Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers.

BACKGROUND: Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway. METHODS: 1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated. RESULTS: A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%. CONCLUSIONS: Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.

PET-CT in the sub-arctic region of Norway 2010-2013. At the edge of what is possible?

BACKGROUND: It is challenging to obtain a similar access to positron emission tomography/computed tomography (PET-CT) within the whole region served. In the subarctic and arctic region of Norway, significant distances, weather conditions and seasonable darkness have been challenging when the health care provider has aimed for a high quality PET-CT service with similar availability to all inhabitants. METHODS: The PET-CT service at the University Hospital of North Norway (UNN) was established in May 2010. The glucose analogue tracer fluorine-18 fluorodeoxyglucose (FDG) was delivered from Helsinki, Finland. An ambulatory PET-CT scanner was initially employed and a permanent local one was introduced in October 2011. In March 2014, we analysed retrospectively all data on the PET-CT exams performed at the Section of Nuclear Medicine, Department of Radiology during a 32 months time period 2010-13. The following patient data were recorded: gender, age, diagnosis, residence and distance of travelling. There were in total 796 exams in 706 patients. RESULTS: Four hundred sixty-one PET-CT exams per million inhabitants were, on average, performed per year. Lung cancer (32.7%), malignant melanoma (11.3%), colorectal cancer (10.9%) and lymphoma (9.7%) constituted two-thirds of all exams. Three-fourths were males and the median age was 63.5 years (range 15.2-91.4 years). The access to PET-CT exam varied within the region. The southern county (Nordland) experienced a significantly less access (p < 0.0001) to the regional service. Except for malignant melanoma, this finding was observed in all major cancer subgroups. In colorectal cancer and lymphoma a lower consumption of PET-CT was also observed in the northeastern county (Finnmark). Patients' mean distance of travelling by car (one way) was 373 km (median 313 km, range 5-936 km). CONCLUSION: PET-CT was not similarly available within the region. Especially, inhabitants in the southern county experienced less access to the regional service. National and regional standards of care, new scanners and improved collaboration between hospital trusts may alter this situation.

A prospective analysis of false positive events in a National Colon Cancer Surveillance Program.

BACKGROUND: The survival benefits of colon cancer surveillance programs are well delineated, but less is known about the magnitude of false positive testing. The objective of this study was to estimate the false positive rate and positive predictive value of testing as part of a surveillance program based on national guidelines, and to estimate the degree of testing and resource use needed to identify a curable recurrence. METHODS: Analysis of clinically significant events leading to suspicion of cancer recurrence, false positive events, true cancer recurrences, time to confirmation of diagnosis, and resource use (radiology, blood samples, colonoscopies, consultations) among patients included in a randomised colon cancer surveillance trial. RESULTS: 110 patients surgically treated for colon cancer were followed according to national guidelines for 1884 surveillance months. 1105 tests (503 blood samples, 278 chest x-rays, 209 liver ultrasounds, 115 colonoscopies) and 1186 health care consultations were performed. Of the 48 events leading to suspicion of cancer recurrence, 34 (71%) represented false positives. Thirty-one (65%) were initiated by new symptoms, and 17 (35%) were initiated by test results. Fourteen patients had true cancer recurrence; 7 resections of recurrent disease were performed, 4 of which were successful R0 metastasis Resections. 276 tests and 296 healthcare consultations were needed per R0 resection; the cost per R0 surgery was £ 103207. There was a 29% probability (positive predictive value) of recurrent cancer when a diagnostic work-up was initiated based on surveillance testing or patient complaints. CONCLUSION: We observed a high false positive rate and low positive predictive value for significant clinical events suggestive of possible colorectal cancer relapse in the setting of a post-treatment surveillance program based on national guidelines. Providers and their patients should have an appreciation for the modest positive predictive value inherent in colorectal cancer surveillance programs in order to make informed choices, which maximize quality of life during survivorship. Better means of tailoring surveillance programs based on patient risk would likely lead to more effective and cost-effective post-treatment follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00572143. Date of trial registration: 11th of December 2007.

Best supportive care in patients with brain metastases and adverse prognostic factors: development of improved decision aids.

