Combined regression score predicts outcome after neoadjuvant treatment of oesophageal cancer.

BACKGROUND: Histopathologic regression following neoadjuvant treatment (NT) of oesophageal cancer is a prognostic factor of survival, but the nodal status is not considered. Here, a score combining both to improve prediction of survival after neoadjuvant therapy is developed. METHODS: Seven hundred and fifteen patients with oesophageal squamous cell (SCC) or adenocarcinoma (AC) undergoing NT and esophagectomy were analysed. Histopathologic response was classified according to percentage of vital residual tumour cells (VRTC): complete response (CR) without VRTC, major response with <10% VRTC, minor response with >10% VRTC. Nodal stage was classified as ypN0 and ypN+. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: Survival analysis identified three groups with significantly different mortality risks: (1) low-risk group for CR (ypT0N0) with 72% 5-year overall survival (5y-OS), (2) intermediate-risk group for minor/major responders and ypN0 with 59% 5y-OS, and (3) high-risk group for minor/major responders and ypN+ with 20% 5y-OS (p < 0.001). Median survival in AC and SCC cohorts were comparable (3.8 (CI 95%: 3.1, 5.3) vs. 4.6 years (CI 95%: 3.3, not reached), p = 0.3). CONCLUSIONS: Histopathologic regression and nodal status should be combined for estimating AC and SCC prognosis. Poor survival in the high-risk group highlights need for adjuvant therapy.

Improved Tissue Processing in Esophageal Adenocarcinoma After Ivor Lewis Esophagectomy Allows Histological Analysis of All Surgically Removed Lymph Nodes with Significant Effects on Nodal UICC Stages.

BACKGROUND: In esophageal carcinoma, the numbers of metastatic and total removed lymph nodes (LN) are well-established variables of long-term prognosis. The overall rate of retrieved LN depends on neoadjuvant treatment, the extent of surgical lymphadenectomy, and the modality of the pathological workup. The question in this study is whether technically extended histopathological preparation can increase the number of detected (metastatic) LN with an impact on nodal UICC staging. PATIENTS AND METHODS: A cohort of 77 patients with esophageal adenocarcinoma was treated with Ivor Lewis esophagectomy including standardized two-field lymphadenectomy. The specimens were grossed, and all manually detectable LN were retrieved. The remaining tissue was completely embedded by the advanced "acetone compression" retrieval technique. The primary outcome parameter was the total number of detected lymph nodes before and after acetone workup. RESULTS: A mean number of 23,1 LN was diagnosed after standard manual LN preparation. With complete embedding of the fatty tissue using acetone compression, the number increased to 40.5 lymph nodes (p < 0.0001). The mean number of metastatic LN increased from 3.2 to 4.2 nodal metastases following acetone compression (p < 0.0001). Additional LN metastases which caused a change in the primary (y)pN stage were found in ten patients (13.0%). CONCLUSIONS: Advanced lymph node retrieval by acetone compression allows a reliable statement on the real number of removed LN. Results demonstrate an impact on the nodal UICC stage. A future multicenter study will examine the prognostic impact of improved lymph node retrieval on long-term oncologic outcome.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Therapy susceptible germline-related BRCA 1-mutation in a case of metastasized mixed adeno-neuroendocrine carcinoma (MANEC) of the small bowel.

BACKGROUND: Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib. CASE PRESENTATION: A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases. CONCLUSION: We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

Complex solutions under shear and pressure: a rheometer setup for X-ray scattering experiments.

A newly developed high-pressure rheometer for in situ X-ray scattering experiments is described. A commercial rheometer was modified in such a way that X-ray scattering experiments can be performed under different pressures and shear. First experiments were carried out on hyaluronan, a ubiquitous biopolymer that is important for different functions in the body such as articular joint lubrication. The data hint at a decreased electrostatic interaction at higher pressure, presumably due to the increase of the dielectric constant of water by 3% and the decrease of the free volume at 300 bar.

Studying solutions at high shear rates: a dedicated microfluidics setup.

The development of a dedicated small-angle X-ray scattering setup for the investigation of complex fluids at different controlled shear conditions is reported. The setup utilizes a microfluidics chip with a narrowing channel. As a consequence, a shear gradient is generated within the channel and the effect of shear rate on structure and interactions is mapped spatially. In a first experiment small-angle X-ray scattering is utilized to investigate highly concentrated protein solutions up to a shear rate of 300000 s(-1). These data demonstrate that equilibrium clusters of lysozyme are destabilized at high shear rates.

