INTRODUCTION:Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients.METHODS:Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis.RESULTS:Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail.CONCLUSION:STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration.

Purpose In this study, we describe our experience with peptide receptor radionuclide therapy (PRRT) for initially unresectable liver disease as a two-steps therapeutic strategy, first in neoadjuvant intention before surgery and then later on in case of disease relapse. Methods We performed a retrospective evaluation of four cases of unresectable liver metastases of NET of different origins treated with neoadjuvant Lu-177-DotaTATE for conversion into resectability first and as rechallenging treatment after disease relapse. Results After treatment with Lu-177-DotaTAE, resectability was reached in three of four cases. In one case, SIRT was additionally performed preoperatively. Relapse occurred in three of four cases after 32, 34, and 37 months, respectively, and was managed with Re-PRRT-treatment. Conclusion Although more data are needed, our retrospective study suggests that treatment with Lu-177-DotaTATE is an important adjunct to surgery not only in neoadjuvant intention but also for treating disease relapse. A register study might deliver more evidence for supporting this strategy.

ZusammenfassungNeuroendokrine Neoplasien (NEN) umfassen eine seltene Tumorentität mit heterogener Biologie, Prognose und therapeutischen Optionen. In Zusammenhang mit der kürzlichen Publikation der ersten deutschen Leitlinie zur Diagnostik und Therapie von NEN erfolgte die Analyse der Kohorte des Deutschen NET-Registers der Deutschen Gesellschaft für Endokrinologie (DGE). Hierzu wurden 2686 Fälle extrahiert und ihre Patientencharakteristika wie Alter, Geschlecht, Primärtumorlokalisation, Grading und Staging dargestellt sowie das Gesamtüberleben berechnet. Zusätzlich wurden die systemischen Behandlungsstrategien in den beiden größten Untergruppen, NEN des Dünndarms und Pankreas, im Stadium der Metastasierung analysiert.Die Verteilung der Primärtumoren, die histopathologische Charakterisierung, das Tumorstadium sowie das Gesamtüberleben waren vergleichbar mit den Ergebnissen internationaler Registerstudien. Somatostatinanaloga (SSA) und die Peptid-Rezeptor-Radionuklid-Therapie (PRRT) waren die häufigsten systemischen Therapieverfahren bei Dünndarm-NEN. Hingegen wurde eine Chemotherapie – in Übereinstimmung mit der neuen Leitlinie – vor allem bei pankreatischen NEN eingesetzt und kam in der Erstlinie in ähnlicher Frequenz wie die SSA-Therapie bzw. in der Zweitlinie ähnlich häufig wie eine PRRT zum Einsatz. Prognostisch relevante Parameter waren die WHO-Klassifikation 2010 und das TNM-Staging.Die aktuelle Analyse des deutschen NET-Registers charakterisiert damit eine multizentrische, interdisziplinäre, deutschlandweite Kohorte von NEN-Patienten und beschreibt die angewendeten systemischen Therapieverfahren, das Gesamtüberleben und die prognostische Bedeutung der WHO-Klassifikation 2010 sowie des TNM-Stadiums.

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. Multicenter analysis of a series of stage I–III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5–187 months) 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 14 months, 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. Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Allogeneic hematopoietic stem cell transplantation represents a curative treatment approach for a large range of hematologic malignancies. Traditionally, high-dose radiochemotherapy as preparative regimen has been thought to be necessary for successful allogeneic stem cell transplantation. However, high-dose conditioning often results in considerable medullary and extramedullary toxicity, contributing to high rates of treatment-related mortality. This limits the use of this procedure to patients below 60 years of age without significant comorbidities. Since the peak incidence of most hematological malignancies is beyond the 5th decade of life, the majority of patients are not eligible for high-dose treatment. During the last 15 years, several dose-reduced or even non-myeloablative conditioning regimens have been developed, offering a curative treatment option for these patients. This review summarizes the history of reduced-intensity conditioning (RIC) transplantations, depicts the differences among regimens, highlights significant patient factors, and describes the impact on selected hematological malignancies.

