Publications by authors named "Alexander Stein"

114 Publications

A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer.

Future Oncol 2021 May 17. Epub 2021 May 17.

Universitätsmedizin der Johannes Gutenberg-Universität Mainz, I. Medizinische Klinik und Poliklinik, Langenbeckstrasse 1, 55131 Mainz, Germany.

To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1-5 and 8-12 of a 28-day cycle, REG on days 2-22. Two dose levels were used: FTD/TPI 25 mg/m b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m b.i.d. + REG 120 mg/d. In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51-5.29), median OS 11.1 months (95% CI: 2.3-18.2). The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.
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http://dx.doi.org/10.2217/fon-2021-0278DOI Listing
May 2021

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Cancer Treat Rev 2021 Jun 2;97:102172. Epub 2021 Mar 2.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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http://dx.doi.org/10.1016/j.ctrv.2021.102172DOI Listing
June 2021

Effects of a structured counselling-based intervention to improve physical activity behaviour of adolescents and young adult cancer survivors - the randomized phase II Motivate AYA - MAYA trial.

Clin Rehabil 2021 Mar 9:269215521997974. Epub 2021 Mar 9.

Department of Oncology and Hematology, BMT with Section Pneumology, Hubertus Wald Tumor Center - University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: To explore whether a structured counselling-based intervention increases vigorous physical activity behaviour of adolescent and young adult cancer survivors.

Design: Randomized controlled phase II trial.

Setting: University Cancer Center Hamburg, Germany.

Subjects: Eighty-nine participants (mean age 24.1 ± 6.3) were randomized to control ( = 44) or intervention group ( = 45).

Interventions: The intervention group was consulted about physical activity behaviour via interview (week 0), and telephone counselling (weeks 1, 3 and 12). The control group only received general physical activity guidelines for cancer survivors (week 0).

Main Measures: The primary outcome was the rate of participants with ⩾9 metabolic equivalent (MET)-hours per week of vigorous activity post-intervention, measured with the International Physical Activity Questionnaire. Secondary outcomes included assessing physical activity behaviour (e.g. amount and type of physical activity) and quality of life. Assessments were completed in weeks 0 (baseline), 12 (post-intervention) and 52 (follow-up).

Results: Sixty-nine participants completed the post-intervention- and 47 the follow-up-assessment. The rate of participants performing vigorous physical activity increased from baseline to post-intervention for both without differing significantly ( = 0.541). Both increased their total metabolic equivalent from baseline to post-intervention (intervention group from 55.2 ± 43.7 to 61.7 ± 29.4, control group from 75.3 ± 81.4 to 88.3 ± 80.2). At follow-up the intervention group (73.7 ± 80.2) was more active than baseline when compared to the control group (78.5 ± 50.0).

Conclusions: A structured counselling-based physical activity intervention did not significantly impact the level of vigorous physical activity behaviour in adolescent and young adult cancer survivors.
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http://dx.doi.org/10.1177/0269215521997974DOI Listing
March 2021

Reply to P. Potemski and K. Bujko.

J Clin Oncol 2021 Apr 23;39(11):1306-1308. Epub 2021 Feb 23.

Hans-Joachim Schmoll, MD, Martin Luther University, Halle, Germany; Murielle E. Mauer, PhD, and Sandrine Marreaud, PhD, EORTC Headquarters, Brussels, Belgium; and Alexander Stein, MD, Hematology-Oncolology Practice Eppendorf, University Cancer Center Hamburg, Hamburg, Germany.

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http://dx.doi.org/10.1200/JCO.20.03687DOI Listing
April 2021

Long-Term Follow-Up of Children, Adolescents, and Young Adult Cancer Survivors.

Oncol Res Treat 2021 16;44(4):184-189. Epub 2021 Feb 16.

Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Background and Summary: Thanks to increasing cure rates to currently >80%, children, adolescents, and young adults (CAYA) survive their cancer much more frequently today than decades ago. Due to their long life expectancy, CAYA cancer survivors are at a particular risk of long-term sequelae from the cancer itself or the therapy applied; this requires specific follow-up, and preventative or even therapeutic interventions. Thus, compared to the normal population, morbidity and mortality may be significantly increased. In 2 of 3 survivors, the cancer and the respective treatment can lead to late effects, even after 30 years, which require specific therapy; in about one-third of these cases, these effects are classed as severe. Applying structured follow-up could identify these late effects at an early stage and initiate immediate treatment. In 2018, a working group dealing with long-term survival after cancer detected <40 years of age was founded within the framework of the National Cancer Plan of the German Federal Ministry of Health.
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http://dx.doi.org/10.1159/000514381DOI Listing
February 2021

A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain.

Nat Commun 2021 01 19;12(1):463. Epub 2021 Jan 19.

Brain and Mind Research Institute and Center for Neurogenetics, Weill Cornell Medicine, New York, NY, USA.

Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 ( www.isoformAtlas.com ). Isoform tests for DIE show better performance than exon tests. We detect hundreds of DIE events traceable to cell types, often corresponding to functionally distinct protein isoforms. Mostly, one cell type is responsible for brain-region specific DIE. However, for fewer genes, multiple cell types influence DIE. Thus, regional identity can, although rarely, override cell-type specificity. Cell types indigenous to one anatomic structure display distinctive DIE, e.g. the choroid plexus epithelium manifests distinct transcription-start-site usage. Spatial transcriptomics and long-read sequencing yield a spatially resolved splicing map. Our methods quantify isoform expression with cell-type and spatial resolution and it contributes to further our understanding of how the brain integrates molecular and cellular complexity.
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http://dx.doi.org/10.1038/s41467-020-20343-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815907PMC
January 2021

Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma: Final Results of the PAPAGEMO Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Feb;7(2):255-262

University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required.

Objective: To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone.

Design, Setting, And Participants: This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020.

Interventions: Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B).

Main Outcomes And Measures: The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates.

Results: A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological.

Conclusions And Relevance: This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma).

Trial Registration: German Clinical Trials Identifier: DRKS00003139.
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http://dx.doi.org/10.1001/jamaoncol.2020.6564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758834PMC
February 2021

Adding cetuximab to paclitaxel and carboplatin for first-line treatment of carcinoma of unknown primary (CUP): results of the Phase 2 AIO trial PACET-CUP.

Br J Cancer 2021 02 25;124(4):721-727. Epub 2020 Nov 25.

Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Background: Patients with carcinoma of unknown primary (CUP) have a dismal prognosis, even when treated with multi-agent chemotherapy. We hypothesised that adding the epidermal growth-factor receptor (EGFR) inhibitor cetuximab to standard first-line chemotherapy with paclitaxel and carboplatin would improve PFS and RR in unfavourable CUP.

Methods: This open-labelled, multicentre Phase 2 study included patients with unfavourable, untreated adeno- or undifferentiated CUP. Patients were randomised to receive either paclitaxel/carboplatin (group A) or paclitaxel/carboplatin plus cetuximab (group B) every 3 weeks for a maximum of 6 cycles followed by cetuximab maintenance in group B. The primary endpoint was PFS in the two groups. Secondary endpoints were RR, toxicity and overall survival (OS).

Results: One-hundred-and-fifty patients were randomised (group A = 72, group B = 78). The median PFS and OS for all patients were 3.8 and 8.1 months (95% confidence interval (CI): 2.9-4.8 and 6.8-9.5). There was no significant difference in PFS (3.7 vs 4.6 months, HR 0.98) or OS (8.1 vs 7.4, HR 1.1) between the two treatment groups. Response rate tended to be better for chemotherapy plus cetuximab compared to chemotherapy alone (22% vs 15%). Adverse events grade ≥3 were comparable between the two groups, except for significantly increased skin toxicity in the cetuximab arm.

Conclusions: Cetuximab plus paclitaxel/carboplatin did not improve PFS, OS and RR in metastatic CUP compared to paclitaxel/carboplatin alone. Addition of cetuximab resulted in additional skin toxicity.

Clinical Trial Registration: The study was registered at clinicaltrials.gov as NCT00894569.
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http://dx.doi.org/10.1038/s41416-020-01141-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884392PMC
February 2021

Sustained response after remdesivir and convalescent plasma therapy in a B-cell depleted patient with protracted COVID-19.

