Ilonka Kreitschmann-Andermahr

Diagnosis and management of acromegaly: the patient’s perspective

AbstractPurposeEarly diagnosis is a success factor for the prevention of long-term comorbidity and premature death in patients with acromegaly, but large-scale data on the diagnostic process and disease management are scarce. Therefore, we aimed to evaluate the diagnostic process, implementation of treatment and changes in life situation in patients with acromegaly, focusing on sex-specific differences.MethodsNon-interventional patient-reported outcome study. 165 patients with clinically and biochemically proven acromegaly were questioned about the diagnostic process and utilization of health care by means of a self-developed standardized postal survey including questions on acromegaly symptoms experienced before diagnosis, number and specialty of consulted doctors, time to diagnosis and aftercare.ResultsThe diagnostic process took 2.9 (SD 4.53) years, during which 3.4 (SD 2.99) physicians were consulted. Women waited longer [4.1 (SD 5.53) years] than men [1.6 (SD 2.69) years; pxa0=xa00.001] for the correct diagnosis, and consulted more doctors in the process [4.0 (SD 2.99) vs. 2.7 (SD 2.84) doctors, pxa0<xa00.001, respectively]. In 48.5xa0% of patients, acromegaly was diagnosed by an endocrinologist (men: 45.1xa0%; women: 52.4xa0%). Overall disease duration from symptom onset until last surgery was 5.5 (SD 6.85) years, with no sex differences. A change in employment status was the most commonly reported event after diagnosis and a quarter of the patients stated that the illness had changed their lives.ConclusionsOur findings confirm the urgent need to increase awareness of the clinical manifestation of acromegaly to facilitate an earlier diagnosis of the disease and to provide diagnostic equality across the sexes.n

Presence of headache and headache types in patients with tumors of the sellar region-can surgery solve the problem? Results of a prospective single center study

PurposeHeadache is a common presenting feature of patients with pituitary adenomas and other tumors of the sellar region. However, at present, it still is unclear whether the headache is actually caused by the tumor. To explore whether there is a relation, we examined in detail the headache types, their relationship to the underlying pathology, and if the headache responded to neurosurgery in a prospective study design.MethodsOne hundred twelve patients with tumors of the sellar region scheduled for neurosurgery in a single center were analyzed for presence and quality of headache before surgery and at least 3 months after surgery. Patients received headache and depression self-rating inventories, presented on a handheld computer (PainDetect®). Clinical variables thought to impact on headache were analyzed in conjunction with the inventories.ResultsFifty-nine (53%) patients reported headache in the 3 months prior to neurosurgery, 49 (44%) had headache at the time of filling in the questionnaires. The four patients with pituitary apoplexy described thunderclap headache. In the other patients diverse headache types were encountered, most frequently migraine. Untreated gonadotroph deficiency was significantly associated with absence of headache, while none of the other clinical and morphological variables related to headache. Presence of headache and disability due to headache were not significantly reduced after surgery.ConclusionApart from pituitary apoplexy we detected no specific headache type in our patient group and no significant improvement of headache after neurosurgery. Headache alone constitutes neither a valid diagnostic marker for the presence of tumors of the sellar region nor a sufficient indication for tumor removal.

EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation

CCM3, also named as PDCD10, is a ubiquitous protein expressed in nearly all tissues and in various types of cells. It is essential for vascular development and post‐natal vessel maturation. Loss‐of‐function mutation of CCM3 predisposes for the familial form of cerebral cavernous malformation (CCM). We have previously shown that knock‐down of CCM3 stimulated endothelial angiogenesis via impairing DLL4‐Notch signalling; moreover, loss of endothelial CCM3 stimulated tumour angiogenesis and promoted tumour growth. The present study was designed to further elucidate the inside signalling pathway involved in CCM3‐ablation‐mediated angiogenesis. Here we report for the first time that silencing endothelial CCM3 led to a significant up‐regulation of EphB4 mRNA and protein expression and to an increased kinase activity of EphB4, concomitantly accompanied by an activation of Erk1/2, which was reversed by treatment with the specific EphB4 kinase inhibitor NVP‐BHG712 (NVP), indicating that silencing CCM3 activates EphB4 kinase forward signalling. Furthermore, treatment with NVP rescued the hyper‐angiogenic phenotype induced by knock‐down of endothelial CCM3 in vitro and in vivo. Additional study demonstrated that the activation of EphB4 forward signalling in endothelial cells under basal condition and after CCM3‐silence was modulated by DLL4/Notch signalling, relying EphB4 at downstream of DLL4/Notch signalling. We conclude that angiogenesis induced by CCM3‐silence is mediated by the activation of EphB4 forward signalling. The identified endothelial signalling pathway of CCM3‐DLL4/Notch‐EphB4‐Erk1/2 may provide an insight into mechanism of CCM3‐ablation‐mediated angiogenesis and could potentially contribute to novel therapeutic concepts for disrupting aberrant angiogenesis in CCM and in hyper‐vascularized tumours.