[Lung cancer and rheumatoid arthritis. An interdisciplinary challenge]. / Lungenkarzinom und rheumatoide Arthritis. Eine interdisziplinäre Herausforderung.

Lung cancer is a frequently occurring disease, particularly in the elderly; however, within the last 10 years the pharmaceutical treatment of lung cancer has been significantly improved. Due to a better understanding of the pathophysiological events and the identification of molecular subgroups of lung tumors, new therapeutic drugs have been developed that significantly prolong survival of patients with the respective molecular pattern. In particular immunotherapeutic agents, such as programmed death-ligand 1 (PD-L1) and programmed death 1 (PD1) antibodies have shown promising clinical results in a subgroup of lung cancer patients. Due to the high incidence of both lung cancer and rheumatic diseases they often occur together, which necessitates an interdisciplinary management. The success of improved therapy of lung cancer has led to a greater focus on the treatment of comorbidities; however, interventions into the immune system by immune checkpoint inhibitors can lead to new challenges when an autoimmune disease is simultaneously present. The possibility of an effective screening for lung cancer in the future also presents the prospect of an improvement in mortality, which raises the question of the optimal monitoring of patients with rheumatoid arthritis (RA) under immunosuppressive therapy. The aim of this review is to discuss the interaction between lung cancer and RA with respect to the currently available data.

How does the way a weight is carried affect spinal loads?

People often have to carry a weight which increases the spinal load. Few in vivo measured spinal loading data exist for carrying a weight. The aim of this study was to measure the force increase on a vertebral body replacement (VBR) caused by carrying weights in different ways. A telemeterised VBR allowing the measurement of six load components was implanted in five patients suffering from lumbar vertebral body fractures. The patients carried different weights laterally in one or both hands, in front of the body and in a backpack. The force increase with respect to standing was more than twice as high for carrying a weight in front of the body compared with carrying it laterally. A weight of 10 kg in a backpack led to an average force increase of only 35 N. The position of the carried weight relative to the spine strongly affected the spinal load. PRACTITIONER SUMMARY: Carrying weights increases spinal loads. The loads on a telemeterised VBR were measured in five patients carrying weights in different ways. Holding a weight in front of the body strongly increased the force, while carrying it in a backpack led to only a minor load increase.

[Surgical therapy of lung metastases from head and neck cancer]. / Chirurgische Therapie pulmonaler Metastasen von Kopf-Hals-Tumoren.

Pulmonary metastasectomy is an established procedure in oncological therapeutic concepts. A systematic literature search and an analysis of all studies published since 01.01.2000 should evaluate the advantage of pulmonary metastasectomy for patients with primary head and neck cancer. Lung metastases develop in 1.9-13% of head and neck cancer patients. Following metastasectomy, patients reach a median survival of 9.5-78 months and 5-year survival rates of up to 58% are achieved. Intrathoracic recurrence occurs in 18.4-81.8% of patients, selected instances of which can be successfully treated by remetastasectomy. Patients with squamous cell carcinoma have the worst prognosis, but could also become long-term survivors (≥ 60 months). Pulmonary metastasectomy is frequently the only potentially curative therapeutic approach and offers a better long-term survival than nonsurgical therapies. Lung metastasectomy is thus the treatment of choice in selected patients with pulmonary metastases from primary head and neck cancer.

Parameters influencing the outcome after total disc replacement at the lumbosacral junction. Part 1: misalignment of the vertebrae adjacent to a total disc replacement affects the facet joint and facet capsule forces in a probabilistic finite element analysis.

PURPOSE: After total disc replacement with a ball-and-socket joint, reduced range of motion and progression of facet joint degeneration at the index level have been described. The aim of the study was to test the hypothesis that misalignment of the vertebrae adjacent to the implant reduces range of motion and increases facet joint or capsule tensile forces. METHODS: A probabilistic finite element analysis was performed using a lumbosacral spine model with an artificial disc at level L5/S1. Misalignment of the L5 vertebra, the gap size of the facet joints, the transection of the posterior longitudinal ligament, and the spinal shape were varied. The model was loaded with pure moments. RESULTS: Misalignment of the L5 vertebra reduced the range of motion up to 2°. A 2-mm displacement of the L5 vertebra in the anterior direction already led to facet joint forces of approximately 240 N. Extension, lateral bending, and axial rotation caused maximum facet joint forces between 280 and 380 N, while flexion caused maximum forces of approximately 200 N. A 2-mm displacement in the posterior direction led to capsule forces of approximately 80 N. Additional moments increased the maximum facet capsule forces to values between 120 and 230 N. CONCLUSIONS: Misalignment of the vertebrae adjacent to an artificial disc strongly increases facet joint or capsule forces. It might, therefore, be an important reason for unsatisfactory clinical results. In an associated clinical study (Part 2), these findings are validated.