Clin Infect Dis 2020 Oct 26. Epub 2020 Oct 26.

Department of Medicine, Gastroenterology and Hepatology, with the Sections Infectious Diseases and Tropical Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

We provide detailed clinical, virological and immunological data of a B-cell depleted patient treated with obinutuzumab for follicular lymphoma with protracted COVID-19 and viremia. A sustained response was achieved after two courses of remdesivir and subsequent convalescent plasma therapy. Immunocompromised patients might require combined and prolonged antiviral treatment regimens.
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http://dx.doi.org/10.1093/cid/ciaa1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665388PMC
October 2020

Targeting the Mutational Landscape of Bystander Cells: Drug-Promoted Blood Cancer From High-Prevalence Pre-neoplasias in Patients on BRAF Inhibitors.

Front Oncol 2020 11;10:540030. Epub 2020 Sep 11.

Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

Drug-promoted cancers are increasingly recognized as a serious clinical problem in patients receiving BRAF inhibitory treatment. Here we report on a patient with mutant hairy cell leukemia and monoclonal B-cell lymphocytosis (MBL), who responded durably to BRAF/MEK inhibitors (BRAFi/MEKi) but experienced transformation of a mutant MBL to chronic lymphocytic leukemia (CLL) with accelerated nodal progression. Hypothesizing that BRAFi triggered excessive MEK-ERK signaling in the MBL/CLL clone via the CRAF/RAS complex as previously described for BRAFi-induced cancers, BRAFi was discontinued inducing a rapid remission of the CLL on MEKi alone. Liquid biopsy monitoring showed a continuous increase of the MBL/CLL clone from the start of BRAFi/MEKi treatment followed by a rapid decline upon BRAFi withdrawal. Next-generation sequencing of a cohort of patients with MBL and monoclonal gammopathy of unclear significance (MGUS) revealed that almost one third of these cases harbored mutations. In view of the population frequency of lymphatic pre-malignant conditions and the prevalence of mutations in such cases, vigilant surveillance remains critical in patients treated with BRAF inhibitors.
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http://dx.doi.org/10.3389/fonc.2020.540030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517330PMC
September 2020

Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD.

J Clin Oncol 2021 01 1;39(1):17-29. Epub 2020 Oct 1.

University Hospitals and KU Leuven, Leuven, Belgium.

Purpose: The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer.

Methods: Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763).

Results: A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% 37.3% and 23.4% 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% 65.5% (HR, 1.02) and OS of 73.5% 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis.

Conclusion: The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.
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http://dx.doi.org/10.1200/JCO.20.01740DOI Listing
January 2021

Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays.

Cancer Lett 2020 11 4;493:179-188. Epub 2020 Sep 4.

Department of Radiotherapy and Radiation Oncology, University Cancer Center Hamburg - Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Trifluridine/tipiracil (FTD/TPI; marketed as Lonsurf®) has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Here we investigated the colorectal cancer cell lines HT29, HCT116, SW48 and Caco-2 to provide a preclinical rationale for FTD/TPI-based chemoradiation treatment. All lines incorporated similar amounts of FTD, irrespective of treatment concentration and duration, then arrested in S phase, showed persistent γH2AX induction and eventually underwent endoreplication, resulting in polyploidy. Clonogenic assays performed for four combined treatment schedules demonstrated additivity for treatments given within 6 h of each other. However, 24 h FTD/TPI treatment prior to irradiation caused 1.6-2.4 fold radiosensitisation. Combined in vivo treatment was well tolerated and caused a marked tumour growth delay, similar to capecitabine radiochemotherapy regimes. Prolonged S phase arrest, persistent γH2AX signalling, endoreplication and polyploidy may contribute to the cytotoxicity of FTD/TPI. The strong radiosensitising effect observed in vitro after prolonged treatment with FTD/TPI and equivalence with capecitabine-based chemoradiation in vivo support a daily fractionated combined regime of FTD/TPI and radiation in rectal cancer treatment. This is now being tested in a phase I/II clinical trial (NCT04177602).
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http://dx.doi.org/10.1016/j.canlet.2020.08.038DOI Listing
November 2020

Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study.