Coping strategies have a strong impact on quality of life, depression, and embitterment in patients with Cushing’s disease

PurposeQuality of life (QoL) and psychosocial well-being are substantially impaired in patients with Cushing’s disease (CD), not only at the acute illness stage but also after therapy; however, the reason for these impairments remains unclear.MethodsIn this cross-sectional, patient-reported outcome study, we conducted a postal survey on psychosocial impairment and coping strategies in patients after surgical treatment of CD in three large tertiary referral centers. In total, 176 patients with CD completed a compilation of self-assessment inventories pertaining to depression (Hospital Anxiety and Depression Scale, HADS), QoL (Short Form SF-36, Tuebingen CD; Tuebingen CD-25), coping style (Freiburg questionnaire on coping with illness, FKV-LIS), and embitterment (Bern Embitterment Inventory), on average 6.8xa0±xa06.66xa0years after surgery. Regression analyses were performed to identify predictors of psychosocial impairment.ResultsAt the time of the study, 21.8xa0% of patients suffered from anxiety, 18.7xa0% experienced an above-average feeling of embitterment, and 13.1xa0% suffered from depression. Maladaptive coping styles (FKV-LIS subscales depressive coping and minimizing importance) emerged as robust and strong predictors of psychosocial impairment in all inventories; while age, sex, and hydrocortisone intake failed to explain the variance in these measures.ConclusionSimilar to several studies in non-pituitary patient cohorts (e.g., patients with multiple sclerosis or lower back pain), our results indicate that psychosocial impairment in CD is significantly influenced by how the patient deals with the illness. Therefore, psychological training of positive coping styles could be a helpful complementary therapy in the overall treatment strategy of CD.

Downregulation of programmed cell death 10 is associated with tumor cell proliferation, hyperangiogenesis and peritumoral edema in human glioblastoma

BackgroundNeovascularization and peritumoral edema are hallmarks of glioblastoma (GBM). Programmed cell death 10 (PDCD10) plays a pivotal role in regulating apoptosis, neoangiogenesis and vessel permeability and is implicated in certain tumor signaling pathways. However, little is known about PDCD10 in GBM. We aimed to investigate the expression pattern of PDCD10 and to identify the association of its expression with some molecular and clinical parameters in human GBM.MethodsmRNA and protein expression of PDCD10 were examined respectively by real-time RT-PCR and Western blotting in GBM (nu2009=u200927), astrocytoma grade II (nu2009=u200913) and control (nu2009=u200911). The protein level of p-Akt and GFAP was detected by Western blot. Double-imunofluorecent staining was performed to reveal the cellular expression profile of PDCD10. Brain edema and microvascular density (MVD) were respectively analyzed based on pre-operative MRI and after laminin immnostaining. MGMT promoter methylation was detected by methylation specific PCR.ResultsmRNA and protein levels of PDCD10 were significantly downregulated in GBM, concomitantly accompanied by the activation of Akt. PDCD10 immunoreactivity was absent in proliferating tumor cells, endothelial cells and GFAP-positive cells, but exclusively present in the hypoxic pseudopalisading cells which underwent apoptosis. Moreover, loss of PDCD10 was associated with a higher MVD and a more severe peritumoral edema but not with MGMT promoter methylation in GBM.ConclusionWe report for the first time that PDCD10 expression is downregulated in GBM, which is associated with the activation of Akt signaling protein. PDCD10 is potentially implicated in tumor proliferation and apoptosis, hyperangiogenesis and peritumoral edema in GBM.