Monitoring the load on a telemeterised vertebral body replacement for a period of up to 65 months.

PURPOSE: To determine the postoperative temporal course of the forces acting on a vertebral body replacement (VBR) for two well reproducible activities. METHODS: A telemeterised VBR was implanted in five patients. It allows the measurement of six load components. Implant loads were measured in up to 28 measuring sessions for different activities, including standing and walking. RESULTS: The postoperative temporal course of the resultant implant forces measured during standing and walking was similar in each patient, but the patterns varied strongly from patient to patient. In one patient, the forces decreased in the first year and then increased in the following 4 years. In another patient, the forces increased in the first few months and then decreased. In a third patient, the forces varied only slightly in the postoperative time. In two patients, there was a strong drop of the implant force in the first two postoperative months. The force was on average approximately 100 N or 71% higher for walking than for standing. CONCLUSIONS: The strong force reduction in the first 2 months is most likely caused by implant subsidence, and the force reduction over a period of more than 6 months is most likely caused by fusion of the vertebrae adjacent to the VBR. The short-term force increase could be attributed to bone atrophy at the index level, and the long-term force increase could be attributed to an increase in the thoracic spine kyphosis angle.

[Proposal for participation in intensive care and emergency medicine studies for patients unable to give informed consent (Cologne Model)]. / Vorschlag für ein Verfahren zur Teilnahme an intensiv- und notfallmedizinischen Studien bei nichteinwilligungsfähigen Patient*innen (Kölner Modell).

When conducting clinical trials in intensive care and emergency medicine, physicians, ethics committees, and legal experts have differing views regarding the inclusion of patients who are incapable of giving consent. These different views on the participation of patients who are not capable of giving consent also complicate how clinical trials are prepared and conducted. Based on the results of a literature search, a consensus model (Cologne Model) was developed by physicians performing clinical research, ethics committees, and lawyers in order to provide patients, those scientifically responsible for the study, ethics committees, and probate (guardianship) judges with a maximum of patient safety and legal certainty, while simultaneously enabling scientific research.

Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation.

Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.

The role of a specialized approach for patients with diabetes, critical ischaemia and foot ulcers not previously considered for proactive management.

AIMS: To analyse the outcome of the proactive management of patients with diabetes, critical limb ischaemia and foot ulcers using percutaneous transluminal angioplasty as the only vascular procedure and adjuvant conservative surgery when indicated. METHODS: A retrospective study of patients with diabetes included in our database who sought a second opinion in our unit and met the following criteria: foot ulcer and critical limb ischaemia in patients for whom any proactive vascular treatment had not previously been considered by other teams. RESULTS: Twenty patients underwent endovascular procedures. Success was achieved in 19 cases (95%). No post-operative mortality (within 30 days after the procedure) was found. Additional surgery was required in eight cases (40%): one calcaneal ostectomy and seven minor amputations. The need for surgery was associated with infection (P < 0.01). Limb salvage was sustained during a mean period of follow-up of 642 days (SD 488) in 19 cases (95%). Healing was achieved in 14 cases (70%), four are still healing (20%), one underwent major amputation (5%) and the last one died before being healed (5%). Three patients died during follow-up (15%). CONCLUSIONS: Management of patients with diabetes, foot ulcers and critical limb ischaemia by means of a proactive approach including endovascular procedures in specialized settings provides a high rate of limb salvage. This may result in lowering the number of lower limb amputations in our community.

[Stiffening effect of a transsacral fusion system for the lumbosacral junction. A probabilistic finite element analysis and sensitivity study]. / Versteifungseinfluss eines transsakralen Fusionssystems. Eine probabilistische Finite-Elemente-Analyse und Sensitivitätsstudie.