PURPOSE: This study aimed to develop a survival prediction model that might aid decision making when choosing between best supportive care (BSC) and brain radiotherapy (RT) for patients with brain metastases and limited survival expectation. METHODS: A retrospective analysis of 124 patients treated with BSC, whole brain radiotherapy (WBRT), or radiosurgery was conducted. All patients had adverse prognostic features defined as 0-1.5 points according to the diagnosis-specific graded prognostic assessment score (DS-GPA) or GPA if primary tumor type was not among those represented in DS-GPA. Kaplan-Meier survival curves were compared between patients treated with BSC or RT in different scenarios, reflecting more or less rigorous definitions of poor prognosis. If survival was indistinguishable and this result could be confirmed in multivariate analysis, BSC was considered appropriate. RESULTS: Irrespective of point sum examined, DS-GPA by itself was not a satisfactory selection parameter. However, we defined a subgroup of 63 patients (51 %) with short survival irrespective of management approach (only 5 % of irradiated patients survived beyond 6 months; they had newly diagnosed, treatment-naïve lung cancer), i.e., patients in whom foregoing RT was unlikely to compromise survival. These were patients with 0-1.5 points and aged ≥ 75 years, had Karnofsky performance status ≤ 50, or had uncontrolled primary tumor with extracranial metastases to at least two organs. CONCLUSIONS: BSC is a reasonable choice in patients with limited life expectancy. After successful external validation of the selection criteria developed in this analysis, identification of patients who are unlikely to benefit from WBRT might be improved.

Quality of obstetric care in the sparsely populated sub-arctic area of Norway 2009-2011.

BACKGROUND: It is challenging to obtain high quality obstetric care in a sparsely populated area. In the subarctic region of Norway, significant distances, weather conditions and seasonable darkness have called for a decentralized care model. We aimed to explore the quality of this care. METHODS: A retrospective study employing data (2009-11) from the Medical Birth Registry of Norway was initiated. Northern Norwegian and Norwegian figures were compared. Midwife administered maternity units, departments at local and regional specialist hospitals were compared. National registry data on post-caesarean wound infection (2009-2010) was added. Quality of care was measured as rate of multiple pregnancies, caesarean section, post-caesarean wound infection, Apgar score <7, birth weight <2.5 kilos, perineal rupture, stillbirth, eclampsia, pregnancy induced diabetes and vacuum or forceps assisted delivery. There were 15,586 births in 15 delivery units. RESULTS: Multiple pregnancies were less common in northern Norway (1.3 vs. 1.7%) (P = 0.02). Less use of vacuum (6.6% vs. 8.3%) (P = 0.01) and forceps (0.9% vs 1.7%) (P < 0.01) assisted delivery was observed. There was no difference with regard to pregnancy induced diabetes, caesarean section, stillbirth, Apgar score < 7 and eclampsia. A significant difference in birth weight < 2.5 kilos (4.7% vs. 5.0%) (P < 0.04) and perineal rupture grade 3 and 4 (1.5% vs. 2.3%) (P < 0.02) were revealed. The post-caesarean wound infection rate was higher (10.5% vs. 7.4%) (P < 0.01). CONCLUSION: Northern Norway had an obstetric care of good quality. Birth weight, multiple pregnancies and post-caesarean wound infection rates should be further elucidated.

Compulsory and voluntary admission in psychiatric hospitals in northern Norway 2009-2010. A national registry-based analysis.

BACKGROUND: During the last decade, Norwegian healthcare authorities have been concerned about the frequent use of coercive measures in psychiatric care. On this background, we aimed to explore the voluntary and compulsory admissions in psychiatric hospitals in northern Norway, the University Hospital of North Norway in Tromsø (UNN-T) and the Nordland Hospital in Bodø (NH-B). METHODS: All voluntary and compulsory admissions (2009-2010) among patients aged ≥18 years registered by the Norwegian Patient Registry (NPR) were analyzed retrospectively. Compulsory admission was registered according to the general practitioner's (GP's) decision and the patients were hospitalized in Bodø or Tromsø. A total of 12,237 admissions and 242,148 days in hospital were identified. The female/male ratio of admission and stay was 1.17 and 1.15, respectively. RESULTS: The admission rate (northern Norway =1.0) varied significantly from south to north (0.60-1.52). Whereas patients living close to the hospitals had the same admission rate as others, the mean hospital stay was significantly longer (ratio =1.32). Furthermore, the UNN-T had a higher re-admission rate (2% vs. 5%). Municipalities with District Psychiatric Centers (DPC) did not differ from others. A significant difference in the use of coercive measures was revealed between hospitals. Forced medication was the most frequent measure employed. CONCLUSIONS: The study documented a south-north gradient in admission rate and indicated differences in the use of coercion. Variation may partly be due to different reporting procedures. This finding and why patients living in the neighborhood of hospitals stay longer should be explored in future studies.

