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Zusammenfassung. Pankreatische neuroendokrine Tumore (PanNET) sind eine seltene und heterogene Gruppe von Tumoren mit sehr unterschiedlicher klinischer Präsentation. Dementsprechend sind diese im klinischen Alltag initial schwierig zu erkennen und die Diagnosestellung erfolgt häufig verzögert. Die nötigen diagnostischen Schritte beinhalten radiologische und funktionelle / nuklearmedizinische Untersuchungen, um einerseits die Ausdehnung des Primärtumors zu bestimmen und andererseits das Vorliegen von Metastasen zu erkennen. Gegeben falls ist eine Tumorbiopsie indiziert. Die daraus resultierenden Behandlungen beinhalten in Abhängigkeit vom Tumortyp sowie -ausbreitung und der Symptomatik die chirurgische Resektion, die Behandlung mittels Somatostatin-Analoga oder multimodale Therapiekonzepte. Die Therapie der Patienten mit neuroendokrinen Tumoren (NET) muss an einem interdisziplinären Tumorboard an einem spezialisierten Zentrum besprochen werden.

BACKGROUND Neuroendocrine neoplasms (NENs) are rare tumours with variable clinical behaviour. Their natural history is ideally best approached in large, multicentre and multinational registries with long-term patients' follow-up. The European Neuroendocrine Tumour Society registry aims to obtain information regarding NEN outcomes and prognostic factors in a European frame. PATIENTS AND METHODS We collected data from 7 national NEN registries (Belgium, Czech Republic, Germany, Greece, Poland, Spain, Switzerland), representing 10,102 patients. Anonymised/pseudonymised data were collected in a secured server. Descriptive statistical methods were applied, as well as Kaplan-Meier survival curves and multivariable analyses for prognostic factors of overall survival (OS). RESULTS median age of the study population was 60 years (range: 18-102), 48% were female. Common primary tumour sites were pancreas (27%) and small intestine (21%). Stage 4 disease was found in 47% of patients, while 26/10/16% had stage 1/2/3 disease, respectively. Grading (n = 6952) was G1/2/3 in 48/37/15% of the patients, respectively. Surgery was the main treatment, provided to 71% of patients, followed by somatostatin analogues (32%), chemotherapy (20%), Peptide receptor Radionuclide Therapy (PRRT) (9%) and targeted therapies (8%). OS at 5 years was 74%, influenced by grade, stage and tissue of origin in multivariate analysis. A Ki67 cut-off value set at 55% within the G3 group allowed to separate 2 groups with a meaningful different OS. CONCLUSION We report the first analysis of the European Neuroendocrine Tumour Society registry, comprising 10,102 patients with NEN from 7 European countries. This large cohort study describes prognostic factors for the survival of NENs throughout Europe, including primary tumour site, grade, stage and treatment.

Neuroendocrine tumor of the pancreas: What is new?

BACKGROUND Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials.��However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES To evaluate the safety and efficacy of therapies for��NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS We identified studies through systematic searches of the following bibliographic databases:��the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947��to December 2020. In addition,��we checked trial registries��for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses.��A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299��participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes��(e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

On 2 July 2021, Kronenfeld et al. [...].

Background Retroperitoneal sarcoma (RPS) is a rare disease often requiring multi-visceral and wide margin resections. Midline incision seems to be the access of choice. Up to now there is no evidence for the best surgical access. This study aimed to analyze the oncological outcome according to the incision used for the resection. Methods All patients treated for RPS between 2007 and 2018 at the Department of Visceral Surgery and Medicine of the University Hospital Bern and receiving a RPS resection in curative intent were included. Patient- and treatment specific factors as well as local recurrence-free survival was analyzed in correlation with the type of surgical access used. Results Thirty-five patients were treated for RPS at our center. The majority received their primary RPS resection at a tertiary medical center (n = 23) the rest of the resection were performed in an external non-tertiary institution (n = 12). Median tumor size was 24 cm. Resections were performed via a midline laparotomy (MI = 31) or flank incision (FI = 4). All FI were performed at a non-tertiary center and received no multi-visceral resection. In ML the macroscopically complete resection (R0/1) rate was 83.9% and 25% in FI (p = 0.021). The local recurrence rate after R0/1 resection was 100% in FI and 61.5% in ML (p = 1.00). Early recurrence or local disease progression was present in 50% of FI compared to 0% in ML (p = 0.01). The median recurrence-free survival after R0/1 resection was lower in FI (p

Introduction The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined. Methods We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis. Results Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component. Conclusions Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.

