot be motivated. Further studies are needed to understand if the differences are based on sex (i.e., biology) or gender (including clinically unmotivated differences in treatment approach)