NTHL1 is a recessive cancer susceptibility gene.

In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482-4101 BC patients and in 1273-3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90-290], P = 6.7 × 10-5) and a low risk for heterozygous women (OR = 1.39 [1.18-1.64], P = 7.8 × 10-5). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.

A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients.

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

The relationship between anger regulation, mood, pain, and pain-related disability in women treated for breast cancer.

OBJECTIVE: Anger, depressive symptoms, and anxiety are known reactions to cancer and suggested to modulate pain experience. We examined the association between anger regulation, mood, and pain in 952 breast cancer patients followed for 3 years. METHODS: Preoperatively, the patients completed questionnaires about depressive symptoms (BDI), state anxiety (STAI), anger regulation (STAXI-2), and pains in the surgical and other areas. Experimental pain sensitivity was tested. In the follow-up, BDI and STAI were assessed at 1 and at 6 months and at 1, 2, and 3 years after surgery. Pain in the surgical area was evaluated during the first 7 days and at 1 and 3 years after surgery. Pain-related disability was assessed at 3 years after surgery. Latent profile analyses were performed to identify mood profiles, and regression analyses to find independent predictors for mood and pain variables. RESULTS: Anger inhibition and pain had associations with ongoing depressive symptoms and anxiety. Pain-related disability was associated with high anxiety at a hazard ratio (HR) of 2.24 (95% CI, 1.17-4.27), with older age (HR 1.07, 95% CI, 1.01-1.13), and with pain in the surgical area (HR 3.04, 95% CI, 2.41-3.85), but not with anger variables. Any relationship between anger regulation and pain intensity disappeared after controlling for age and mood. CONCLUSIONS: Different forms of pain are important to recognize and treat to support breast cancer patients' psychological well-being. Anger inhibition could be a target for psychotherapeutic intervention, to help with ongoing mood symptoms. The relationship between anger regulation and pain is not straightforward.

Cancer Patients' Symptom Burden and Health-related Quality of Life (HRQoL) at Tertiary Cancer Center from 2006 to 2013: A Cross-sectional Study.

BACKGROUND/AIM: To observe changes in symptoms and health-related quality of life (HRQoL) over 7 years among cancer patients at different stages of the disease. PATIENTS AND METHODS: This prospective cross-sectional study at the Helsinki University Hospital Cancer Center, was carried out in 2006 and repeated in 2013. All participants filled in the EORTC-QLQ-C30 questionnaire. RESULTS: Altogether, 581 patients responded (49% in 2006 and 54% in 2013). The disease was local in 51% and advanced in 49% of patients. The HRQoL was significantly lower, except for emotional and cognitive functions, and the symptom burden more severe in advanced cancer. The most prevalent symptoms were fatigue (93% and 85%; moderate/severe 22% and 9%), pain (65% and 47%; moderate/severe 16% and 5%), and insomnia (64% and 60%; moderate/severe 20 and 21%), respectively. No changes in HRQoL or symptoms were found at 7 years. CONCLUSION: There is a need for early integrated palliative care to improve HRQoL during cancer treatments.

Machine-learning-derived classifier predicts absence of persistent pain after breast cancer surgery with high accuracy.

BACKGROUND: Prevention of persistent pain following breast cancer surgery, via early identification of patients at high risk, is a clinical need. Supervised machine-learning was used to identify parameters that predict persistence of significant pain. METHODS: Over 500 demographic, clinical and psychological parameters were acquired up to 6 months after surgery from 1,000 women (aged 28-75 years) who were treated for breast cancer. Pain was assessed using an 11-point numerical rating scale before surgery and at months 1, 6, 12, 24, and 36. The ratings at months 12, 24, and 36 were used to allocate patents to either "persisting pain" or "non-persisting pain" groups. Unsupervised machine learning was applied to map the parameters to these diagnoses. RESULTS: A symbolic rule-based classifier tool was created that comprised 21 single or aggregated parameters, including demographic features, psychological and pain-related parameters, forming a questionnaire with "yes/no" items (decision rules). If at least 10 of the 21 rules applied, persisting pain was predicted at a cross-validated accuracy of 86% and a negative predictive value of approximately 95%. CONCLUSIONS: The present machine-learned analysis showed that, even with a large set of parameters acquired from a large cohort, early identification of these patients is only partly successful. This indicates that more parameters are needed for accurate prediction of persisting pain. However, with the current parameters it is possible, with a certainty of almost 95%, to exclude the possibility of persistent pain developing in a woman being treated for breast cancer.

Pain in 1,000 women treated for breast cancer: a prospective study of pain sensitivity and postoperative pain.

BACKGROUND: This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women. METHODS: One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43° and 48°C, 5 s) and cold (2-4°C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone. RESULTS: The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4-5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures. CONCLUSIONS: Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain.

2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial.

BACKGROUND: Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. METHODS: Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. FINDINGS: 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). INTERPRETATION: Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. FUNDING: Sanofi.

[Long-term morbidity caused by breast cancer therapy]. / Rintasyövän hoidon aiheuttama pitkäaikainen sairastavuus.