Purpose of Review Classification and nomenclature of neuroendocrine neoplasms (NEN) have frequently changed over the last years. These changes reflect both increasing knowledge and international standardisation. Recent Findings The most recent changes in the Gastro-Entero-Pancreatic system induced the concept of well-differentiated NET with high proliferation rate (NET G3), explaining partially the heterogeneity of G3 NEN. Even if the nomenclature in pulmonary NEN is still different, the terms ‘carcinoid’ and ‘atypical carcinoid’ are widely overlapping with NET G1 and NET G2. Molecular data shows an additional heterogeneity both in well-differentiated NET and poorly differentiated NEC. However, no studies are available demonstrating clinical usefulness yet. Summary The heterogeneity of NEN regarding the organ of origin, differentiation and molecular subtypes make development of personalised therapy a challenge needing more international and interdisciplinary collaborations and clinical trials allowing stratification according to biological subgroups.

According to the World Health Organization (WHO) classification, tumors showing hematogenous spread in less than 2% of cases are categorized as "rarely metastasizing" and constitute a group of neoplasms of intermediate malignancy. Since its introduction in 2002, chondroblastoma has been considered one of the prototypic examples of this category of lesions. In the fifth and only recently published edition of the WHO classification of bone and soft tissue tumors, however, chondroblastoma was re-classified from rarely metastasizing to benign due to the rarity of cases with systemic spread. Here, we present a remarkable case of a 54-year-old male who presented with an expansile tumor in his left acromion that was diagnosed as chondroblastoma following biopsy. Three years later a local recurrence was noted during routine follow-up and a bone scan detected hypermetabolic lesions in a rib and the thoracic spine. Over time, he developed multifocal skeletal spread as well as soft tissue and pulmonary metastases, which histologically all revealed conventional chondroblastoma morphology and the highly specific H3-3B point mutation (p.Lys36Met). Thirteen years after initial diagnosis he is currently treated with experimental immunotherapy and shows stable but disseminated disease. Our case highlights that although metastasizing chondroblastoma is rare, potential systemic spread should be kept in mind in patients with chondroblastoma despite the new WHO classification.

11502 Background: Outcome in EwS has improved by the implementation of dose or time intense systemic treatment. Aim of the study was evaluate whether treatment delays have impact on outcome of patients with localized Ewing sarcoma (EWS). Methods: Data from 692 patients with a tumor of the extremities, the pelvis, the chest wall and the trunk registered in the international database of the German Society for Pediatric Oncology and Hematology (GPOH) and treated in the Euro-E.W.I.N.G. 99 trial (NCT00020566) were analyzed. All patients underwent surgical treatment after induction chemotherapy. The optimal interval cut-off values for survival analyses were calculated with receiver operating characteristics curves. Hazard ratios (HR) were estimated with respective 95% confidence intervals (CI) in multivariate Cox regression models. Results: As per protocol, patients were to receive six cycles of VIDE induction chemotherapy in 21-day intervals. The duration between induction cycles as per protocol was fulfilled in only 5% of patients. In 72% of patients, the average interval duration between induction chemotherapy cycles was 25 days. Median interval between day 1 of the first induction chemotherapy cycle and definitive tumor surgery was 141 (IQR, 133 – 153) days in patients receiving six VIDE cycles prior to surgery. The optimal cut-off value for survival analyses in these patients amounted to 150 days. Patients with a duration of induction chemotherapy > 150 days were at higher risk to develop an event (HR, 1.546; 95% CI, 1.103 – 2.166) and had a higher risk of death (HR, 1.574; 95% CI, 1.095 – 2.262), compared to patients with a duration of induction chemotherapy < 150 days. Patients with delays during the induction chemotherapy also experienced a significant delay between VIDE 6 and surgery (36 vs. 27 days, p < 0.001) and were treated significantly more often at smaller low-volume centers (63% vs. 48%, p = 0.005). Patients with a prolonged interval > 21 days between surgery and day one of postoperative chemotherapy were at a higher risk to develop an event (HR, 1.406; 95% CI, 1.011 – 1.955), and also had a significantly higher rate of postoperative complications (26% vs. 11%, p < 0.001), compared to patients with a shorter interval. Conclusions: Delays between induction chemotherapy and surgery and between surgery and consolidation chemotherapy are independently associated with a poor outcome in patients with localized EWS. Our results also underscore the need to treat EWS patients in larger and experienced sarcoma centers. The implementation of new and standardized methods in the operative strategy and optimized supportive care during systemic therapy are required to reduce perioperative morbidity and treatment delays.

