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.

A perivascular niche in the bone marrow hosts quiescent and proliferating tumorigenic colorectal cancer cells

Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones—a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity.     

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.