Complex medical history of a patient with a compound heterozygous mutation in C1QC.

INTRODUCTION: C1q is an essential part of the classical pathway of complement activation. Genetic deficiencies, caused by homozygous mutations in one of the C1q genes, are rare and are strongly associated with development of systemic lupus erythematosus (SLE). Here we describe a C1q-deficient patient with a compound heterozygous mutation. MATERIAL AND METHODS: Serum was analysed with enzyme-linked immunosorbent assay (ELISA) and Western blot for the presence of C1q, and DNA and RNA sequencing was performed to identify the mutations and confirm that these were located on different chromosomes. RESULTS: The medical history of the patient includes SLE diagnosis at age 11 years with cerebral involvement at age 13, various infections, osteonecrosis and hemophagocytic syndrome. Using ELISA and Western blot, we confirmed the absence of C1q in the serum of the patient. Using DNA sequencing, two mutations in the C1QC gene were identified: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X). With RNA sequencing we confirmed that the mutations are located on different chromosomes. DISCUSSION: The patient described in this case report has a compound heterozygous mutation in C1QC resulting in C1q deficiency.

Are serum autoantibodies associated with brain changes in systemic lupus erythematosus? MRI data from the Leiden NP-SLE cohort.

OBJECTIVE: The effect of serum autoantibodies on the brain of systemic lupus erythematosus (SLE) patients remains unclear. We investigated whether serum autoantibodies, individually and assessed in groups, are associated with specific brain-MRI abnormalities or whether these structural changes are associated with other SLE-related or traditional cardiovascular disease risk factors. METHODS: All patients underwent brain 3Tesla-MRI. White matter hyperintensities (WMHs), ischemic lesions, inflammatory-like lesions and cerebral atrophy were scored. Serum autoantibodies analyzed included lupus anticoagulant (LAC), anticardiolipine (aCL) IgG and IgM (first 3 also grouped into antiphospholipid autoantibodies (aPL)), anti-dsDNA, anti-SSA, anti-SSB, anti-RNP, and anti-Sm (the latter 5 grouped into SLE-related autoantibodies). Associations were assessed using logistic regression analysis adjusted for potential confounders. Furthermore, a sensitivity analysis including anti-Beta2 glycoprotein-1 antibodies (anti-ß2GP1) in the aPL group was performed and the potential modification role of the neuropsychiatric clinical status in the model was assessed. RESULTS: 325 patients (mean age 42 years (SD 14), 89% female) were included. The following MRI-brain abnormalities were found: WMHs (71%), lacunar infarcts (21%), gliosis (11%), micro-hemorrhages (5%), large hemorrhages (2%), inflammatory-like lesions (6%) and atrophy (14%). No associations were found between individual or total SLE-related autoantibodies and inflammatory-like lesions. A higher number of positive aPL was associated with lacunar infarcts (OR 1.37 (95%CI 1.02-1.99) and gliosis (OR 2.15 (1.37-3.37)). LAC was associated with lacunar infarcts in white matter (OR 3.38 (1.32-8.68)) and atrophy (OR 2.49 (1.01-6.15)), and aCL IgG with gliosis (OR 2.71 (1.05-7.02)). Among other variables, SLE patients with hypertension presented a higher chance for WMHs (OR 5.61 (2.52-12.48)) and lacunar infarcts in WM (OR 2.52 (1.10-5.74)) and basal ganglia (OR 8.34 (2.19-31.70)), while cumulative SLE-damage was correlated with lacunar infarcts in WM (OR 1.43 (1.07-1.90)), basal ganglia (OR 1.72 (1.18-2.51)) and cerebellum (OR 1.79 (1.33-2.41)). These associations were confirmed in the sensitivity analysis. CONCLUSIONS: Brain abnormalities in SLE represent different underlying pathogenic mechanisms. aPL are associated with ischemic brain changes in SLE, while the presence of SLE-related serum autoantibodies is not related to inflammatory-like lesions. Hypertension and cumulative SLE-damage associate with ischemic MRI-brain changes in SLE, suggesting the importance of accelerated atherosclerosis in this process.