J Clin Oncol 2020 10 24;38(30):3555-3564. Epub 2020 Aug 24.

Vivantes Clinic Berlin-Spandau, Berlin-Spandau, Germany.

Purpose: Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity.

Patients And Methods: Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis.

Results: Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients.

Conclusion: Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.
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http://dx.doi.org/10.1200/JCO.20.00714DOI Listing
October 2020

Dabrafenib plus trametinib in patients with BRAF-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.

Lancet Oncol 2020 09 17;21(9):1234-1243. Epub 2020 Aug 17.

Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA.

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAF-mutated biliary tract cancer.

Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAF-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.

Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAF-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.

Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF mutations should be considered in patients with biliary tract cancer.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(20)30321-1DOI Listing
September 2020

Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer.

J Clin Oncol 2020 Aug 20:JCO2001225. Epub 2020 Aug 20.

Department of Oncology, University of Turin, Mauriziano Hospital, Turin, Italy.

Purpose: A proper estimation of the magnitude of the overall survival (OS) benefit from infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab versus doublets + bevacizumab is lacking because all trials that have investigated this regimen had primary end points other than OS. To test OS with higher power and to explore the interaction of treatment effect with main patient and disease characteristics, we performed an individual patient data (IPD) meta-analysis.

Patients And Methods: IPD from 5 eligible trials were collected: CHARTA (ClinicalTrials.gov identifier: NCT01321957), OLIVIA (ClinicalTrials.gov identifier: NCT00778102), STEAM (ClinicalTrials.gov identifier: NCT01765582), TRIBE (ClinicalTrials.gov identifier: NCT00719797), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116). The primary end point was OS. Secondary end points were progression-free survival (PFS), objective response rate (ORR), R0 resection rate, grade 3/4 adverse events, and subgroup analyses according to clinical and molecular characteristics.

Results: A total of 1,697 patients were randomly assigned to FOLFOXIRI + bevacizumab (n = 846) or doublets + bevacizumab (n = 851). Most (78%) had an Eastern Cooperative Oncology Group performance status of 0, and the median age was 61 years. After a median follow-up of 39.9 months, patients assigned to FOLFOXIRI + bevacizumab had significantly longer OS than those assigned to doublets + bevacizumab (median, 28.9 24.5 months; hazard ratio [HR], 0.81; 95% CI, 0.72 to 0.91; < .001), with no significant heterogeneity among trials ( = .39; I = 2%). No significant interaction effect between treatment arm and investigated characteristics was demonstrated. Patients assigned to FOLFOXIRI + bevacizumab had longer PFS (median, 12.2 9.9 months; HR, 0.74; 95% CI, 0.67 to 0.82; < .001), higher ORR (64.5% 53.6%; < .001), higher R0 resection rate (16.4% 11.8%; = .007), and higher rates of grade 3/4 neutropenia (45.8% 21.5%; < .001), febrile neutropenia (6.3% 3.7%; = .019), and diarrhea (17.8% 8.4%; < .001).

Conclusion: FOLFOXIRI + bevacizumab significantly and meaningfully improves survival of patients with metastatic colorectal cancer compared with doublets + bevacizumab and provides advantage in PFS, ORR, and R0 resection rate at the price of a moderate increase in toxicity. No increased benefit is observed among patients with -mutant tumors.
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http://dx.doi.org/10.1200/JCO.20.01225DOI Listing
August 2020

Off and On Again: De- and Reubiquitination during Membrane Protein Degradation.

Mol Cell 2020 07;79(2):203-204

Research Group Membrane Protein Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany. Electronic address:

In this issue of Molecular Cell, Hu et al. (2020) show that the cytosolic E3 ligase RNF126 reubiquitinates membrane proteins after their extraction from the membrane of the endoplasmic reticulum to target them for proteasomal degradation.
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http://dx.doi.org/10.1016/j.molcel.2020.06.036DOI Listing
July 2020

Selinexor (KPT-330), an Oral Selective Inhibitor of Nuclear Export (SINE) Compound, in Combination with FOLFOX in Patients with Metastatic Colorectal Cancer (mCRC) - Final Results of the Phase I Trial SENTINEL.