BACKGROUND In recent years, several treatment modalities have proved to be effective in the treatment of neuroendocrine tumours (NETs). However, there is currently no consensus on the sequence in which these options are best used. METHODS In this observational study, we analysed the treatment modalities and sequences of all patients included in the Swiss NeuroEndocrine Tumour registry (SwissNET). SwissNET is a national registry, which has prospectively included patients with a NET from all regions of Switzerland since 2008. RESULTS The registry includes 1366 patients; 1063 had documented therapies after the main diagnosis and were included in the analysis. The median follow-up time was 1.86 years. The most common primary site was the small intestine (291 patients, 27%) followed by pancreas (254 patients, 24%), lung (172 patients, 16%) and appendix (163 patients, 15%). A total of 167 different therapy sequences were observed. In 708 (67%) patients, surgery was the only treatment. The sequence of surgery followed by chemotherapy was most frequently documented in poorly (G3) differentiated (24 patients, 60%) and pancreatic (15 patients, 34%) NETs. Tumours treated with surgery followed by biotherapy or followed by peptide receptor radionuclide therapy (PRRT) were predominantly well-differentiated G1 NETs of the small intestine. In patients who were treated with either PRRT or systemic therapy (chemotherapy or molecular therapy) or both, PRRT was used more frequently than systemic therapy in patients with a small intestinal NET (35 patients, 62% vs 30, 54%), whereas the opposite held true in pancreatic (44 patients, 59% vs 56, 70%) and lung NETs (6 patients, 14% vs 40, 97%). If both chemotherapy and molecular therapy were used, chemotherapy was applied prior to molecular therapy in 13 of 19 (68%) patients with a pancreatic NET. CONCLUSION Surgery represents the treatment of choice in most patients with a NET irrespective of tumour stage. In patients receiving additional treatment, an impressive variety of treatment sequences were documented. In small intestinal NETs, patients received PRRT more often than chemotherapy, whereas the opposite holds true for patients with pancreatic and lung NETs.

Cardiac myxoma can embolize and cause early and delayed sequelae including stroke, growth into intracranial fusiform aneurysms and cerebral tumors with risk of hemorrhage and mass effect. Here, we report the rare coincidence of all these manifestations in a 63-year-old man who presented with cognitive and behavioral changes, and seizures 9 months after an embolic stroke from the heart tumor. C-reactive protein (CRP) was elevated at the time of stroke and cardiac myxoma diagnosis but was normal at late neurologic manifestation with isolated myxoma-related intracranial tumors and aneurysms. Low-dose whole-brain radiotherapy can be helpful to diminish cerebral myxoma tumors and fusiform aneurysms despite reported increased risk of aneurysm rupture.

Background: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. Patients and Methods: Multicenter analysis of a series of stage I–III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. Results: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23months (5–187months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. Conclusions: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Background Research on soft-tissue sarcoma (STS) and bone sarcoma (BS) is increasingly in the focus of physicians and pharmaceutical companies. Expanding knowledge has improved the management of sarcoma and possibly survival. Here we provide the first population-based data on time trends of incidence, mortality, and survival of STS and BS diagnosed in Switzerland between 1996 and 2015. Methods We performed a retrospective registry study with data from the National Institute for Cancer Epidemiology and Registration (NICER) database in Switzerland between 1996 and 2015. Results We identified 5384 STS patients and 940 BS patients. The three most common STS subtypes were undifferentiated/unclassified sarcoma (22.3%), liposarcoma (20.6%) and leiomyosarcoma (20.6%). Chondrosarcoma, osteosarcoma and Ewing sarcoma represented 40.4%, 27.0% and 15.2% of the BS group, respectively. The age-standardized incidence and mortality rates in 2011–2015 were 4.43 and 1.42 per 100,000 person-years for STS, and 0.91 and 0.42 for BS. Age-standardized incidence of STS in males was significantly higher during 1996–2000 than during 2001–2015; however, mortality rates did not change significantly over time. Five-year relative survival (RS) for STS improved significantly from 56.4% (95%CI 52.9–59.7 for 1996–2001) to 61.6% (95%CI 58.6–64.4 for 2011–2015) (p = 0.025). No improvement in 5-year RS for BS could be observed (RS 1996–2000: 69.6%, 95%CI 61.2–76.6; RS 2011–2015: 73.1%, 95%CI 66.6–78.6; p = 0.479). Conclusion Incidence rates of STS and BS have been stable since 2001. The longer RS in STS can be attributed to advances in sarcoma patient management.

Passenger car unit is an important comparison factor that helps the traffic engineer to describe the impact of heterogeneous traffic flows on the traffic performance of the infrastructure elements,...