All forms of breast cancer therapies are associated with both acute adverse effects and manifold long-term morbidity. Due to the common occurrence and favorable prognosis of breast cancer, the number of those suffering from complications worsening the quality of life is considerable. In a significant proportion, the long-term adverse effects caused by the therapy can be alleviated. The importance of follow-up visits of a breast cancer patient is not limited to diagnosing or excluding of relapses. During these visits, the elucidation of long-term adverse effects and their treatment alternatives and even discussing the symptoms and supporting the patient are important with respect to the quality of life.

Lymphoedema therapy in breast cancer patients: a systematic review on effectiveness and a survey of current practices and costs in Finland.

BACKGROUND: This study systematically evaluates the effects and harms of physiotherapy methods and explores current treatment practices and costs in relation to lymphoedema in breast cancer patients in Finland. MATERIAL AND METHODS: A systematic review of randomized controlled trials (RCTs) on physiotherapy interventions for breast cancer patients with lymphoedema. A postal survey to lymph therapists, a telephone and register survey for therapy costs. RESULTS: We identified 14 RCTs, of which two had moderate and the others high risk of bias. There was moderate evidence that compression bandages decreased lymphoedema, and that pneumatic pumps had no effect on lymphoedema. In Finland lymph therapy practice is a combination of manual lymph drainage (MLD), compression bandages, therapeutic exercises and guidance for self-treatment, with an annual average cost of EUR 799 per patient. CONCLUSIONS: Compression bandages are likely to reduce upper limb lymphoedema in breast cancer patients. Evidence on other physiotherapy methods and their combinations is limited due to the poor quality of the trials. No evidence was found on any outcomes other than upper limb volume. We call for well-designed trials with patient-related outcomes on the effectiveness of MLD, guidance and therapeutic exercises.

How palliative care of cancer patients is organised between a university hospital and primary care in Finland.

The aim of this study was to find out how palliative care is organised between the Helsinki University Central Hospital (University Hospital) and primary care. The study consisted of 102 patients whose oncological treatment was terminated and the responsibility of palliative care was transferred to primary care. The patients were interviewed by phone using a structured questionnaire. Another questionnaire form was sent to the primary care physicians. Half of the patients were treated in more than one primary care unit. One third of the outpatients were unaware who was responsible for the care. Most of the patients wanted to be at home but this was achieved in less than half of the cases. Most patients were symptomatic while leaving the University Hospital and no improvement was seen thereafter. Every third patient reported of poor quality of palliative care in the primary care. Also the physicians reported a need for training in palliative care.

Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial.

AIMS: To study in a randomized placebo-controlled design the efficacy of the antidepressant venlafaxine, a serotonin and a weak noradrenaline reuptake inhibitor, in the treatment of atypical facial pain (AFP). METHODS: The study was a randomized, double-blind, crossover comparison of venlafaxine and a placebo. It consisted of 2 treatment periods, each of 4 weeks' duration, separated by a 2-week washout period. Thirty patients suffering from chronic pain who had been diagnosed with AFP after a thorough clinical examination were recruited. Pain intensity and pain relief were registered at 6 visits. Anxiety, depression, and adverse effects were recorded. Venous blood samples were collected at the end of each treatment period for the determination of serum levels of venlafaxine and its metabolites. RESULTS: Twenty patients completed the trial. Eight patients discontinued because of adverse effects and 2 patients were excluded because of noncompliance. Two patients completed the trial but were excluded from the analysis because they experienced no pain at the baseline visit. There was no significant difference in pain intensity reduction between the maximum tolerated dose of venlafaxine (75 mg in most cases) and the placebo. Pain relief was significantly greater with venlafaxine than with the placebo treatment. Significantly more escape medication was consumed during the placebo period compared with the venlafaxine period. No significant correlation was found between the serum concentration of the drug and the response to treatment. Anxiety and depression scores did not differ between venlafaxine and placebo treatment. Adverse effects were equally common during both treatments. CONCLUSION: Venlafaxine was only modestly effective in the treatment of AFP.

Venlafaxine in neuropathic pain following treatment of breast cancer.

Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. However, adverse effects are a major problem. Venlafaxine has no anticholinergic effects and could have a better compliance. The aim of the study was to evaluate the effectiveness of venlafaxine in neuropathic pain. The study was a randomized, double-blind, crossover comparison of venlafaxine and inactive placebo. The study lasted 10 weeks. The number of tablets (18.75 mg) taken daily was increased by one at a 1 week interval. Pain intensity and pain relief were registered daily by a diary and by a questionnaire and a computer program (Painscreen) on each visit. Adverse effects were evaluated with the diaries and a 10-item list on each visit. Also, anxiety and depression were measured on each visit. Venous blood samples were collected before the treatment and at 4 weeks for the determination of the serum levels of venlafaxine and its three metabolites. Thirteen patients were analysed. The average daily pain intensity as reported in the diary (primary outcome) was not significantly reduced by venlafaxine compared with placebo. However, the average pain relief (diary) and the maximum pain intensity (retrospective assessment by the computer program) were significantly lower with venlafaxine compared with placebo. Anxiety and depression were not affected. Adverse effects did not show significant differences between treatments. The two poor responders had low venlafaxine concentrations whereas the two slow hydroxylizers had high venlafaxine concentrations and excellent pain relief. Thus, higher doses could be used in order to improve pain relief.