Towards improved prognostic scores predicting survival in patients with brain metastases: a pilot study of serum lactate dehydrogenase levels.

Accurate prognostic information is desirable when counselling patients with brain metastases regarding their therapeutic options and life expectancy. Based on previous studies, we selected serum lactate dehydrogenase (LDH) as a promising factor on which we perform a pilot study investigating methodological aspects of biomarker studies in patients with brain metastases, before embarking on large-scale studies that will look at a larger number of candidate markers in an expanded patient cohort. For this retrospective analysis, 100 patients with available information on LDH treated with palliative whole-brain radiotherapy were selected. A comprehensive evaluation of different LDH-based variables was performed in uni- and multivariate tests. Probably, the most intriguing finding was that LDH kinetics might be more important, or at least complement, information obtained from a single measurement immediately before radiotherapy. LDH and performance status outperformed several other variables that are part of prognostic models such as recursive partitioning analyses classes and graded prognostic assessment score. LDH kinetics might reflect disease behaviour in extracranial metastatic and primary sites without need for comprehensive imaging studies and is a quite inexpensive diagnostic test. Based on these encouraging results, confirmatory studies in a larger cohort of patients are warranted.

Admission and stay in psychiatric hospitals in northern Norway among Sami and a control group: a registry-based study.

BACKGROUND: The aim of this study was analyze the admission and inpatient stay at psychiatric hospital in northern Norway among people from the Sami-speaking municipalities (Sami group) and a control group (non-Sami group). Are they treated equally? METHODS: All admissions and inpatient stay from the administration area of the Sami language law (eight municipalities) was matched with a control group of 11 municipalities. All adult patients treated during the 2-year time period 2009-2010 and registered by the Norwegian Patient Registry (NPR) were included in the study. Population data as of 2009 was accessed from Statistics Norway. The admission rate and the days in hospital (DiH) rate per 10,000 inhabitants/year were set as 1.0. RESULTS: Both study groups had a significantly higher admission and DiH-rate than northern Norwegians in general. The median annual admission rate/10,000 inhabitants was 284 (Sami) and 307 (non-Sami), respectively (P = 0.23). Whereas there were no difference between groups with regard to DiH/10,000 inhabitants/year (P = 0.24), the males of the Sami group spent significantly fewer DiH when any form of coercion was used (RR = 0.41). CONCLUSIONS: Sami did not experience significantly more or fewer admissions (voluntary and compulsory) to psychiatric hospitals than the control group. There were significant intergroup variations in both groups.

Comorbidity, use of common medications, and risk of early death in patients with localized or locally advanced prostate cancer.

In this paper, we analyze predictive factors for early death from comorbidity (defined as death within 3 years from diagnosis and unrelated to prostate cancer) in patients with localized or locally advanced prostate cancer. Such information may guide individually tailored treatment or observation strategies, and help to avoid overtreatment. We retrospectively analyzed baseline parameters including information on comorbidity and medication use among 177 patients (median age at diagnosis 70 years). Actuarial survival analyses were performed. During the first 3 years, two patients (1.1%) died from progressive prostate cancer after they had developed distant metastases. The risk of dying from other causes (3.4%) was numerically higher, although not to a statistically significant degree. Six patients who died from other causes had age-adjusted Charlson comorbidity index (CCI) scores ≥5 (CCI is a sum score where each comorbid condition is assigned with a score depending on the risk of dying associated with this condition). The main comorbidity was cardiovascular disease. The two statistically significant predictive factors were medication use and age-adjusted CCI score ≥5 (univariate analysis). However, medication use was not an independent factor as all patients with age-adjusted CCI score ≥5 also used at least one class of medication. Median survival was 30 months in patients with age-adjusted CCI score ≥5. Prediction of non-prostate cancer death may be important to prevent overtreatment in patients who are more threatened by comorbidity. Our data suggest that simple parameters such as use of medications vs. none, or presence of serious cardiac disease vs. none, are not sufficient, and that age-adjusted CCI scores outperform the other factors included in our analysis.