Background The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre- and postoperative chemotherapy is unclear and debated among experts. Materials and Methods Medical oncology experts of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group were asked to participate in this survey on the use of pre- and postoperative chemotherapy in STS. Experts from 12 centers in Belgium, France, Germany, Great Britain, Italy, Switzerland, and The Netherlands agreed to participate and provided their treatment algorithm. Answers were converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies. Results Several criteria used for decision-making in extremity STS were identified: chemosensitivity, fitness, grading, location, and size. In addition, resectability and resection status were relevant in the pre- and postoperative setting, respectively. Preoperative chemotherapy is considered in most centers for marginally resectable tumors only. Yet, in some centers, neoadjuvant chemotherapy is used routinely and partially combined with hyperthermia. Although most centers do not recommend postoperative chemotherapy, some offer this treatment on a regular basis. Radiotherapy is an undisputed treatment modality in extremity STS. Conclusion Due to lacking evidence on the utility of pre- and postoperative chemotherapy in localized extremity STS, treatment strategies vary considerably among European experts. The majority recommended neoadjuvant chemotherapy for marginally resectable grade 2–3 tumors; the majority did not recommend postoperative chemotherapy in any setting. Implications for Practice The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre- and postoperative chemotherapy is unclear and debated among experts. This study analyzed the decision-making process among 12 European experts on systemic therapy for STS. A wide range of recommendations among experts regarding the use of perioperative chemotherapy was discovered. Discrepancies in the use of decision criteria were also uncovered, including the definition of what constitutes high-risk cancer, which is a basis for many to recommend chemotherapy. Before any standardization is possible, a common use of decision criteria is necessary.

On 2 July 2021, Kronenfeld et al. [...]

Importance Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs). Objective To assess the relative safety and efficacy of therapies for NETs. Data Sources PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. Study Selection Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. Data Extraction and Synthesis Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Main Outcomes and Measures Disease control, progression-free survival, overall survival, adverse events, and quality of life. Results The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]) interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]) , and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]) and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. Conclusions and Relevance The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.

We aimed to assess the risk of developing diabetes mellitus and its effects on all-cause mortality after radiopeptide therapy for neuroendocrine tumors (NET). Methods: NET patients received somatostatin radiopeptide therapy with yttrium-90-DOTATOC and/or lutetium-177-DOTATOC. The incidence of diabetes mellitus and its mortality were assessed using univariate and multivariate regression. Results: Overall, 1535 NET patients were enrolled, and received 3807 treatment cycles. After treatment, 72 patients developed diabetes mellitus, including 47 cases after yttrium-90-DOTATOC and 25 cases after combined treatment. The diabetes mellitus risk was higher before than after DOTATOC (Estimate: 0.0032, P < 0.001), and overall survival was similar in patients with and without diabetes mellitus (HR: 1.13, 95%CI: 0.91-1.39, n = 1535, P = 0.27). Conclusion: Radiopeptide therapy does not appear to increase the risk of developing diabetes mellitus in NET patients, while diabetes mellitus does not appear to increase the mortality of NET patients undergoing receptor-targeted radiopeptide therapy.

Thromboangiits obliterans (Buerger’s disease) is a non-atherosclerotic, segmental inflammatory and obliterative disease affecting small and medium sized arteries and veins. The etiology is still unknown, but it is in close relationship with tobacco use. Symptoms begin under the age of 45 years and the undulating course is typical. Patients usually present with acute and chronic ischemic or infectious acral lesions. Diagnosis is usually based on clinical and angiographic criteria and it is important to exclude autoimmune disease, thrombophilia, diabetes, and proximal embolic sources. Even though Buerger’s disease most commonly involves the arteries of the extremities, the pathologic findings sometimes affect the cerebral, coronary and internal thoracic, renal and mesenteric arteries as well. The authors present the history of a patient with known Buerger’s disease and acute ischemic stroke. Brain imaging detected acute and chronic ischemic lesions caused by middle cerebral non-atherosclerotic arteriopathy on the symptomatic side. Other etiology was excluded by detailed investigations. Orv. Hetil., 2016, 157(30), 1207–1211.