Neuropsychiatric symptoms in systemic lupus erythematosus: impact on quality of life.

Objective Assess quality of life in patients with systemic lupus erythematosus (SLE) presenting with neuropsychiatric symptoms (neuropsychiatric SLE, NPSLE). Methods Quality of life was assessed using the Short-Form 36 item Health Survey (SF-36) in patients visiting the Leiden NPSLE clinic at baseline and at follow-up. SF-36 subscales and summary scores were calculated and compared with quality of life of the general Dutch population and patients with other chronic diseases. Results At baseline, quality of life was assessed in 248 SLE patients, of whom 98 had NPSLE (39.7%). Follow-up data were available for 104 patients (42%), of whom 64 had NPSLE (61.5%). SLE patients presenting neuropsychiatric symptoms showed a significantly reduced quality of life in all subscales of the SF-36. Quality of life at follow-up showed a significant improvement in physical functioning role ( p = 0.001), social functioning ( p = 0.007), vitality ( p = 0.023), mental health ( p = 0.014) and mental component score ( p = 0.042) in patients with neuropsychiatric symptoms not attributed to SLE, but no significant improvement was seen in patients with NPSLE. Conclusion Quality of life is significantly reduced in patients with SLE presenting neuropsychiatric symptoms compared with the general population and patients with other chronic diseases. Quality of life remains considerably impaired at follow-up. Our results illustrate the need for biopsychosocial care in patients with SLE and neuropsychiatric symptoms.

Outcomes of neuropsychiatric events in systemic lupus erythematosus based on clinical phenotypes; prospective data from the Leiden NP SLE cohort.

Objective The objective of this study was to assess whether clinical and patient's reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p < 0.001) and especially inflammatory neuropsychiatric systemic lupus erythematosus ( B = 0.827; p < 0.001) had better clinical outcome, with change in disease activity being the only important predictor. The change in SF-36 MCS was also independently associated with neuropsychiatric systemic lupus erythematosus ( B = 5.783; p < 0.05) and inflammatory neuropsychiatric systemic lupus erythematosus ( B = 11.133; p < 0.001). Disease duration and change in disease activity were the only predictors in both cases. The change in SF-36 PCS was only negatively associated with age. Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Cervical esophageal cancer: a gap in cancer knowledge.

BACKGROUND: The aim of this systematic review is to provide an overview of the diagnosis, treatment options and treatment-related complications of cervical esophageal carcinoma (CEC) and to subsequently provide recommendations to improve quality of care. DESIGN: Studies were identified in PubMed, EMBASE and Web of Science. A total of 107 publications fulfilled the inclusion criteria and were included. RESULTS: CEC is uncommon, accounting for 2%-10% of all esophageal carcinomas. These tumors are often locally advanced at presentation and have a poor prognosis, with a 5-year overall survival of 30%. Tobacco and alcohol consumption seem to be the major risk factors for developing CEC. Surgery is usually not possible due to the very close relationship to other organs such as the larynx, trachea and thyroid gland. Therefore, the current standard of care is definitive chemoradiation (dCRT) with curative intent. Treatment regimens used to treat CEC are adapted by established regimens in lower esophageal squamous cell carcinoma and head and neck squamous cell carcinoma. However, dCRT may be accompanied by severe side-effects and complications. Several diagnostic and predictive markers have been studied, but currently, there is no other biomarker than clinical stage to determine patient management. Suggestions to improve patient outcomes are to determine the exact radiation dose needed for adequate locoregional control and to combine radiotherapy with optimal systemic therapy backbone. CONCLUSION: CEC remains unchartered territory for many practising physicians and patients with CEC have a poor prognosis. To improve the outcome for CEC patients, future studies should focus on the identification of new diagnostic biomarkers or targets for radiosensitizers, amelioration of radiation schedules, optimal combination of chemotherapeutic agents and/or new therapeutic targets.