Curr Cancer Drug Targets 2020 ;20(10):811-817

II. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1.

Objective: To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients.

Methods: In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival.

Results: Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed.

Conclusion: In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.
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http://dx.doi.org/10.2174/1568009620666200628105727DOI Listing
January 2020

Doa10 is a membrane protein retrotranslocase in ER-associated protein degradation.

Elife 2020 06 26;9. Epub 2020 Jun 26.

Research Group Membrane Protein Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.

In endoplasmic reticulum-associated protein degradation (ERAD), membrane proteins are ubiquitinated, extracted from the membrane, and degraded by the proteasome. The cytosolic ATPase Cdc48 drives extraction by pulling on polyubiquitinated substrates. How hydrophobic transmembrane (TM) segments are moved from the phospholipid bilayer into cytosol, often together with hydrophilic and folded ER luminal protein parts, is not known. Using a reconstituted system with purified proteins from , we show that the ubiquitin ligase Doa10 (Teb-4/MARCH6 in animals) is a retrotranslocase that facilitates membrane protein extraction. A substrate's TM segment interacts with the membrane-embedded domain of Doa10 and then passively moves into the aqueous phase. Luminal substrate segments cross the membrane in an unfolded state. Their unfolding occurs on the luminal side of the membrane by cytoplasmic Cdc48 action. Our results reveal how a membrane-bound retrotranslocase cooperates with the Cdc48 ATPase in membrane protein extraction.
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http://dx.doi.org/10.7554/eLife.56945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319771PMC
June 2020

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.

Gastroenterology 2020 10 22;159(4):1417-1430.e3. Epub 2020 Jun 22.

Georgia Cancer Center, Augusta University, Augusta, Georgia.

Background & Aims: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice.

Methods: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf, Lta, and Ltb mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times.

Results: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC.

Conclusions: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.
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http://dx.doi.org/10.1053/j.gastro.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607422PMC
October 2020

[Prerequisites of magnetic resonance imaging for treatment planning in locally advanced rectal cancer - Interdisciplinary recommendations].

Z Gastroenterol 2020 Jun 16;58(6):577-582. Epub 2020 Jun 16.

Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim.

For the purpose of indication and patient stratification of perioperative treatment of locally advanced rectal cancer, magnetic resonance imaging (MRI) has become indispensable. In this report, we describe the importance of MRI diagnostics and the qualitative conditions.
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http://dx.doi.org/10.1055/a-1085-6874DOI Listing
June 2020

Ipilimumab or FOLFOX with Nivolumab and Trastuzumab in previously untreated HER2-positive locally advanced or metastatic EsophagoGastric Adenocarcinoma - the randomized phase 2 INTEGA trial (AIO STO 0217).

BMC Cancer 2020 Jun 1;20(1):503. Epub 2020 Jun 1.

Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumorzentrum/UCCH, Martinistr. 52, 20246, Hamburg, Germany.

Background: Esophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer.

Methods: The INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response.

Discussion: Recent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm.

Trial Registration: NCT03409848 24.01.2018.
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http://dx.doi.org/10.1186/s12885-020-06958-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268753PMC
June 2020

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family.

BMC Gastroenterol 2020 May 3;20(1):129. Epub 2020 May 3.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer.

Case Presentation: A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy.

Conclusion: Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.
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http://dx.doi.org/10.1186/s12876-020-01283-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197118PMC
May 2020

[Biliary tract cancer: on the way to a personalized therapy].

Dtsch Med Wochenschr 2020 04 1;145(7):442-446. Epub 2020 Apr 1.

Universitäres Cancer Center Hamburg-Eppendorf.