The novel transsacral fusion system AxiALIF allows stabilization of the lumbosacral junction. The system consists of a screw with two different diameters. With additional facet screws or internal fixation devices 360° fusion can be achieved. The effects of different parameters such as length, diameter combination and material of the transsacral screw, type of additional fixation and stiffness of the bone are unknown. In a probabilistic finite element analysis, the input parameters were randomly varied. The rotational angles and the axial forces in the various implants were calculated for four different load scenarios. In a subsequent sensitivity study the influences of single input parameters on the variance of the results were calculated. A transsacral screw significantly reduces the motion in the treated segment, except for axial rotation. An additional fixation has a strong effect on the variance of rotation angles. The other parameters usually explain less than 10% of the variance. The novel lumbosacral fusion system allows good stabilization of the segment, especially when additional fixation via facet screws or fixators is performed.

[Tyrosine kinase inhibitors in oncology]. / Thyrosinkinaseinhibitoren in der Onkologie.

Tyrosin kinase inhibitors are still are relatively new group of drugs in oncology. But in the past few years they have gained an increasing importance due to the major and long lasting clinical benefit they induce in a subgroup of tumor patients. This success of tyrosin kinase inhibitors is based on the exquisite importance of tyrosin kinases for growth and survival of tumor cells. Prominent examples of such an oncogene dependency are the BCR-ABL fusion in chronic myeloid leukemia or EGFR mutations in lung adenocarcinoma. Many further tumor entities with clinically tractable oncogene dependencies can be expected in the upcoming years. An intense interaction between clinical science in clinical trials, preclinical research and excellent molecular quality controlled diagnostics is crucial for the further development.

Distribution of tumor-infiltrating-T-lymphocytes and possible tumor-escape mechanisms avoiding immune cell attack in locally advanced adenocarcinomas of the esophagus.

INTRODUCTION: The inflammatory microenvironment has emerged as one of the focuses of cancer research. Little is known about the immune environment in esophageal adenocarcinoma (EAC) and possible tumor-escape mechanisms to avoid immune cell attack. PATIENTS AND METHODS: We measured T cell inflammation (CD3, CD8) in the microenvironment using a standardized software-based evaluation algorithm considering different predefined tumor areas as well as expression of MHC class 1 and PD-L1 on 75 analyzable primarily resected and locally advanced (≥ pT2) EACs. We correlated these findings statistically with clinical data. RESULTS: Patients with high amounts of T cell infiltration in their tumor center showed a significant survival benefit of 41.4 months compared to 16.3 months in T cell poor tumors (p = 0.025), although CD3 fails to serve as an independent prognostic marker in multivariate analysis. For the invasion zone, a correlation between number of T-cells and overall survival was not detectable. Loss of MHC1 protein expression on tumor cells was seen in 32% and PD-L1 expression using the combined positive score (CPS) in 21.2%. Most likely due to small numbers of cases, both markers are not prognostically relevant, even though PD-L1 expression correlates with advanced tumor stages. DISCUSSION: Our analyses reveal an outstanding, though not statistically independent, prognostic relevance of T-cell-rich inflammation in our group of EACs, in particular driven by the tumor center. For the first time, we describe that the inner part of the invasion zone in EACs shows significantly fewer T-cells than other tumor segments and is prognostically irrelevant. We also demonstrate that the loss of antigen presenting ability via MHC1 downregulation by the carcinoma cells is a common escape mechanism in EACs. Future work will need to show whether tumors with MHC class 1 loss respond less well to immunotherapy.

Tuning the exciton binding energies in single self-assembled InGaAs/GaAs quantum dots by piezoelectric-induced biaxial stress.

We study the effect of an external biaxial stress on the light emission of single InGaAs/GaAs(001) quantum dots placed onto piezoelectric actuators. With increasing compression, the emission blueshifts and the binding energies of the positive trion (X+) and biexciton (XX) relative to the neutral exciton (X) show a monotonic increase. This phenomenon is mainly ascribed to changes in electron and hole localization and it provides a robust method to achieve color coincidence in the emission of X and XX, which is a prerequisite for the possible generation of entangled photon pairs via the recently proposed "time reordering" scheme.

Salvage of a subacute failure in femoral dialysis loop graft using stent covering the arterial and venous anastomosis.

Endovascular treatment can be considered the first line therapy in the majority of dysfunctioning arteriovenous fistula. However, when early thrombosis of the arteriovenous access occurs, surgical treatment is recommended. In these cases, technical problems are the most frequent cause of the malfunction. We report a case of a subacute thrombosis of an arteriovenous fistula, femoral artery to femoral vein looped ePTFE with venous anastomosis occlusion and subocclusion lesion at the arterial anastomosis. Both anastomoses were treated using self-expandable stents, and no other intervention was necessary until the one-year follow-up for maintain patency.