Resource utilization in patients with brain metastases managed with best supportive care, radiotherapy and/or surgical resection: a Markov analysis.

OBJECTIVE: In spite of the large number of patients and increasing financial pressure on health care budgets worldwide, limited data on resource utilization after diagnosis of brain metastases are available. METHODS: Prospective data were collected on all patients diagnosed with brain metastases during a time period of 2 years (n = 53). Treatment was best supportive care (BSC), primary radiotherapy (RT) and/or surgical resection. Eighty-five percent of patients had active extracranial disease. Costs were calculated from the hospital and nursing home's point of view. RESULTS: Overall, 11,532 patient days were analyzed. Treatment per patient amounted to 0.8 courses of whole-brain RT, 0.2 neurosurgical procedures, 0.1 radiosurgical procedures and 1.3 cycles of chemotherapy. Median survival in the BSC, RT and neurosurgery groups was 1.4, 4.6 and 11.0 months, respectively. Chemotherapy was associated with longer median survival. Four percent of the remaining lifetime was spent in nursing homes and 8% within hospitals. Forty-three percent of all hospital days and 47% of deaths were related to non-neurologic causes. The total cost per patient was 24,649 EUR (34,841 USD) and the corresponding cost per life year was 43,955 EUR (62,130 USD). Hospital care was the main cost factor. CONCLUSIONS: A considerable amount of resources is utilized in this patient group. Better tools for avoiding overtreatment and selecting patients for appropriate therapy are needed to achieve maximum value for money.

Management of patients with metastatic prostate cancer (mPC) in a rural part of North Norway with a scattered population: does living near the department of oncology translate into a different pattern of care and survival?

The goal of the Norwegian Ministry of Health and Care Services is to offer an equal health-care service with the same outcomes wherever people are living within the country. The aim of this study was to evaluate whether this was true for patients diagnosed with metastatic prostate cancer (mPC) and living in Nordland County, a region with a challenging geography and climate and having, several small and remote communities and only 1 department of oncology. The latter is located in the main city, Bodø. We also compared a subgroup living in communities having lower average annual income (less than NOK 240,000 (equivalent to USD 28,600)) with patients living in Bodø (NOK 285,000 (USD 33,900)). Overall 288 patients were included and stratified into 3 subgroups (favourable distance and income, unfavourable distance and income, and unfavourable distance and favourable income). No statistically significant differences were observed regarding patient characteristics. There was no indication towards under-treatment among patients from the distant regions or the lower income region. Given that disparities were not observed, it was not surprising to see comparable survival outcomes (p=0.35). In conclusion, these results suggest that the health-care system in Nordland County successfully delivers state-of-the-art oncology care to patients with mPC.

Initiation of Systemic Therapy During the Last 30 Days of Life in Patients With Metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Compared to intravenous taxane chemotherapy, newer orally-available and/or less toxic agents for metastatic castration-resistant prostate cancer (MCRPC) may be associated with higher likelihood of starting treatment in patients with adverse prognostic features and limited life expectancy. To test this hypothesis, we analyzed the rates of treatment initiation during the last 30 days of life in a real-world cohort of men with MCRPC. PATIENTS AND METHODS: This was a retrospective analysis of 146 patients. RESULTS: Seven patients (5%) who started any systemic treatment during the last 30 days of life were identified. The likelihood of treatment initiation in the last 30 days of life correlated significantly with the number of lines of systemic treatment (higher risk for previously treated patients) and non-use of bone-targeted agents. CONCLUSION: Initiation of systemic therapy in the last 30 days of life was uncommon. This endpoint might complement other quality-of-care indicators.

Prophylactic bilateral salpingo-oophorectomy (PBSO) with or without prophylactic bilateral mastectomy (PBM) or no intervention in BRCA1 mutation carriers: a cost-effectiveness analysis.

