Risk of coronary stenosis after adjuvant radiotherapy for breast cancer.

PURPOSE: Adjuvant radiotherapy (RT) for breast cancer is associated with an increased risk of ischemic heart disease. We examined the risk of coronary artery stenosis in a large cohort of women with breast cancer receiving adjuvant RT. METHODS: A cohort of women diagnosed with breast cancer between 1992 and 2012 in three Swedish health care regions (n = 57,066) were linked to the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) to identify women receiving RT who subsequently underwent a percutaneous coronary intervention (PCI) due to coronary stenosis. Cox regression analyses were performed to examine risk of a coronary intervention and competing risk analyses were performed to calculate cumulative incidence. RESULTS: A total of 649 women with left-sided breast cancer and 494 women with right-sided breast cancer underwent a PCI. Women who received left-sided RT had a significantly higher risk of a PCI in the left anterior descending artery (LAD) compared to women who received right-sided RT, hazard ratio (HR) 1.44 (95% confidence interval [CI] 1.21-1.77, p < 0.001). For the proximal, mid, and distal LAD, the HRs were 1.60 (95% CI 1.22-2.10), 1.38 (95% CI 1.07-1.78), and 2.43 (95% CI 1.33-4.41), respectively. The cumulative incidence of coronary events at 25 years from breast cancer diagnosis were 7.0% in women receiving left-sided RT and 4.4% in women receiving right-sided RT. CONCLUSION: Implementing and further developing techniques that lower cardiac doses is important in order to reduce the risk of long-term side effects of adjuvant RT for breast cancer.

Serum inflammatory markers in relation to prostate cancer severity and death in the Swedish AMORIS study.

Inflammation is a well-documented driver of cancer development and progression. However, little is known about its role in prostate carcinogenesis. Thus, we examined the association of C-reactive protein (CRP), haptoglobin, albumin and white blood cells (WBC) with prostate cancer (PCa) severity (defined by PCa risk category and clinicopathological characteristics) and progression (defined by PCa death). We selected 8,471 Swedish men with newly diagnosed PCa who had exposure measurements taken approximately 14 years prior to diagnosis. We calculated odds ratio (OR) and 95% confidence interval (CI) for the associations between the inflammatory markers and PCa severity using logistic regression, while Cox proportional hazard regression was used for the associations with overall and PCa death. Serum CRP levels were associated with increased odds of high risk and metastatic PCa, and high PSA levels (≥20 µg/L) (OR: 1.29; 95% CI: 1.06-1.56, 1.32; 1.05-1.65 and 1.51; 1.26-1.81, respectively). Similarly, higher haptoglobin levels were associated with increased odds of metastatic PCa, high PSA level and possibly high grade PCa (1.38; 1.10-1.74, 1.50; 1.17-1.93 and 1.25; 1.00-1.56, respectively). Albumin was positively associated with Gleason 4 + 3 tumour (1.38; 1.02-1.86) and overall death (HRunit increase in log : 1.60; 95% CI: 1.11-2.30), but inversely associated with high risk PCa and high PSA levels (≥20 µg/L) (0.71; 0.56-0.89 and 0.72; 0.5 9-0.90). WBC was associated with increased odds of T3-T4 PCa. Except for albumin, none of these markers were associated with PCa death or overall death. Systemic inflammation as early as 14 years prior to diagnosis may influence prostate cancer severity.

Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study.

Background: Old age at prostate cancer diagnosis has been associated with poor prognosis in several studies. We aimed to investigate the association between age at diagnosis and prognosis, and if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. Patients and methods: We conducted a nation-wide cohort study including 121 392 Swedish men aged 55-95 years in Prostate Cancer data Base Sweden 3.0 diagnosed with prostate cancer in 1998-2012 and followed for prostate cancer death through 2014. Data were available on age, stage, grade, prostate-specific antigen (PSA)-level, mode of detection, comorbidity, educational level and primary treatment. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: With increasing age at diagnosis, men had more comorbidity, fewer PSA-detected cancers, more advanced cancers and were less often treated with curative intent. Among men with high-risk or regionally metastatic disease, the proportion of men with unknown M stage was higher among old men versus young men. During a follow-up of 751 000 person-years, 23 649 men died of prostate cancer. In multivariable Cox-regression analyses stratified by treatment, old age at diagnosis was associated with poorer prognosis among men treated with deferred treatment (HRage 85+ versus 60-64: 7.19; 95% CI: 5.61-9.20), androgen deprivation therapy (HRage 85+ versus 60-64: 1.72; 95% CI: 1.61-1.84) or radical prostatectomy (HRage 75+ versus 60-64: 2.20; 95% CI: 1.01-4.77), but not radiotherapy (HRage 75+ versus 60-64: 1.08; 95% CI: 0.76-1.53). Conclusion: Our findings argue against a strong inherent effect of age on risk of prostate cancer death, but indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment.

