Bone Health, Osteoporosis and Fracture Risk in Neurofibromatosis 1 - An Emphasis on Osteoclasts

Neurofibromatosis 1 (NF1) is an autosomal dominant hereditary syndrome, affecting skin, neural tissues and skeleton. Hallmarks of NF1 include benign cutaneous neurofibroma tumors, pigmentation lesions on the skin and in the iris, learning disabilities and predisposition to selected malignancies. Low bone mineral density (BMD) and osteopenia/osteoporosis are common in NF1. Osteoporosis is a systemic disorder characterized by low bone mineral density and increased fracture risk. Treatment of osteoporosis aims to prevent falls and decrease fracture risk. Osteoporosis is diagnosed in adults by measuring BMD and evaluating clinical risk factors of the patient. Bone turnover is a process of old bone resorbed by osteoclasts and new bone formed by osteoblasts. Multinuclear osteoclasts are derived from osteoclast progenitors, which can be isolated from peripheral blood. Osteoclast progenitors were isolated from 17 NF1 patients and healthy controls, and cultured in vitro to osteoclasts. NF1 osteoclasts are hyperactive, displaying increased differentiation and resorption capacity, abnormal morphology and tolerance to serum deprivation compared to control osteoclasts. These findings expanded the study to evaluate the effects of bisphosphonates, drugs designed to treat osteoporosis, in osteoclasts derived from blood samples of 20 NF1 and control persons. The number of control osteoclasts was expectedly reduced after bisphosphonate treatment. However, NF1 osteoclasts tolerated the apoptotic effect of alendronate, zoledronic acid and clodronate in vitro compared to controls. NF1-related osteoporosis was found in ~20 % of the patients, and selected laboratory parameters were measured. Patients with NF1 have increased levels of serum CTX and PINP, reflecting increased bone turnover in vivo. BMD decreases progressively in NF1 as evaluated in 19 NF1 patients 12 years after their initial BMD measurement. Patients with NF1-related osteopenia often progress to osteoporosis. This was found in patients aged 37-76.Siirretty Doriast

Smoking is an Independent Marker of Poor Prognosis in Cutaneous Melanoma

Previous studies have suggested that persistent tobacco smoking impairs survival in cutaneous melanoma, but the effects of smoking and other prognostic factors have not been described in detail. This study examined the association of smoking (persistent, former, or never) with melanoma-specific (MSS) and overall survival (OS) in patients with cutaneous melanoma treated in Southwest Finland during 2005 to 2019. Clinical characteristics were obtained from electronic health records for 1,980 patients. Smoking status was available for 1,359 patients. Patients were restaged according to the 8th edition of the tumour-node-metastasis (TNM) classification. Smoking remained an independent prognostic factor for inferior melanoma-specific survival regardless of age, sex, stage, and comorbidities. The hazard ratio of death from melanoma was 1.81 (1.27-2.58, p = 0.001) in persistent and 1.75 (1.28-2.40, p = 0.001) in former smokers compared with never smokers. In 351 stage IV patients, smoking was associated with increased melanoma-specific and overall mortality: median MSS 10.4 (6.5-14.3), 14.6 (9.1-20.1), and 14.9 (11.4-18.4) months, p = 0.01 and median OS 10.4 (6.5-14.3), 13.9 (8.6-19.2), and 14.9 (11.7-18.1) months, p = 0.01 in persistent, former, and never smokers, respectively. In conclusion, since smoking represents an independent modifiable poor prognostic factor in patients with cutaneous melanoma, smoking habits should be proactively asked about by healthcare professionals, in order to support smoking cessation.</p

Signaling pathways in human osteoclasts differentiation: ERK1/2 as a key player

Little is known about the signaling pathways involved in the differentiation of human osteoclasts. The present study evaluated the roles of the Ras/PI3K/Akt/mTOR, Ras/Raf/MEK1/2/ERK1/2, calcium-PKC, and p38 signaling pathways in human osteoclast differentiation. Mononuclear cells were isolated from the peripheral blood of control persons and patients with neurofibromatosis 1 (NF1), and the cells were differentiated into osteoclasts in the presence of signaling pathway inhibitors. Osteoclast differentiation was assessed using tartrate-resistant acid phosphatase 5B. Inhibition of most signaling pathways with chemical inhibitors decreased the number of human osteoclasts and disrupted F-actin ring formation, while the inhibition of p38 resulted in an increased number of osteoclasts, which is a finding contradictory to previous murine studies. However, the p38 inhibition did not increase the bone resorption capacity of the cells. Ras-inhibitor FTS increased osteoclastogenesis in samples from control persons, but an inhibitory effect was observed in NF1 samples. Inhibition of MEK, PI3K, and mTOR reduced markedly the number of NF1-deficient osteoclasts, but no effect was observed in control samples. Western blot analyses showed that the changes in the phosphorylation of ERK1/2 correlated with the number of osteoclasts. Our results highlight the fact that osteoclastogenesis is regulated by multiple interacting signaling pathways and emphasize that murine and human findings related to osteoclastogenesis are not necessarily equivalent.</p

Transient Changes in Serum CEA, CA19-9, CRP, YKL-40, and IL-6 during Adjuvant Chemotherapy and Survival of Patients with Colorectal Cancer

