Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia ...(ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to ...several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO.
We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO.
Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval CI = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77).
In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.
Our objective was to investigate effects of an oral nutritional supplement containing n-3 polyunsaturated fatty acids (FAs) on quality of life, performance status, handgrip strength and physical ...activity in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment.
In a double-blind experiment, 40 patients with stage III NSCLC were randomised to receive 2 cans/day of a protein- and energy-dense oral nutritional supplement containing n-3 polyunsaturated FAs (2.02 g eicosapentaenoic acid+0.92 g docosahexaenoic acid/day) or an isocaloric control supplement, during multimodality treatment. Quality of life, Karnofsky Performance Status, handgrip strength and physical activity (by wearing an accelerometer) were assessed. Effects of intervention were analysed by generalised estimating equations. P-values <0.05 were regarded as statistically significant.
The intervention group reported significantly higher on the quality of life parameters, physical and cognitive function (B=11.6 and B=20.7, P<0.01), global health status (B=12.2, P=0.04) and social function (B=22.1, P=0.04) than the control group after 5 weeks. The intervention group showed a higher Karnofsky Performance Status (B=5.3, P=0.04) than the control group after 3 weeks. Handgrip strength did not significantly differ between groups over time. The intervention group tended to have a higher physical activity than the control group after 3 and 5 weeks (B=6.6, P=0.04 and B=2.5, P=0.05).
n-3 Polyunsaturated FAs may beneficially affect quality of life, performance status and physical activity in patients with NSCLC undergoing multimodality treatment.
BACKGROUND The risk of recurrent oncological disease due to the reintroduction of cancer cells via autotransplantation of cryopreserved ovarian tissue is unknown. METHODS A systematic review of ...literature derived from MEDLINE, EMBASE and the Cochrane Library was conducted. Studies on follow-up after autotransplantation; detection of cancer cells in ovarian tissue from oncological patients by histology, polymerase chain reaction or xenotransplantation; and epidemiological data on ovarian metastases were included. RESULTS A total of 289 studies were included. Metastases were repeatedly detected in ovarian tissue obtained for cryopreservation purposes from patients with leukaemia, as well as in one patient with Ewing sarcoma. No metastases were detected in ovarian tissue from lymphoma and breast cancer patients who had their ovarian tissue cryopreserved. Clinical studies indicated that one should be concerned about autotransplantation safety in patients with colorectal, gastric and endometrial cancer. For patients with low-stage cervical carcinoma, clinical data were relatively reassuring, but studies focused on the detection of metastases were scarce. Oncological recurrence has been described in one survivor of cervical cancer and one survivor of breast cancer who had their ovarian tissue autotransplanted, although these recurrences may not be related to the transplantation. CONCLUSIONS It is advisable to refrain from ovarian tissue autotransplantation in survivors of leukaemia. With survivors of all other malignancies, current knowledge regarding the safety of autotransplantation should be discussed. The most reassuring data regarding autotransplantation safety were found for lymphoma patients.
Purpose
Considering the comparable prognosis in early-stage breast cancer after breast-conserving therapy (BCT) and mastectomy, quality of life should be a focus in treatment decision(s). We ...retrospectively collected PROs and analyzed differences per type of surgery delivered. We aimed to obtain reference values helpful in shared decision-making.
Patients and Methods
pTis-T3N0-3M0 patients operated between January 2005 and September 2016 were eligible if: (1) no chemotherapy was administered < 6 months prior to enrolment, and (2) identical surgeries were performed in case of bilateral surgery. After consent, EQ-5D-5L, EORTC-QLQ-C30/BR23, and BREAST-Q were administered. PROs were evaluated per baseline characteristics using multivariable linear regression models. Outcomes were compared for different surgeries as well as for primary (PBC) and second primary or recurrent (SBC) breast cancer patients using analyses of variance (ANOVAs).
Results
The response rate was 68%. PROs in 612 PBC patients were comparable to those in 152 SBC patients. Multivariable analyses showed increasing age to be associated with lower “physical functioning”
β
− 0.259,
p
< 0.001 and “sexual functioning”
β
− 0.427,
p
< 0.001, and increasing time since surgery with less “fatigue”
β
− 1.083,
p
< 0.001. Mastectomy
β
− 13.596,
p
= 0.003 and implant reconstruction
β
− 13.040,
p
= 0.007 were associated with lower “satisfaction with breast” scores than BCT. Radiation therapy was associated with lower satisfaction scores than absence of radiotherapy.
Discussion
PRO scores were associated with age, time since surgery, type of surgery, and radiation therapy in breast cancer patients. The scores serve as a reference value for different types of surgery in the study population and enable prospective use of PROs in shared decision-making.
BACKGROUND
Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.
METHODS
We identified a nationwide historic cohort of 19 146 women who received IVF ...treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997–1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group.
RESULTS
After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16–2.56. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62–6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25–14.33 and 2.14; 95% CI = 1.07–4.25, respectively, adjusted for age, parity and subfertility cause).
CONCLUSIONS
Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.
Background: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the ...basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history. Methods: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates. Results: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk. Conclusions: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families.
Despite much debate, there is little evidence on consequences of consent procedures for residual tissue use. Here, we investigated these consequences for the availability of residual tissue for ...medical research, clinical practice, and patient informedness.
We conducted a randomised clinical trial with three arms in six hospitals. Participants, patients from whom tissue had been removed for diagnosis or treatment, were randomised to one of three arms: informed consent, an opt-out procedure with active information provision (opt-out plus), and an opt-out procedure without active information provision. Participants received a questionnaire six weeks post-intervention; a subsample of respondents was interviewed. Health care providers completed a pre- and post-intervention questionnaire. We assessed percentage of residual tissue samples available for medical research, and patient and health care provider satisfaction and preference. Health care providers and outcome assessors could not be blinded.
We randomised 1,319 patients, 440 in the informed consent, 434 in the opt-out plus, and 445 in the opt-out arm; respectively 60.7%, 100%, and 99.8% of patients' tissue samples could be used for medical research. Of the questionnaire respondents (N = 224, 207, and 214 in the informed consent, opt-out plus, and opt-out arms), 71%, 69%, and 31%, respectively, indicated being (very) well informed. By questionnaire, the majority (53%) indicated a preference for informed consent, whereas by interview, most indicated a preference for opt-out plus (37%). Health care providers (N = 35) were more likely to be (very) satisfied with opt-out plus than with informed consent (p = 0.002) or opt-out (p = 0.039); the majority (66%) preferred opt-out plus.
We conclude that opt-out with information (opt-out plus) is the best choice to balance the consequences for medical research, patients, and clinical practice, and is therefore the most optimal consent procedure for residual tissue use in Dutch hospitals.
Dutch Trial Register NTR2982.
The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of ...gonadal function.
TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3–20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function.
In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, 95% confidence interval (CI) 1.5–3.3 compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels <15 nmol/l (22%) have an increased risk of the MS (OR 4.1, 95% CI 1.8–9.3).
The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.
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