Determinants of non-adherence to adjuvant endocrine treatment in women with breast cancer: the role of comorbidity.

PURPOSE: To examine factors associated with non-adherence during 5 years of endocrine treatment, including the possible influence of comorbidity burden and specific medical conditions. METHODS: From all women diagnosed with stage I-III, ER-positive breast cancer in Stockholm-Gotland, Uppsala-Örebro and Northern Sweden between 2006 and 2009, we included 4645 women who had at least one dispensation of tamoxifen or aromatase inhibitors (AIs) and 5 years of follow-up without distant recurrence. A medical possession ratio of < 80% was used to define non-adherence. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of non-adherence. RESULTS: During follow-up, 977 (21%) women became non-adherents. Non-adherence was associated with greater comorbidity burden assessed by Charlson comorbidity index (CCI) during follow-up (OR 1.43; 95% CI 1.08-1.88 for ≥ 2 additional scores compared to 0), pre-diagnostic HRT use (OR 1.99; 1.58-2.49), not married (OR 1.42; 1.23-1.64), high educational level (OR 1.25; 1.02-1.53 compared to lowest level), and use of symptom-relieving drugs. HER-2 positivity (OR 0.61; 0.45-0.81) and adjuvant chemotherapy (OR 0.42; 0.35-0.52) were associated with lower odds of non-adherence. Similar patterns were observed for the presence of lymph node metastasis, higher tumour grade, and use of AIs compared to tamoxifen. Myocardial infarction and chronic pulmonary disease was suggested as leading conditions associated with non-adherence in women with increasing CCI. CONCLUSION: We identified subgroups of women with breast cancer at increased risk of non-adherence. Our findings related to comorbidity suggest the importance of focusing on the presence of specific co-existing conditions when monitoring adherence.

Shoulder and Lower Back Joint Reaction Forces in Seated Double Poling.

Overuse injuries in the shoulders and lower back are hypothesized to be common in cross-country sit-skiing. Athletes with reduced trunk muscle control mainly sit with the knees higher than the hips (KH). To reduce spinal flexion, a position with the knees below the hips (KL) was enabled for these athletes using a frontal trunk support. The aim of the study was to compare the shoulder joint (glenohumeral joint) and L4-L5 joint reactions of the KL and KH sitting positions. Five able-bodied female athletes performed submaximal and maximal exercise tests in the sitting positions KL and KH on a ski ergometer. Measured pole forces and 3-dimensional kinematics served as input for inverse-dynamics simulations to compute the muscle forces and joint reactions in the shoulder and L4-L5 joint. This was the first musculoskeletal simulation study of seated double poling. The results showed that the KH position was favorable for higher performance and decreased values of the shoulder joint reactions for female able-bodied athletes with full trunk control. The KL position was favorable for lower L4-L5 joint reactions and might therefore reduce the risk of lower back injuries. These results indicate that it is hard to optimize both performance and safety in the same sit-ski.

A latent class model for competing risks.

Survival data analysis becomes complex when the proportional hazards assumption is violated at population level or when crude hazard rates are no longer estimators of marginal ones. We develop a Bayesian survival analysis method to deal with these situations, on the basis of assuming that the complexities are induced by latent cohort or disease heterogeneity that is not captured by covariates and that proportional hazards hold at the level of individuals. This leads to a description from which risk-specific marginal hazard rates and survival functions are fully accessible, 'decontaminated' of the effects of informative censoring, and which includes Cox, random effects and latent class models as special cases. Simulated data confirm that our approach can map a cohort's substructure and remove heterogeneity-induced informative censoring effects. Application to data from the Uppsala Longitudinal Study of Adult Men cohort leads to plausible alternative explanations for previous counter-intuitive inferences on prostate cancer. The importance of managing cardiovascular disease as a comorbidity in women diagnosed with breast cancer is suggested on application to data from the Swedish Apolipoprotein Mortality Risk Study. Copyright © 2017 John Wiley & Sons, Ltd.

Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors.

BACKGROUND: High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. PATIENTS AND METHODS: Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤ 1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population. RESULTS: We enrolled 43 male patients, median age 30 (20-49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1-5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm(+)) (N = 8), PRm(-) (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9-84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively. CONCLUSIONS: Sequential bevacizumab/GemDMC-bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population. CLINICALTRIALSGOV: NCT00936936.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Mammography casting-type calcification and risk of local recurrence in DCIS: analyses from a randomised study.