Serum carcinoembryonic antigen (CEA) is frequently monitored to detect colorectal cancer (CRC) recurrence after surgery. The clinical significance of transiently increased CEA during adjuvant chemotherapy is poorly understood. Serum CEA, CA19-9, CRP, YKL-40, and IL-6 were measured before, during, and after adjuvant 5-fluorouracil-based chemotherapy in the randomised LIPSYT study population. The biomarker kinetic patterns were classified into three groups: no increase, a transient increase (≥10% increase followed by a decrease), and a persistent increase during the adjuvant treatment, and the associations of these patterns with disease free-survival (DFS) and overall survival (OS) were investigated by using Cox regression analyses. The findings were validated in two single-centre cohorts that received modern adjuvant chemotherapy. A transient increase in CEA occurred in about a half of the patients during chemotherapy, in all the cohorts. The patients with a transient increase had a roughly similar DFS and OS to the patients with no increase, and a more favourable survival compared to the patients with a persistent increase. In the LIPSYT cohort, the hazard ratio was 0.21 for DFS (CI95% 0.07–0.66) and 0.24 for OS (CI95% 0.08–0.76). Transient increases in CA19-9 and YKL-40 tended to be associated with a favourable survival. A transient increase in CEA during adjuvant chemotherapy is associated with a favourable survival when compared with a persistent increase

Controlled register-based study of road traffic accidents in 12,651 Finnish cancer patients during 2013-2019

Background: Little controlled evidence exists on road traffic accident (RTA) risk among patients diagnosed with cancer, while clinicians are often requested to comment their ability to drive. The aim of this study was to evaluate RTA risk in a population-based cohort of cancer patients living in Southwest Finland.Patients: All adult patients diagnosed with cancer in 2013-2019 were included. Acute appendectomy/cholecystectomy and actinic keratosis patients without cancer were selected from the same region as the control cohort. Participants were cross-referenced to a national driving licence database, yielding 12,651 cancer and 6334 control patients with a valid licence. Due to marked differences in their clinical presentation, the cancer cohort was divided into nine cancers of interest (breast, prostate, colorectal, lung, melanoma, head & neck, primary brain tumours, gynaecological and haematological malignancies). The nationwide law-regulated motor liability insurance registry was searched for all RTAs leading to injury with claims paid to not- or at-fault participants. At-fault drivers were verified based on sex and birth year.Results: During a median follow-up of 34 months, 167 persons were at-fault drivers in RTAs leading to injury. Among the nine cancers of interest, RTA risk did not differ from the control cohort. Among cancer patients, multivariable regression suggested male sex and opioid use, but not advanced cancer stage or given systemic therapy, as the most influential risk factors for RTA.Conclusions: Cancer diagnosis itself was not associated with increased RTA risk, but other associated symptoms, medications, comorbidities or specific cancer subgroups may.</p

An easily adaptable validated risk score predicts cancer-specific survival in stage II colon cancer

Non peer reviewe

Trends in presentation, treatment and survival of 1777 patients with colorectal cancer over a decade: a Biobank study

Background: Most survival data in colorectal cancer (CRC) is derived from clinical trials or register-based studies. Hospital Biobanks, linked with hospital electronic records, could serve as a data-gathering method based on consecutively collected tumor samples. The aim of this Biobank study was to analyze survival of colorectal patients diagnosed and treated in a single-center university hospital over a period of 12 years, and to evaluate factors contributing to outcome.Material and methods: A total of 1777 patients with CRC treated during 2001–2012 were identified from the Auria Biobank, Turku, Finland. Longitudinal clinical information was collected from various hospital electronic records and date and cause of death obtained from Statistics Finland.Results: Cancer-specific, overall and disease-free survival was higher in patients diagnosed during 2004–2008 as compared with patients diagnosed in 2001–2003. Further improvement was not seen during years 2009–2012. Potential factors contributing to the improvement were introduction of multidisciplinary meetings, centralization of rectal cancer surgery, use of adjuvant chemotherapy and systematic preoperative radiotherapy of rectal cancer. The proportion of patients with stage I–IV CRC remained similar over the study period, but a marked decrease in non-metastatic rectal cancer with biopsy only (locally advanced disease) was observed. In stage I–III rectal cancer, Cox multivariate analysis suggested age, comorbidity, R1 resection, T staging and tumor grade as prognostic factors. In colon cancer, prognostic factors were age, comorbidity, gender and presence of lymph node metastases.Conclusions: Organizational changes in the treatment of CRC patients made since 2004 coincide with improved survival in CRC and a marked reduction in locally advanced rectal cancers. The clinical presentation of CRC has remained similar between 2001 and 2012.</p

Improved risk prediction of chemotherapy-induced neutropenia-model development and validation with real-world data

Background The existing risk prediction models for chemotherapy-induced febrile neutropenia (FN) do not necessarily apply to real-life patients in different healthcare systems and the external validation of these models are often lacking. Our study evaluates whether a machine learning-based risk prediction model could outperform the previously introduced models, especially when validated against real-world patient data from another institution not used for model training.Methods Using Turku University Hospital electronic medical records, we identified all patients who received chemotherapy for non-hematological cancer between the years 2010 and 2017 (N = 5879). An experimental surrogate endpoint was first-cycle neutropenic infection (NI), defined as grade IV neutropenia with serum C-reactive protein >10 mg/l. For predicting the risk of NI, a penalized regression model (Lasso) was developed. The model was externally validated in an independent dataset (N = 4594) from Tampere University Hospital.Results Lasso model accurately predicted NI risk with good accuracy (AUROC 0.84). In the validation cohort, the Lasso model outperformed two previously introduced, widely approved models, with AUROC 0.75. The variables selected by Lasso included granulocyte colony-stimulating factor (G-CSF) use, cancer type, pre-treatment neutrophil and thrombocyte count, intravenous treatment regimen, and the planned dose intensity. The same model predicted also FN, with AUROC 0.77, supporting the validity of NI as an endpoint.Conclusions Our study demonstrates that real-world NI risk prediction can be improved with machine learning and that every difference in patient or treatment characteristics can have a significant impact on model performance. Here we outline a novel, externally validated approach which may hold potential to facilitate more targeted use of G-CSFs in the future.</p