Can metformin improve 'the tomorrow' of patients treated for oesophageal cancer?

INTRODUCTION: Recent studies suggest that the use of metformin is associated with reduced cancer incidence and improved prognosis in patients with oesophageal cancer. We explored the relationship between the use of metformin and outcome (pathologic response rate, distant metastasis-free and overall survival) in our mono-institutional cohort of patients treated for oesophageal cancer. MATERIAL AND METHODS: Between 2008 and 2014, a total of 196 patients with oesophageal cancer (ages ranged from 37 to 82 years) eligible for curative treatment entered the study. Patients were categorized as non-diabetic (n = 172), diabetic not taking metformin (n = 5) or diabetic taking metformin (n = 19). The majority of patients were treated with trimodality therapy (n = 189). Pathologic response was graded according to Mandard's tumour regression score at the time of surgery. Distant metastasis-free and overall survival were calculated using the Kaplan-Meier method with log rank comparisons performed to determine significance. RESULTS: The overall pathologic complete response rate for the study population was 26%. It was 25% for patients not using metformin and 39% for diabetics taking metformin (p = 0.260). The two-year overall survival rate for the whole group was 59%. Use of metformin was associated with a significantly better distant metastasis-free survival rate (p = 0.040) or overall survival rate (p = 0.012). Multivariate analysis using Cox regression found that metformin treatment significantly prolonged survival (p = 0.043). CONCLUSION: In our population-based study, the use of metformin was associated with an improved overall and distant metastasis-free survival rate in patients with oesophageal cancer. These data are complementary to one other clinical study and warrant further prospective study.

Image-guided stereotactic ablative radiotherapy for the liver: a safe and effective treatment.

AIMS: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for inoperable patients or patients with irresectable liver tumors. Outcome and toxicity were evaluated retrospectively in this single-institution patient cohort. PATIENTS AND METHODS: Between 2010 and 2014, 39 lesions were irradiated in 33 consecutive patients (18 male, 15 female, median age of 68 years). All the lesions were liver metastases (n = 34) or primary hepatocellular carcinomas (n = 5). The patients had undergone four-dimensional respiration-correlated PET-CT for treatment simulation to capture tumor motion. We analyzed local control with a focus on CT-based response at three months, one year and two years after treatment, looking at overall survival and the progression pattern. RESULTS: All patients were treated with hypofractionated image-guided stereotactic radiotherapy. The equivalent dose in 2 Gy fractions varied from 62.5 Gy to 150 Gy, delivered in 3-10 fractions (median dose 93.8 Gy, alpha/beta = 10). The CT-based regression pattern three months after radiotherapy revealed partial regression in 72.7% of patients with a complete remission in 27.3% of the cases. The site of first progression was predominantly distant. One- and two-year overall survival rates were 85.4% and 68.8%, respectively. No toxicity of grade 2 or higher according to the NCI Common Terminology Criteria for Adverse Events v4.0 was observed. CONCLUSION: SABR is a safe and efficient treatment for selected inoperable patients or irresectable tumors of the liver. Future studies should combine SABR with systemic treatment acting in synergy with radiation, such as immunological interventions or hypoxic cell radiosensitizers to prevent distant relapse.

Do rehabilitation tools cover the perspective of patients with rheumatoid arthritis? A focus group study using the ICF as a reference.