Women with germline BRCA1 mutation have a significant risk of breast and/or ovarian cancer. Prophylactic bilateral mastectomy (PBM) and prophylactic bilateral salpingo-oophorectomy (PBSO) prevent cancer in mutation carriers. The cost-effectiveness of PBSO (age of 35 years) with or without PBM five years earlier was compared to a no intervention setting employing a marginal cost analysis. National data on cancer incidence, mortality rates and costs were implemented together with observed Norwegian BRCA1 data in a Markov model and PBSO was assumed to reduce the risk of ovarian cancer by 90%. A 3% discount rate was used. The additional health care cost per mutation carrier undergoing PBSO and PBM was euro 15,784, and 6.4 discounted life years gained (LYG) was indicated (PBSO alone with 100% acceptance 3.1 LYG). The additional cost per LYG was euro 1973 (PBSO alone euro 1749/LYG). Including all resource use, the figure was a cost of euro 496 and euro 1284 per LYG, respectively. PBSO with or without PBM in BRCA1 mutation carriers is cost-effective. A testing of all incident breast cancers to identify mutation carrying families should be explored.

Bladder and rectal toxicity of BeamCath application in radiotherapy of prostate cancer.

BACKGROUND: Patient-reported toxicity in two radiotherapy regimens for early stage prostate cancer was investigated. In 2003, the Swedish BeamCath technique was adapted for Northern Norway. MATERIALS AND METHODS: Ninety men underwent radiotherapy for early-stage prostate cancer in February 2002 to March 2005. They were invited to participate in a telephone interview employing a questionnaire guide focusing on bladder, intestinal and sexual function. RESULTS: Eighty patients responded, which represents 89% of all patients. The treatment group (23 patients) had received 76 Gy with the BeamCath technique and the control group (57 patients) received 70 Gy employing a conformal technique. The BeamCath technique was associated with a lower median rectal (p=0.004; 50.6 Gy versus 56.2 Gy) and bladder dose (p=0.017; 48.5 Gy versus 61.5 Gy). There were no differences in scores on masculinity and sexual function. In conclusion, the BeamCath technique did not increase rectal or bladder toxicity.

Practice and costs of red blood cell (RBC) transfusion in an oncological unit.

BACKGROUND: Cancer related anemia impairs patient functioning. Red blood cell (RBC) transfusion and erythropoietin (EPO) may relieve fatigue. Cost-effectiveness data have been requested. PATIENTS AND METHODS: All transfusions administered at the Department of Oncology, University Hospital of North Norway (UNN) in 2005 were analysed, with a total of 118 patients entering the study. A cost of transfusion analysis was added and a sensitivity analysis conducted to clarify robustness. The 118 patients received 613 units of erythrocytes. In 6% of cases, the transfusion was the only cause of a hospital visit. One fourth of patients had bone marrow infiltration and two-thirds had undergone chemotherapy. The mean Hb levels of patients prior to and following transfusion were in the range 8.4-8.8 g/dl and 10.2-10.6 g/dl, respectively; one-third reached a non-anemic level (Hb > or = 11.0 g/dl). The median time interval between transfusions was three weeks and the annual cost was calculated at Euro 1,069/patient. CONCLUSION: RBC-transfusion has a low cost.

Should the surgeon or the general practitioner (GP) follow up patients after surgery for colon cancer? A randomized controlled trial protocol focusing on quality of life, cost-effectiveness and serious clinical events.

BACKGROUND: All patients who undergo surgery for colon cancer are followed up according to the guidelines of the Norwegian Gastrointestinal Cancer Group (NGICG). These guidelines state that the aims of follow-up after surgery are to perform quality assessment, provide support and improve survival. In Norway, most of these patients are followed up in a hospital setting. We describe a multi-centre randomized controlled trial to test whether these patients can be followed up by their general practitioner (GP) without altering quality of life, cost effectiveness and/or the incidence of serious clinical events. METHODS AND DESIGN: Patients undergoing surgery for colon cancer with histological grade Dukes's Stage A, B or C and below 75 years of age are eligible for inclusion. They will be randomized after surgery to follow-up at the surgical outpatient clinic (control group) or follow-up by the district GP (intervention group). Both study arms comply with the national NGICG guidelines. The primary endpoints will be quality of life (QoL) (measured by the EORTC QLQ C-30 and the EQ-5D instruments), serious clinical events (SCEs), and costs. The follow-up period will be two years after surgery, and quality of life will be measured every three months. SCEs and costs will be estimated prospectively. The sample size was 170 patients. DISCUSSION: There is an ongoing debate on the best method of follow-up for patients with CRC. Due to a wide range of follow-up programmes and paucity of randomized trials, it is impossible to draw conclusions about the best combination and frequency of clinic (or family practice) visits, blood tests, endoscopic procedures and radiological examinations that maximize the clinical outcome, quality of life and costs. Most studies on follow-up of CRC patients have been performed in a hospital outpatient setting. We hypothesize that postoperative follow-up of colon cancer patients (according to national guidelines) by GPs will not have any impact on patients' quality of life. Furthermore, we hypothesize that there will be no increase in SCEs and that the incremental cost-effectiveness ratio will improve. TRIAL REGISTRATION: This trial has been registered at ClinicalTrials.gov. The trial registration number is: NCT00572143.