Single center experience with treatment of spinal dural arteriovenous fistulas

Spinal dural arteriovenous fistulas (SDAVFs) are rare pathologies with a yearly incidence of 5–10 new cases/million, constituting 60–80xa0% of spinal arteriovenous malformations. Clinical symptoms include progressive paraparesis, paresthesias, bladder, and bowel disturbances. The pathophysiology of SDAVFs is not well elucidated. Microneurosurgery and endovascular techniques are established treatment modalities for permanent fistula occlusion, which are oftentimes accompanied by an amelioration of neurological deficits in the long run. Here, we report our interdisciplinary neurosurgical/neuroradiological management strategy of SDAVFs in 32 patients who were evaluated retrospectively. We focused on clinical presentation, microneurosurgical and interventional technique, early, and late neurological results. Quality of life (QoL) was additionally assessed in 12 patients at last follow-up. We discuss the results against the background of the current literature. Our series and the literature indicate that clinical outcome after treatment of SDAVF is favorable in general. Both neurosurgical and neurointerventional therapies appear to be safe and effective, but short-term neurological deterioration after the intervention constitutes an as-of-yet unsolved problem. Beyond age and preoperative neurological state, presence of comorbidities had a significant influence on neurological outcome in our study sample. Self-assessed physical and mental QoL at long-term follow-up was reduced in quite a number of patients and was associated with a poorer neurological result as well as presence of comorbidities. The patients’ perspective in terms of QoL was first investigated in this study, but further research on QoL and psychosocial impairment of SDAVF patients is needed to enable individualized counseling and rehabilitation strategies.

Pituitary apoplexy – A single center retrospective study from the neurosurgical perspective and review of the literature

OBJECTIVEnThunderclap headache and visual disturbances are typical clinical features of pituitary apoplexy (PA). Because of the acute symptomatology, many patients are referred to a neurosurgical department without prior endocrinological assessment. It is the aim of the present study to analyze initial presenting symptoms, outcome and associated endocrine disturbances in a cohort of patients with pituitary apoplexy primarily seen by neurosurgeons.nnnPATIENTS AND METHODSnRetrospective single-center study in a neurosurgical department. Patients records were reviewed for clinical, neuropathological and endocrinological findings. The diagnosis of PA was based on clinical, imaging and histological findings.nnnRESULTSnA total of 60 patients were studied. They were referred most often by neurologists (n=16), and family physicians (n=12). Only 2 patients received an endocrinological work-up prior to admission. The most frequently documented presenting symptoms were headache (n=54), visual field defects (n=13), reduction of visual acuity (n=17) and/or diplopia (n=19). An endocrinological history had rarely been taken and hormone blood tests were oftentimes incomplete or not ordered. At 3-month follow-up 18/44 patients had complete anterior hypopituitarism. At 12 months, 21/60 patients were lost to endocrinological follow-up.nnnCONCLUSIONSnThe classic neurological symptoms of PA were well documented in our patient cohort, whereas endocrinological symptoms, especially those indicative of pituitary dysfunction were underreported. Neurologists and neurosurgeons need to be aware of the endocrinological sequelae of pituitary apoplexy in order to avoid potentially lethal complications. Patients should be counselled to adhere to long-term endocrinological and neurosurgical follow-up.

Support Needs of Patients with Cushing’s Disease and Cushing’s Syndrome: Results of a Survey Conducted in Germany and the USA

