Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced,Programmed Death Ligand 1–Expressing NSCLC

Introduction

In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1–expressing (tumor proportion score ≥ 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here.

The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis

Background The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the “cholinergic inflammatory pathway.” Through stimulation of the acetylcholine receptors located upon the macrophages, the “unspecific” immune system can be directly influenced. Methods The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model. Results After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis. Conclusion The vagal nerve is therefore an important modulator of the immune system. W. Kessler and T. Traeger contributed equally to this work Best of Forum Papers presented at the Annual Meeting of the German Society of Surgery, 2–5 May 2006, Berlin, Germany     

Total lymphoid irradiation in chronic polyarthritis--a new therapeutic concept

Eleven patients with refractory rheumatoid arthritis were submitted to a total lymphoid irradiation up to a dose of 20 Gy. A constant improvement of clinical symptoms was observed in four out of the eleven patients already during the treatment and in the other patients not later than two months after. The frequency of attacks decreased and the number of joints involved in the attack was reduced. Morning rigidity and joint swellings decreased. One patient developed joint empyemas 4 and 26 months after the treatment. Four patients died in the meantime. In two patients the cause of death were renal insufficiency and a postoperative cardiogenic shock associated with generalized amyloidosis. The third patient died because of a toxically induced left cardiac decompensation with sepsis that could not be controlled by antibiotic drugs and multiple joint empyemas. The fourth patient developed an abscess after surgical treatment of a Kaposi syndrome. She died three months later from acute left cardiac decompensation. The therapy induced a lymphocytopenia with decrease of T helper lymphocytes and unchanged number of T suppressor lymphocytes. The constant therapy results of total lymphoid irradiation in primary chronic polyarthritis is probably due to this modification in the immune regulation.     

XX. Ueber den Einfluss des inducirten und constanten Stromes auf die Thätigkeit des menschlichen Herzens

Ohne ZusammenfassungHierzu Taf. III.     

Tendon injuries of the knee joint extensor mechanism

Diagnosis, aetiology and therapy of injuries to the extensor mechanism of the knee joint are presented. 22 cases of ruptures and discisions of the lig. patellae or the quadriceps tendon could be reexamined. All cases but one, with operation within the first week after injury, suturing with absorbable or non absorbable material, immobilisation for 6 weeks and following physical therapy, had a good functional result. No rerupture occurred. In one case a limitation of the range of movement had to be seen afer an open discision of the lig. patellae. After transposition of the tuberositas tibiae, discission of the scares and functional therapy a good result could also be achieved.     

Treatment of fecal incontinence by temporary sacral nerve stimulation

Summary BACKGROUND: Sacral nerve stimulation (SNS) is an option for the treatment of fecal incontinence in patients with morphologically intact, but weak external anal sphincter. METHODS: In ten patients a percutaneous test-SNS was performed. Two patients suffered from fecal incontinence after surgery, one patient after incomplete leg palsy after traumatic spine injury and seven patients from idiopathic incontinence. Incontinence score, anorectal manometry and patient diary were performed before and after test-SNS. RESULTS: Intraoperative response (Bellows action) could be achieved in 90% of patients. Test-SNS was successful in 50% of patients. In these patients, resting pressure was increased by 100.1% and squeeze pressure by 84.5%. CONCLUSIONS: SNS is an effective therapy in a subset of patients with fecal incontinence. Fifty percent of patients tested are eligible for implantation of a permanent stimulation device.      

Combined sclerotherapy and operation for the treatment of bleeding oesophageal varices.

OBJECTIVE--To identify prognostic factors in a consecutive series of patients with bleeding oesophageal varices and develop an optimum regimen of treatment. DESIGN--Retrospective review. SETTING--I Department of Surgery, University Hospital, Vienna, Austria. PATIENTS--301 consecutive patients with bleeding oesophageal varices. OUTCOME MEASURES--Median survival and survival at one year after sclerotherapy alone (n = 213), or sclerotherapy with portosystemic shunt (n = 54), Hassab's devascularisation (n = 29), or liver transplantation (n = 5). RESULTS--Prognosis was dependent on the severity of liver damage at the start of treatment. Median survival for Child's class A was 47 months, for Child's class B 54 months, and for Child's class C 2 months. The overall one year survival for patients in Child's class C was 33%, for sclerotherapy alone 28%, and for sclerotherapy and portosystemic shunt 42%, Hassab's devascularisation 50%, and liver transplantation 80%. CONCLUSION--Despite the small number of patients who underwent liver transplantation and their poor initial prognosis (Child's class C, n = 4; class B, n = 1) our results suggest that liver transplantation should be considered for the treatment of patients with end stage cirrhosis and bleeding varices.     

Primary pulmonary hypertension in childhood--clinical course and morphologic correlations with particular reference to the endocrine heart

This is a case report of a 13-year-old girl who developed clinical symptoms of primary pulmonary hypertension (PPH). The prognosis is determined by progressive overloading of the right heart. Tissue from both the right and the left atria was examined using immunohistochemical methods. Cardiodilatin/alpha-ANP (atrial natriuretic peptide)-producing myoendocrine cells were analysed. As recent investigations have shown, the atrium and especially the atrial appendages of the heart function as an endocrine organ which is stimulated by pressure and volume overload, and which produces a natriuretic and vasodilatory peptide hormone from myoendocrine cells. In our case we found a general hyperplasia of the myoendocrine cells of the right atrium which is interpreted as a secondary reaction towards an increasing overload. This also means a temporary compensation of the progressive obstruction of the small pulmonary arteries, initiated by vasodilatory heart peptides. These investigations are in agreement with those of other groups who found an increased production of cardiac hormones in atrial overload. In the perinuclear area, electron microscopy shows zones of autophagolysis and the typical specific atrial granules which account for a dysfunction of atrial myoendocrine cells, as seen in other cardiac diseases. Our results may contribute to a better understanding of the pathogenesis of PPH and may help in diagnosis and therapy.