Background Pelvic tumors are usually resected through the utilitarian pelvic incision, an extended ilioinguinal/iliofemoral approach. The pararectus approach, an intrapelvic anatomical approach with extraperitoneal access to the pelvis, has been established previously for the treatment of pelvic and acetabular fractures. However, it has not been used to address pelvic tumors. The study aimed at investigating the feasibility of this approach for pelvic tumor surgery and the possibilities of combining this approach with standard approaches to the hip joint. Methods Thirteen patients that underwent pelvic tumor resections were retrospectively reviewed. Tumor resections were performed through the pararectus (n = 10) or extended pararectus approach (n = 3). In six of those cases, the pararectus approach was combined with extrapelvic approaches including the modified Gibson (n = 4), the Kocher-Langenbeck (n = 1), and the trochanteric flip approach (n = 1). The mean follow-up was 32.6 ± 9.1 months. Results In all cases, the tumor resections were carried out according to the preoperative plan. In seven of 13 cases, wide resections were performed; six of 13 cases were planned close resections. Four cases of major complications were observed (vascular injury, deep infection, iliac vein thrombosis, total hip arthroplasty dislocation). Minor complications were observed in two cases. One tumor recurred locally. At the final follow-up, 10 patients were alive, eight of those without evidence of disease. Conclusion The study demonstrated the suitability of the pararectus approach for pelvic tumor resections. The possibility to combine the approach with standard approaches to the hip joint allowed for single-stage reconstructions of the pelvis and the hip joint without sacrificing surgical margins and function. The pararectus approach is a versatile option adding to the established approaches for musculoskeletal tumor surgery of the pelvis.

Background The outcome for patients with unresectable or metastatic soft tissue sarcoma (STS) is poor. Following failure from first-line doxorubicin based chemotherapy no standard therapy has been established. Combination treatment with docetaxel/gemcitabine (gem) has emerged as an effective regimen but administration is limited to fit patients only due to the toxicity profile. Nanoparticle albumin bound paclitaxel (nab-PC) was invented for avoidance of the toxicities related to polyethylated castor oil. In this context, we want to evaluate toxicity and antitumor effect of biweekly nab-PC 150mg/m2 / gem 1000mg/m2 administration in STS patients. Methods We conducted this proof-of-concept phase I trial to assess the safety of biweekly nab-PC/gem administration in the 2nd and 3rd line setting of STS. Results As of 1 April 2019, 6 pts were treated within the phase I. Three pts were male (50%); median age was 67 yrs (range 44 – 72). The current total number of biweekly doses received is 29 (median biweekly doses per patient is 5, range 2 – 7). One dose reduction due to skin toxicity occurred. 3 pts remain on study, 3 stopped treatment due to treatment unrelated reasons (refusal, death unrelated to progression or toxicity and investigator’s decision). The most common treatment-emergent AEs Gr1-2 were fatigue (3 pts), alopecia (3 pts), and neutropenia (2 pts). There were no dose-limiting toxicities or discontinuations due to AEs. We were able to confirm the tolerability of the regimen and are currently accruing patients to a prospective single arm phase II trial. Treatment will be given biweekly until progression, unacceptable toxicity or patient withdrawal. The primary endpoint of the trial is progression-free rate (PFR) at 12 weeks. Secondary endpoints are PFS, overall survival and symptom-specific quality of life. A total of 8 Swiss sites will participate for a total of 37 patients, as required by Simon’s two-stage design. Conclusions These preliminary results indicate that biweekly administration of nab-PC/gem was well tolerated. The phase I established dose and schedule were selected for further evaluation in phase II trial. Clinical trial identification NCT03524898. Editorial acknowledgement Celgene Corporation. Legal entity responsible for the study Swiss Group for Clinical Cancer Research (SAKK). Funding Swiss League Against Cancer, Celgene. Disclosure A. Digklia: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen, PharmaMar, Servier, BMS; Research grant / Funding (self), Research grant / Funding (institution): Research Funding Recipient Institution. C. Britschgi: Advisory / Consultancy: Roche, Pfizer,takeda,AstraZeneca. Y. Metaxas: Advisory / Consultancy: Roche, MSD, Pierre Fabre, Merck-Serono, BMS. F. Krasniqi: Advisory / Consultancy: Roche Pharma (Schweiz) AG, Mundipharma Medical Company (Schweiz), Celgene GmbH. A. Stathis: Travel / Accommodation / Expenses: Abvie, PharmaMar; Research grant / Funding (institution): Amgen, Bayer, Novartis, Roche, MEI-Pharma. T. Rordorf: Advisory / Consultancy: Bristol-Myers Squibb and Merck KGaA. N. Mach: Honoraria (institution), Advisory / Consultancy: Amgen, AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp and Dohme, Merck Serono, Novartis, Pharma Mar, as well as honorarium for talks in a company’s organised public event from Bristol-Myers Squibb and Pharma Mar. C.A. Rothermundt: Advisory / Consultancy: BMS, Astellas Pharma Schweiz, GSK, Novartis, Roche, Pfizer, PharmaMar; Research grant / Funding (institution): Research Funding Recipient Institution. All other authors have declared no conflicts of interest.