Background Cushings disease (CD) and Cushings syndrome (CS) are chronic illnesses, characterized by symptoms of prolonged hypercortisolism, which often changes to hypocortisolism after successful treatment. In view of the high disease burden of CD/CS patients and long-term impaired quality of life, the present survey was conducted to gain information about subjective illness distress and patients specific needs in terms of supportive measures beyond medical interventions. Patients and Methods Cross-sectional questionnaire study including patients with CD treated in 2 German neurosurgical tertiary referral centers and CD/CS patient members of a US-based patient support group completed a survey inquiring about disease burden, coping strategies, and support needs. Additionally, the degree of interest in different offers, e.g., internet-based programs and seminars, was assessed. Results 84 US and 71 German patients answered the questionnaire. Patients in both countries indicated to suffer from Cushing-related symptoms, reduced performance, and psychological problems. 48.8% US patients and 44.4% German patients stated that good medical care and competent doctors helped them the most in coping with the illness. US patients were more interested in support groups (p = 0.035) and in courses on illness coping (p = 0.008) than the German patients, who stated to prefer brochures (p = 0.001). 89.3% of US patients would attend internet-based programs compared to 75.4% of German patients (p = 0.040). There were no differences between groups for the preferred duration of and the willingness to pay for such a program, but US patients would travel longer distances to attend a support meeting (p = 0.027). Conclusion Patients in both countries need skilled physicians and long-term medical care in dealing with the effects of CD/CS, whereas other support needs differ between patients of both countries. The latter implies that not only disease-specific but also culture-specific training programs would need to be considered to satisfy the needs of patients in different countries.

Oro-dental pathologies in acromegaly

PurposeOro-dental pathologies (ODP) such as enlargement of the tongue, mandibular prognathism, and spaced teeth are characteristic features of acromegaly. Their frequency of occurrence during the course of the disease is largely unresolved. Purpose of this study was to assess ODP and oro-dental treatments in patients with acromegaly with regard to the length of the diagnostic process, tumor histology, and quality of life (QoL).MethodsSingle-center retrospective survey study using questionnaires on dental symptoms, diagnostic process, and treatment in patients with acromegaly operated on a growth hormone-secreting pituitary adenoma. The association between ODP and QoL was assessed using the Short-Form 36 (SF-36) Health Survey.Results145/314 patients completed the questionnaires. 80.7% were affected by any ODP, most frequently enlargement of the tongue (57.9%), spaced teeth (42.8%), mandibular growth (24.1%), and mandibular prognathism (22.1%). ODP were significantly more frequent in patients with sparsely vs. densely granulated adenomas (pu2009=u20090.045). Early diagnosis within 2 years was associated with significantly fewer ODP than later diagnosis (68.5 vs. 87.2%, pu2009=u20090.009). Treatments included dental crowns (16.6%), dental bridges (12.4%), dental implants (9.7%), dental prostheses (3.4%), orthodontal (i.e., braces, 6.9%), and surgical correction of the teeth (2.1%). Physical QoL was significantly lower in patients with ODP than in those without (pu2009=u20090.014).ConclusionIn our large series of patients, four of five patients were affected by ODP at any time during the course of the disease. The results highlight the importance of early identification and treatment of oro-dental problems in patients with acromegaly as hallmarks of the disease.

Sleep quality and health-related quality of life among long-term survivors of (non-) Hodgkin lymphoma in Germany

This study investigated sleep quality and health-related quality of life (HRQOL) among long-term survivors of Hodgkin (HL) and non-Hodgkin lymphoma (NHL). The aim was to explore the impact of personal and health-related factors on sleep quality as well as associations between sleep quality and HRQOL. For the postal survey, participants with a minimum age of 18 years initially treated between 1998 and 2008 were recruited via the population-based cancer registry in Schleswig-Holstein, Northern Germany. Questionnaires included amongst others the Pittsburg Sleep Quality Index (PSQI) and the 36-Item Short Form Health Survey (SF-36v1). Descriptive and comparative statistics were performed. Additionally, a regression analysis was conducted to identify predictors of sleep quality. In total, we recruited 515 participants (398 NHL, 117 HL) with a mean age of 63.1 years. Approximately half of the survivors were classified as good sleepers. HRQOL scores differed between good and poor sleepers with lower scores in poor sleepers. In a prediction model, self-reported depression, exhaustion, higher age, inability to work, endocrinological disorders and female gender classified as predictors of sleep quality. This study highlights the impact of sleep quality on HRQOL in long-term survivors of NHL and HL. Thus, sleep quality should be routinely assessed during follow-up of cancer survivors with special attention to patients with potential risk factors.