BACKGROUND: We studied the association between mammographic calcifications and local recurrence in the ipsilateral breast. METHODS: Case-cohort study within a randomised trial of radiotherapy in breast conservation for ductal cancer in situ of the breast (SweDCIS). We studied mammograms from cases with an ipsilateral breast event (IBE) and from a subcohort randomly sampled at baseline. Lesions were classified as a density without calcifications, architectural distortion, powdery, crushed stone-like or casting-type calcifications. RESULTS: Calcifications representing necrosis were found predominantly in younger women. Women with crushed stone or casting-type microcalcifications had higher histopathological grade and more extensive disease. The relative risk (RR) of a new IBE comparing those with casting-type calcifications to those without calcifications was 2.10 (95% confidence interval (CI) 0.92-4.80). This risk was confined to in situ recurrences; the RR of an IBE associated with casting-type calcifications on the mammogram adjusted for age and disease extent was 16.4 (95% CI 2.20-140). CONCLUSION: Mammographic appearance of ductal carcinoma in situ of the breast is prognostic for the risk of an in situ IBE and may also be an indicator of responsiveness to RT in younger women.

Patterns of metastasis in women with metachronous contralateral breast cancer.

BACKGROUND: The understanding of metastatic patterns after metachronous contralateral breast cancer (CBC) may help determine the biological nature of CBC. METHODS: A cohort of 8478 women with breast cancer treated at Guy's and St Thomas' NHS Foundation Trust between 1975 and 2006 were studied. Organ-specific 5-year cumulative incidence and incidence rate ratios were assessed for women diagnosed with unilateral breast cancer (UBC), CBC within 5 years and CBC more than 5 years of the initial diagnosis. RESULTS: Women diagnosed with CBC within 5 years had a higher incidence of metastases in all organs compared with UBC. Women with a short interval time to CBC developed metastasis more rapidly and were more likely to develop visceral and distant cutaneous metastases compared with bone metastasis. CONCLUSION: These findings explain poor prognosis of women with early occurring CBC and suggest that some of these CBCs are indicators of aggressive and/or systemic disease.

Anti-androgen prescribing patterns, patient treatment adherence and influencing factors; results from the nationwide PCBaSe Sweden.

PURPOSE: Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment. METHODS: A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose. RESULTS: First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to ≥80 %. Age above 75 years and less severe disease were both negatively associated with adherence. CONCLUSIONS: Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

Estimation of muscular metabolic power in two different cross-country sit-skiing sledges using inverse-dynamics simulation.

The aim of this study was to estimate and compare the muscular metabolic power produced in the human body using musculoskeletal inverse-dynamics during cross-country sit-skiing. Two sitting positions were adapted for athletes with reduced trunk and hip muscle control, knee low with frontal trunk support (KL-fix), and knee high (KH). Five female national class able-bodied cross-country skiers performed submaximal and maximal exercise in both sitting positions, while recording 3-D kinematics, pole forces, electromyography and respiratory variables. Simulations were performed from these experimental results and muscular metabolic power was computed. The main part of the muscle metabolic power was produced in the upper limbs for both sitting positions, but KH produced more muscle metabolic power in lower limbs and trunk during maximal intensity. KH was also more efficient, utilizing less muscular metabolic power during submaximal intensities, relatively less power in the upper limbs and more power in the trunk, hip and lower limb muscles. This implies that sitting position KH is preferable for high power output when using able-bodied simulation models. This study showed the potential of using musculoskeletal simulations to improve the understanding of how different equipment design and muscles contribute to performance.

Colorectal cancer screening with fecal immunochemical testing or primary colonoscopy: An analysis of health equity based on a randomised trial.

Background: We have addressed health equity attained by fecal immunochemical testing (FIT) and primary colonoscopy (PCOL), respectively, in the randomised controlled screening trial SCREESCO conducted in Sweden. Methods: We analysed data on the individuals recruited between March 2014, and March 2020, within the study registered with ClinicalTrials.gov, NCT02078804. Swedish population registry data on educational level, household income, country of birth, and marital status were linked to each 60-year-old man and woman who had been randomised to two rounds of FIT 2 years apart (n = 60,123) or once-only PCOL (n = 30,390). Furthermore, we geo-coded each study individual to his/her residential area and assessed neighbourhood-level data on deprivation, proportion of non-Western immigrants, population density, and average distance to healthcare center for colonoscopy. We estimated adjusted associations of each covariate with the colonoscopy attendance proportion out of all invited to respective arms; ie, the preferred outcome for addressing health equity. In the FIT arm, the test uptake and the colonoscopy uptake among the test positives were considered as the secondary outcomes. Findings: We found a marked socioeconomic gradient in the colonoscopy attendance proportion in the PCOL arm (adjusted odds ratio [95% credibility interval] between the groups categorised in the highest vs. lowest national quartile for household income: 2·20 [2·01-2·42]) in parallel with the gradient in the test uptake of the FIT × 2 screening (2·08 [1·96-2·20]). The corresponding gradient in the colonoscopy attendance proportion out of all invited to FIT was less pronounced (1·29 [1·16-1·42]), due to higher proportions of FIT positives in socioeconomically disadvantaged groups. Interpretation: The unintended risk of exacerbating inequalities in health by organised colorectal cancer screening may be higher with a PCOL strategy than a FIT strategy, despite parallel socioeconomic gradients in uptake. Funding: This work was supported by the Swedish Cancer Society under Grant 20 0719. CB and US provided economic support from the Swedish Research Council for Health, Working life, and Welfare under Grant 2020-00962.