WHAT THIS PAPER ADDS Minimally invasive interventional procedures tend to be even less invasive. In this spirit, 4F sheath compatible femoropopliteal stents have been developed. The number of studies regarding the safety, clinical outcome, and fracture rate of 4F stents is limited. Access site complications occurred in 2% of the patients.The overall primary patency rate was 80% with 85% freedom from target lesion revascularization at 12 months. The incidence of stent fractures was 26% after an average follow up of 25 months. These results confirm the validity of 4F stents in patients with femoropopliteal occlusive disease. Objective: To determine the safety, clinical outcome, and fracture rate of femoropopliteal interventions using 4F stents. Methods: Between January 2010 and December 2011, 112 symptomatic patients were treated by stent implantation. Ten patients were lost to follow up; therefore, 102 patients (62 men; mean age 66.4 � 10.1 years) were retrospectively analyzed. The indication for femoropopliteal revascularization was severe claudication (RutherfordeBecker score ¼ 3) in 63 (62%) patients and chronic critical limb ischemia (RutherfordeBecker score ¼ 4e6) in 39 (38%). Follow up included palpation of peripheral pulses and measurement of ankle brachial index. In patients with suspected in-stent restenosis duplex ultrasonography was performed. In 2013, patients were asked to return for a fluoroscopic examination of the stents. Results: 114 lesions (Trans-Atlantic InterSociety Consensus-C and D, n ¼ 45) were treated with 119 stents (Astron Pulsar, n ¼ 42; Pulsar-18, n ¼ 77). Lesions were long (� 100 mm) in 49 cases and heavily calcified in 35. Stents were long (� 120 mm) in 46 cases. Ten stents were partially overlapped. The technical and clinical success rates were 100%. Two puncture related complications were noted, neither of which required surgical repair. Eleven patients died (myocardial infarction, n ¼ 4; stroke, n ¼ 2; cancer, n ¼ 5) and nine patients underwent major amputation (above knee, n ¼ 4). The primary patency rate was 83% at 6 months and 80% at 12 months. The primary assisted patency rate was 97% at 6 months and 94% at 12 months. The secondary patency rate was 86% at 6 months and 85% at 12 months. The prevalence of fractures was 26% (type III and IV, 10%) after an average follow up of 25 months. Conclusion: Femoropopliteal stenting using a 4F compatible delivery system can be accomplished with a low complication rate, acceptable fracture rate, and with similar 12 month patency and revascularization rates as

In the junction capacity calculation methods the passenger car unit has a very important effect, because heavy vehicle traffic flow can only be counted with passenger car unit. Since not the proper passenger car unit values are used in the current practice, the results of junction capacity calculations cannot be regarded as correct, either. This research is focused on finding an answer as to whether the results are more precise if models with three junctions are examined rather than models with one junction.

Soft tissue sarcomas are rare tumors of mesenchymal origin comprising about 1% of all adult malignant diseases. Systemic therapy for locally advanced and metastatic disease was restricted for decades to a few effective and approved agents, such as doxorubicin or ifosfamide. However, numerous clinical trials and new drug developments such as trabectedin, pazopanib, olaratumab or eribulin have recently enriched the therapeutic armamentarium in the treatment of patients with advanced soft tissue sarcomas and will be presented in the following review.

Contains fulltext : 170335.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

In this research it will be accomplished the supervision of valid passenger car unit values, which are applied in effective road technical specifications. It was used VISSIM micro simulation program made by PTV Ag. It has been examined four different types of junctions (T-intersections, 4-leg intersections, signalized intersections, roundabouts).Simulation running have been completed to the different types of junctions with different types of vehicles, random factors and volume of traffic from which it could be defined those PCU values, which indicate current traffic situations. They have been compared to values applied at the moment and I propose PCU values for capacity calculations.

Liposarcoma (LS) represents one of the most common soft tissue sarcomas. There are three major subtypes, namely, well/dedifferentiated, myxoid/round cell and pleomorphic LS. In general, LS is known to be a relatively chemo-resistant sarcoma subtype with the exception of the myxoid variant. Conventional chemotherapy with doxorubicin and ifosfamide represents the mainstay of systemic treatment in the first line. Other active cytotoxic agents include gemcitabine and docetaxel and the marine-derived compounds trabectedin. Recent progress in molecular diagnostics of each single LS subtype has improved the knowledge of the molecular characteristics and has led to two recent treatment targets: the amplification of mouse double minute 2 homolog and cyclin-dependent kinase-4 in well- and dedifferentiated LS. Thus far, only early-phase trials are reported and no new drugs have been introduced in daily clinical practice. The focus of this review is on current systemic treatment options, including novel strategies.