The potential of digital monochrome images versus colour slides in telescreening for diabetic retinopathy.

We explored the potential of digital monochrome images as an alternative to colour slides in screening for diabetic retinopathy. Twenty-eight patients with diabetes were recruited for the study and 20 actually participated. Using a fundus camera (Nikon 505AF) one set of three digital images and one set of three colour slides were taken per eye. Two independent ophthalmologists graded the colour slides and the digital images for diabetic retinopathy. The ophthalmologists spent about two minutes grading each set of images, suggesting that specialists could potentially screen a large number of patients. The agreement between the two screening methods was 0.95 and 0.89, with respect to disease or no disease. The agreement (kappa) between the two ophthalmologists for grade of retinopathy was 0.47 when colour slides were employed and 0.61 when digital monochrome images were employed. The results indicate that digital red-free monochrome images represent a superior screening tool for diabetic retinopathy. Tele-screening may be beneficial when patients have to travel substantial distances to visit an ophthalmologist.

Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature.

BACKGROUND: Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%-90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy. PATIENTS AND METHODS: A systematic review was done. We searched for documents and articles published in English language and registered in Cochrane Library, National Health Service (NHS) Centre for Reviews and Dissemination (CRD), Embase or Medline. The search terms were (A) (Lung cancer or NSCLC) with (pembrolizumab or nivolumab) with PD-L1 with (tobacco or smoking) and (B) Lung Neoplasms and Immunotherapy and (smoking cessation or patient compliance). 68 papers were detected and two more were added during review process (references) and six based on information from the manufacturers. RESULTS: Nine papers were selected. High PD-L1 expression (≥50%) was correlated with current/ever smoking history in three studies. Six studies revealed a higher overall response rate (ORR) among current/former smokers. The ORR was generally (six studies) better among the current/former smoker group. So also when tumours had a molecular 'smoking signature' (one study). This was probably due to a higher mutational burden. In two studies, minor or no difference was revealed.One study (KEYNOTE-024) compared former and current smokers, and documented pembrolizumab being more effective among former smokers than current smokers. CONCLUSIONS: Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation.

Caesarean Section Rates and Activity-Based Funding in Northern Norway: A Model-Based Study Using the World Health Organization's Recommendation.

OBJECTIVE: Caesarean section (CS) rates vary significantly worldwide. The World Health Organization (WHO) has recommended a maximum CS rate of 15%. Norwegian hospitals are paid per CS (activity-based funding), employing the diagnosis-related group (DRG) system. We aimed to document how financial incentives can be affected by reduced CS rates, according to the WHO's recommendation. METHODS: We employed a model-based analysis and included the 2016 data from the Norwegian Patient Registry (NPR) and the Medical Birth Registry of Norway (MBRN). The vaginal birth rate and CS rates of each hospital trust in Northern Norway were analyzed. RESULTS: There were 4,860 deliveries and a 17.5% CS rate (range 13.9-20.3%). The total funding of the deliveries was €16,351,335 (CS: €6,389,323; vaginal births: €9,962,012). The CS rate varied significantly and was lower in the southern region (P < 0.002). Consequently, the introduction of a cutoff at a 15% CS rate would gain the two southern hospital trusts by a budget increase of 0.2%. The two northern ones would experience 6.4% less resources. A total of €644,655 could be allocated to further quality and safety initiatives in obstetrics. CONCLUSION: The economic consequences of the model-based financial incentive were low, but probably sufficient to get the necessary attention and influence on the CS rate. RECOMMENDATIONS: A financial incentive for the reduction of CS rates should be tested as a supplement to other instruments.