Completeness of case ascertainment and survival time error in English cancer registries: impact on 1-year survival estimates.

BACKGROUND: It has been suggested that cancer registries in England are too dependent on processing of information from death certificates, and consequently that cancer survival statistics reported for England are systematically biased and too low. METHODS: We have linked routine cancer registration records for colorectal, lung, and breast cancer patients with information from the Hospital Episode Statistics (HES) database for the period 2001-2007. Based on record linkage with the HES database, records missing in the cancer register were identified, and dates of diagnosis were revised. The effects of those revisions on the estimated survival time and proportion of patients surviving for 1 year or more were studied. Cases that were absent in the cancer register and present in the HES data with a relevant diagnosis code and a relevant surgery code were used to estimate (a) the completeness of the cancer register. Differences in survival times calculated from the two data sources were used to estimate (b) the possible extent of error in the recorded survival time in the cancer register. Finally, we combined (a) and (b) to estimate (c) the resulting differences in 1-year cumulative survival estimates. RESULTS: Completeness of case ascertainment in English cancer registries is high, around 98-99%. Using HES data added 1.9%, 0.4% and 2.0% to the number of colorectal, lung, and breast cancer registrations, respectively. Around 5-6% of rapidly fatal cancer registrations had survival time extended by more than a month, and almost 3% of rapidly fatal breast cancer records were extended by more than a year. The resulting impact on estimates of 1-year survival was small, amounting to 1.0, 0.8, and 0.4 percentage points for colorectal, lung, and breast cancer, respectively. INTERPRETATION: English cancer registration data cannot be dismissed as unfit for the purpose of cancer survival analysis. However, investigators should retain a critical attitude to data quality and sources of error in international cancer survival studies.

Can results from clinical trials be generalized?

Randomized clinical trials are powerful tools to refute old prejudices and establish new therapeutic regimes. We propose that they should be afforded a more widespread application in modern clinical medicine.

Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy.

The complete coding region of the p53 gene was sequenced from 316 consecutively presented breast cancers, of which 97 were lymph node positive and 206 were node negative. The p53 status was related to prognosis and effect of adjuvant therapy. In all, 69 individual mutations, 29 in node-positive tumours, were demonstrated throughout the whole coding sequence. The mutation sites were partly different for node-positive and node-negative patients. p53 mutations in the evolutionary conserved regions II and V were associated with significantly worse prognosis. Adjuvant systemic therapy, especially with tamoxifen, along with radiotherapy seemed to be of less value to p53 mutation- and lymph node-positive tumours.

Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort.

A large proportion of women with lymph node negative breast cancer do not benefit from chemotherapy. Proliferation markers have been shown to recognize patients at high risk for recurrence. The Ki67 protein has recently been included in the St Gallen guidelines. The authors investigated the prognostic importance of cyclin B1 in node negative breast cancer and included a study of reproducibility. In a population-based case-control study, 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death were defined as controls. Inclusion criteria were tumor size

Radiation to supraclavicular and internal mammary lymph nodes in breast cancer increases the risk of stroke.

The aim of this study was to assess whether adjuvant treatment of breast cancer (BC) affects the risk of stroke, and to explore radiation targets and fraction doses regarding risk and location of stroke. In a Swedish BC cohort diagnosed during 1970-2003, we carried out a nested case-control study of stroke after BC, with relevant details extracted from medical records. The odds ratio (OR) for radiotherapy (RT) vs that of no RT did not differ between cases and controls (OR=0.85; confidence interval, CI=0.6-1.3). Radiotherapy to internal mammary chain (IMC) and supraclavicular (SCL) lymph nodes vs that of no RT was associated with a higher, although not statistically significant, risk of stroke (OR=1.3; CI=0.8-2.2). In a pooled analysis, RT to IMC and SCL vs the pooled group of no RT and RT to breast/chest wall/axilla (but not IMC and SCL), showed a significant increase of stroke (OR=1.8; CI=1.1-2.8). There were no associations between cancer laterality, targets of RT, and location of stroke. The radiation targets, IMC and SCL, showed a statistically significant trend for an increased risk of stroke with daily fraction dose. Our finding of a target-specific increased risk of stroke and a dose-response relationship for daily fraction dose, indicate that there may be a causal link between RT to the IMC and SCL and risk of stroke.