To the Editor, Neurofibromatosis type 2 is a hereditary tumor predisposition syndrome manifesting with bilateral vestibular schwannomas, schwannomas of other cranial nerves, meningiomas, spinal sch...

PRINCIPLES Neuroendocrine neoplasms (NENs) are believed to be associated with an increased risk for additional malignancies (AMs). We aimed to (1) assess the occurrence of AM in NEN patients (2) investigate the characteristics and temporal relationship of NEN patients with and without AM. METHODS The SwissNET registry has prospectively documented patients with NEN since 2008, covering the entire area of Switzerland. Clinical characteristics, functionality, location and histology of NEN as well as survival of all consecutive patients were retrieved. The characteristics of the AM (location, histology, time point of diagnosis in relation to diagnosis of NEN) were extracted. RESULTS Out of 934 patients, 193 patients (21%) presented with AMs. There was no statistically significant difference with regard to location, functionality and grading (G1-G3) between the NEN patients with and without AM. AMs were diagnosed synchronously (±3 months), before (>-3 months) and after (>+3 months) diagnosis of NEN in 82 (42%), 96 (50%) and 13 (7%) patients, respectively. Location of NEN correlated with the anatomical origin of the AM. Age- and gender- corrected survival was not significantly different between NEN patients with and without AM. CONCLUSION The prevalence of AM in NEN is high. The comparable characteristics with regard to functionality and grading in the NEN cohorts with and without AM and the similar location of AM and NEN suggest a selection bias towards frequent imaging procedures in NEN patients with AM.

Thromboangiits obliterans (Buerger's disease) is a non-atherosclerotic, segmental inflammatory and obliterative disease affecting small and medium sized arteries and veins. The etiology is still unknown, but it is in close relationship with tobacco use. Symptoms begin under the age of 45 years and the undulating course is typical. Patients usually present with acute and chronic ischemic or infectious acral lesions. Diagnosis is usually based on clinical and angiographic criteria and it is important to exclude autoimmune disease, thrombophilia, diabetes, and proximal embolic sources. Even though Buerger's disease most commonly involves the arteries of the extremities, the pathologic findings sometimes affect the cerebral, coronary and internal thoracic, renal and mesenteric arteries as well. The authors present the history of a patient with known Buerger's disease and acute ischemic stroke. Brain imaging detected acute and chronic ischemic lesions caused by middle cerebral non-atherosclerotic arteriopathy on the symptomatic side. Other etiology was excluded by detailed investigations. Orv. Hetil., 2016, 157(30), 1207-1211.

PurposePleomorphic rhabdomyosarcoma (RMS) represents a rare sarcoma subtype of the adult population. Due to its clinical characteristics, treatment is currently based on the guidelines for adult soft tissue sarcoma therapy. Hence, in the metastatic setting, doxorubicin-containing regimens are used in the sarcoma community, with limited treatment benefit. Scanty published data are available on the efficacy of systemic treatment. Whether treatment response and outcome of these patients could be improved by using pediatric protocols used typically in other RMS subtypes, like embryonal and alveolar RMS, is unclear. We report on an impressive effect of multiagent pediatric chemotherapy in an adult patient with metastatic pleomorphic RMS.MethodsWe present the case of a 70-year-old man with metastatic pleomorphic RMS of his left thigh. Systemic chemotherapy according to the VAC regimen (vincristine, actinomycin, cyclophosphamide) was initiated. Follow-up clinical and radiologic assessment demonstrated an impressive treatment response.ResultsSixteen months after primary diagnosis, computed tomography scan shows no signs of tumor progression.ConclusionsOur case report emphasizes that multiagent systemic therapy according to pediatric protocols should be considered in adult patients with pleomorphic RMS.

4095Background: Global European high quality epidemiologic data on Neuroendocrine Neoplasms (NEN) are lacking. There is limited knowledge on the contribution of prognostic factors on patient (pt) m...

Gastrointestinal stromal tumours (GIST) represent the most common mesenchymal neoplasm in the gastrointestinal tract with an annual worldwide incidence of approximately 15 cases per million per year. They are thought to arise from the interstitial cells of Cajal, which are part of the autonomic nervous system of the intestine. The primary treatment goal in early-stage disease is complete surgical resection, but recurrence and metastasization can be documented in more than 40 % of cases during follow-up.