BACKGROUND: Despite the advocated use of rehabilitation tools in clinical rehabilitation of with rheumatoid arthritis (RA) patients, little is known about the representation of the patient perspective in these tools. AIM: Aim of the study was to explore the experiences of RA patients with rehabilitation and the coverage by rehabilitation tools. DESIGN AND POPULATION: Qualitative focus group study with RA patients about experiences with rehabilitation. SETTING: Rheumatology rehabilitation clinic of a Dutch university hospital. METHODS: Focus groups were tape recorded and transcribed verbatim. From the meaningful units, concepts were extracted and linked to the International Classification of Functioning, Disability and Health (ICF). Rehabilitation tools validated for RA were identified using a structured literature search. Using the ICF as common framework, we determined for each concept identified in the focus groups the coverage by each rehabilitation tool. RESULTS: Nineteen patients participated in 4 focus groups. Fifty-one concepts were identified in 368 meaningful units derived from the transcribed data. From the literature the ICF Core Sets for RA, Canadian Occupational Performance Measure, Rehabilitation Activities Profile and WHO Disability Assessment Schedule II were elected. The concepts from the focus groups were best covered by the ICF Core Sets (44 out of 51; 86%), followed by the WHODAS II (39%), RAP (35%) and COPM (16%). CONCLUSION: With the exception of the ICF Core Sets for RA, current rehabilitation tools poorly cover the RA patients' perception on rehabilitation. CLINICAL REHABILITATION IMPACT: The ICF Core Sets can serve as a checklist to guide multidisciplinary assessment, goal-setting and evaluation in RA rehabilitation.

Whole abdominopelvic radiotherapy in the palliative treatment of pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by mucinous peritoneal disease arising from disseminated peritoneal adenomucinosis. Primary treatment involves a combination of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). There is no consensus on the proper treatment of recurrent PMP. In selected patients, repeated cytoreductive surgery with or without HIPEC might improve outcome. However, every repeated debulking procedure becomes less effective with increased morbidity. CASE REPORT: We present a case of a patient with intestinal obstruction caused by recurrent pseudomyxoma peritonei. We treated the patient with whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT) to a total dose of 33 Gy, delivered in 22 daily fractions. The treatment was well tolerated and resulted in resolution of the obstruction for a period of 24 months. CONCLUSION: To the best of our knowledge, we present the first case report showing the possibility of resolving intestinal obstruction with WAPRT in a patient with recurrent PMP. It is our opinion that WAPRT delivered by IMAT, in analogy with ovarian cancer, should be considered as a palliative treatment option in managing patients with recurrent PMP especially in case of obstruction.

Randomized comparison of a multidisciplinary team care program with usual care in patients with systemic sclerosis.

OBJECTIVE: To compare the effectiveness of a multidisciplinary team care program with usual outpatient care in patients with systemic sclerosis (SSc; scleroderma). METHODS: We performed a randomized controlled trial comparing a 12-week multidisciplinary team care program (1 day per week; individual treatments, group exercises, and group education) with outpatient clinic care. Outcome measures included the Hand Mobility in Scleroderma (HAMIS) test, grip strength, maximal mouth opening (MMO), 6-minute walk distance (6MWD), maximum aerobic capacity (VO(2max) ), Checklist Individual Strength 20 (CIS-20), SSc Health Assessment Questionnaire (HAQ), and Short Form 36 (SF-36), assessed at 0, 12, and 24 weeks. Statistical comparisons of change scores were done by analysis of covariance. RESULTS: Twenty-eight patients were assigned to the intervention group (mean age 53.9 years, 15 of 28 with diffuse SSc) and 25 were assigned to the control group (mean age 51.7 years, 15 of 25 with diffuse SSc). Twenty-five patients (89%) in the intervention group completed the treatment program. At 12 weeks, there was a significantly greater improvement in grip strength (2.2 versus -1.8 kg; P = 0.001), MMO (1.4 versus -0.9 mm; P = 0.011), 6MWD (42.8 versus 3.9 meters; P = 0.021), and HAQ score (-0.18 versus 0.13; P = 0.025) in the intervention group, whereas differences for the other outcome measures did not reach significance. At 24 weeks, the effect on grip strength persisted. CONCLUSION: In patients with SSc, a 12-week multidisciplinary day patient treatment program was more effective than regular outpatient care with respect to 6MWD, grip strength, MMO, and HAQ score, but not for VO(2max) , HAMIS test, CIS-20, SF-36, and visual analog scale for pain. This study provides a first step in quantifying the effect of a multidisciplinary team care program and warrants the conduct of further intervention studies.