Patients receiving high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) are at high risk of infections, especially bacteraemia. A prospective, double-blind, randomised, placebo-controlled, single-centre, pilot study was performed on oral moxifloxacin 400 mg versus placebo for preventing bacteraemia in PBSCT recipients. Patients received moxifloxacin or placebo for the duration of neutropenia or until emergence of fever or other infections necessitating intravenous antibiotic treatment. Of 68 patients included in the trial, 2 were excluded from the trial before taking their first dose. The remaining 66 patients were eligible for evaluation in the intention-to-treat analysis set. Neutropenia with an absolute neutrophil count of <500 cells/μL developed in 30 moxifloxacin-treated patients (88.2%) and 21 patients in the placebo group (65.6%) (P < 0.03). Nine patients (26.5%) and eight patients (25.0%), respectively, were prematurely discontinued from study treatment. Breakthrough bacteraemia occurred in 3 moxifloxacin-treated patients (8.8%) and 9 patients in the placebo group (28.1%) (P = 0.042). The time period until fever was 9.5 days [95% confidence interval (CI) 8.06–10.94 days) and 7.69 days (95% CI 6.51–8.85 days), respectively (P = 0.0499). There was no difference in adverse events or toxicities between the groups. Moxifloxacin prevented bacteraemia and shortened febrile episodes in patients receiving autologous PBSCT. No significant increase of adverse events in the moxifloxacin arm was observed, possibly due to the rather small sample size.

The expression of CD30 is restricted to cells of the immune system and strictly regulated under physiological conditions. However, active immune cells express CD30 and soluble CD30 (sCD30) is released. Several investigators reported the relevance for sCD30 as a predictive marker for allograft rejection following organ transplantation. We investigated the role of sCD30 in 30 patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. sCD30 was measured at different time points until day 120 post transplant. There was a great variety of sCD30 at baseline before transplantation. At time of engraftment, patients who developed no or only mild signs of acute graft-versus-host-disease (aGvHD) until day 120 had significant lower levels of sCD30 than patients who developed severe aGvHD. Moreover, all patients with aGvHD degrees III/IV showed a clear increase in sCD30 levels before clinical signs of aGvHD. Levels of sCD30 decreased if patients responded to aGvHD-therapy. We suggest a potential role of sCD30 serum levels in prediction of aGvHD following allogeneic stem cell transplantation.

Background: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. Methods: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. Results: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P <0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P <0.01) and a reduction of 91% in the hazard of death ( P <0.05). Conclusion: Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment.

Abstract Hodgkin’s disease can be cured by chemotherapy in the majority of cases. However a small proportion of patients show an aggressive course with multiple relapses after chemotherapy including autologous stem cell transplantation. Whether allogeneic stem cell transplantation constitutes a valid therapeutic option for these patients remains highly controversial. We report on our experience on 9 patients with Hodgkin’s disease receiving an allogeneic stem cell transplant from matched related (n=3), matched unrelated (n=1) or mismatched unrelated (2× 9/10, 2 ×8/10, 1× 7/10) donors. Median age was 28 years (range 18 – 35). All patients were extensively pre-treated including high-dose chemotherapy with autologous stem cell transplantation in 8 of 9 cases. The disease status before transplantation was CR (n=1), PR (n=5), SD (n=2) or progressive disease in 1 case. Conditioning treatment consisted of fludarabine 30 mg/m2 day -8 to -4, melphalan 70 mg/m2 day -3 to -2 and ATG 10–20 mg/kg day -4 to -2. Ciclosporin A and short course methotrexate was used for prophylactic immunosuppression. All patients showed prompt engraftment. Acute GvHD was found in 2 patients (Grade IV n=1, Grade I n=1), chronic GvHD did not occur after a median follow up of 471 days for the surviving patients. Two patients died from treatment-related causes, one from GvHD and one from septicemia. Estimated 2 year survival is 78%. Three patients have relapsed so far at day 128, 192 and 201 post transplant and received donor lymphocyte infusions or chemotherapy. The estimated 2 year disease free survival is 57%. Our results show a good feasibility of an allogeneic stem cell transplantation with reduced intensity conditioning for relapsed Hodgkin’s disease despite extensive pre-treatment and mostly partial remissions at transplant. The rate of acute and chronic GvHD was remarkably low in view of the fact, that 5 of 9 patients had mismatched unrelated donors. In summary allogeneic stem cell transplantation should be further exploited as treatment option for refractory and relapsed Hodgkin’s disease in younger patients.