In this trial, stopping bevacizumab after completion of induction chemotherapy was associated with a shorter time to progression, but no statistically significant difference in overall survival compared with the bevacizumab continuation strategy. Non-inferiority could not be demonstrated. Treatment costs are substantially higher for continuous bevacizumab treatment. Background Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. Patients and methods In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4–6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. Results The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1–5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8–3.8) months for no continuation; HR 0.74 (95% CI 0.58–0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63–1.1;P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30 000 USD per patient. Conclusions Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4–6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. Clinical trial registration ClinicalTrials.gov, number NCT00544700.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. There is an urgent need to better diagnose and monitor IPF patients as new treatments are now available which slow down disease progression. Exhaled breath condensate (EBC) is easily and non-invasively collected, but analysis of potential biomarkers is difficult due to low concentrations and methodological limitations. We now used a non-targeted metabolomics approach to identify further discriminatory metabolic profiles that distinguish IPF patients from controls. We collected EBC from 10 stable IPF patients and 10 lung healthy controls. Samples were analyzed by ultra high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) in positive and negative ion mode. An in-house established bioinformatics pipeline was applied for data processing and analysis. In total 31 metabolites were found to be discriminative between IPF patients and controls. By univariate statistics of both datasets, 8 metabolic features remained significant (standardized abundance, FDR p-value < 0.05). Of them, all were detected in positive ion mode. Changes up to 3-fold were observed and all candidates were down-regulated in IPF patients compared to controls. Even though a discriminative metabolite signature was found between IPF patients and controls, the identities of the individual metabolites still remain elusive. Our preliminary results identified a distinguished EBC profile of IPF patients compared to controls. Although these results need to be confirmed in additional individuals, EBC sampling as a method to diagnose and/or monitor IPF patients is a promising, exciting new method, which deserves further exploration. The EBC samples have been obtained within the clinical trial NCT02173145 at baseline.

REPLY: We thank Drs. Pakzad and Safiri for their interest in our paper ([1][1]). We agree that there are a variety of methodologic questions to potentially be discussed ([2][2]–[4][3]), but we disagree with their criticism of our paper. First, they prefer an analysis of cause-specific survival

Background and aim. Hepatocellular carcinoma (HCC) is a frequent cancer. Its prognosis is highly dependent on early diagnosis. Patients at risk for developing HCC should be enrolled in a surveillance programme. Nevertheless, many patients at risk are not regularly screened. We aimed at exploring the characteristics that affect enrolment in a surveillance programme. Material and methods. The characteristics of the patients included in the prospective Bern HCC cohort between August 2010 and August 2011 were analysed according to their participation in a surveillance programme. Results. Among the 82 patients included in the cohort during this period of time, 48 were in a surveillance program before the diagnosis of HCC. Thirty five percent of cirrhotic patients were not screened. Age, sex, level of education, Child-Pugh status and MELD score were similar between the patients who were screened and those who were not screened. Patients with a private insurance and patients treated by a liver specialist were more frequently enrolled in a surveillance program. Sixty seven percent of the screened patients were eligible for curative treatment whereas only 15% of the non-screened patients were. Conclusions. In conclusion the surveillance of patients at risk for developing HCC increases their chances to be diagnosed at an early stage to allow curative treatment. More than one third of cirrhotic patients were not regularly screened. Patients with chronic liver disease should be referred to identify those at risk and enrol them in a surveillance program.

The activation of cytoplasmic signal transduction pathways by a number of growth factors and their tyrosine-kinase receptors, including hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met, exerts an inhibitory influence on apoptosis induced by ionizing radiation in vitro. The clinical relevance of the aforementioned ligand-receptor pair, of Bcl-xL, which is targeted by HGF/SF/c-met signaling, and of Bcl-2, was assessed by evaluating their predictive and prognostic impact in a cohort of 97 patients with radically irradiated squamous cell cancers of the oropharynx. Immunohistochemical expression of c-met and Bcl-xL was correlated with decreased rates of complete remission of the primary tumor in both the univariate (c-met: P = 0.01; Bcl-xL: P = 0.001) and multivariate analyses. Expression of c-met was, moreover, a significant and independent predictor of impaired local failure-free survival (P = 0.003), disease-free survival (P = 0.003) and overall survival (p = 0.001). Bcl-2 expression was, on the other hand, associated with a favorable outcome, in terms of both local failure-free survival (P = 0.01) and overall survival (P = 0.001). In accordance with in vitro data, c-met and Bcl-xL appear to be involved in the resistance of oropharyngeal cancers to ionizing radiation, and may therefore represent attractive targets for radiosensitization.

Purpose: To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. Materials and Methods: 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of ×200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. Results: Increasing IMD (range, 54–282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0.0001; IMD categorical: ≤ 80: baseline, 81–110: risk ratio = 2.71, 111–130: risk ratio = 4.55, > 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). Conclusion: IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.