Biliary tract cancer (BTC) is a rare disease with a heterogeneous nomenclature. Carcinomas of the intra- and extrahepatic biliary tract as well as gallbladder cancer are oftentimes combined in clinical research and treatment algorithms. However, these different cancer types vary not only in their anatomical features, but also in the underlying molecular alterations.Surgery remains the only chance of cure. Adjuvant chemotherapy with capecitabine for 6 months should be recommended after curative intended surgery. In the palliative first-line treatment of advanced BTC, the combination chemotherapy gemcitabine and cisplatin remains the only evidence-based standard. For second-line treatment, the combination of 5-FU, folinic acid and oxaliplatin (FOLFOX) is a treatment option based on preliminary data from a randomized phase 3 study. Potential targeted therapies showing efficacy in prospective clinical studies are, for example, IDH-, BRAF-/MEK- and FGFR-inhibitors as well as immunotherapy. Therefore, in the era of personalized medicine, molecular testing should be offered to all patients with advanced disease and indication for systemic treatment.
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http://dx.doi.org/10.1055/a-0974-9694DOI Listing
April 2020

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

JAMA Neurol 2020 06;77(6):755-763

Columbia University Irving Medical Center, New York, New York.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.

Conclusions And Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
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http://dx.doi.org/10.1001/jamaneurol.2020.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483960PMC
June 2020

Hrd1 forms the retrotranslocation pore regulated by auto-ubiquitination and binding of misfolded proteins.

Nat Cell Biol 2020 03 24;22(3):274-281. Epub 2020 Feb 24.

Department of Cellular Biochemistry, University Medical Centre Göttingen, Göttingen, Germany.

During endoplasmic-reticulum-associated protein degradation (ERAD), misfolded proteins are polyubiquitinated, extracted from the ER membrane and degraded by the proteasome. In a process called retrotranslocation, misfolded luminal proteins first need to traverse the ER membrane before ubiquitination can occur in the cytosol. It was suggested that the membrane-embedded ubiquitin ligase Hrd1 forms a retrotranslocation pore regulated by cycles of auto- and deubiquitination. However, the mechanism by which auto-ubiquitination affects Hrd1 and allows polypeptides to cross the membrane and whether Hrd1 forms a membrane-spanning pore remained unknown. Here, using purified Hrd1 incorporated into different model membranes, we show that Hrd1 auto-ubiquitination leads to the opening of a pore. Substrate binding increases the pore size and its activity, whereas deubiquitination closes the pore and renders it unresponsive to substrate. We identify two binding sites for misfolded proteins in Hrd1, a low-affinity luminal site and a high-affinity cytoplasmic site formed following auto-ubiquitination of specific lysine residues in Hrd1's RING domain. We propose that the affinity difference between the luminal and cytoplasmic binding sites provides the initial driving force for substrate movement through Hrd1.
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http://dx.doi.org/10.1038/s41556-020-0473-4DOI Listing
March 2020

Cancer Cells Expressing Oncogenic Rat Sarcoma Show Drug-Addiction Toward Epidermal Growth Factor Receptor Antibodies Mediated by Sustained MAPK Signaling.

Front Oncol 2019 21;9:1559. Epub 2020 Jan 21.

Department of Oncology and Hematology, BMT With Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Epidermal growth factor receptor (EGFR) antibodies may have detrimental effects in patients with metastatic colorectal cancer expressing oncogenic Rat sarcoma (RAS). Since a significant number of patients acquire RAS-mediated resistance during EGFR-directed treatment, understanding the molecular mechanism underlying these antibody-mediated tumor-promoting effects is of relevance to design more resistance-preventive treatment approaches. To test this, we set up a Ba/F3 cellular model system transformed to EGFR/RAS dependency to be able to study proliferation, RAS activity as well as MAPK signaling upon inhibition of wild-type RAS isoforms by therapeutic EGFR antibodies. Here, we show that the EGFR antibodies cetuximab and panitumumab induce paradoxical stimulation and enhance proliferation in cells expressing oncogenic RAS (KRAS G12V). These experiments clearly showed that the stimulatory effect is a direct result of the antibody-EGFR interaction leading to prolonged mitogen-activated protein-Kinase (MAPK) signaling. The effect was also induced by antibody-chemotherapy combinations but always depended on simultaneous low-level ligand-dependent EGFR pathway activation. Moreover, we observed significant growth retardation of RAS mutant cells after antibody withdrawal compatible with a drug-addiction phenotype. Our data suggests that EGFR antibodies paradoxically sustain MAPK signaling downstream of oncogenic RAS thereby driving proliferation of RAS mutant tumors or tumor subclones. The observed drug-addiction encourages fixed-duration or liquid-biopsy-guided drug holiday concepts to preventively clear RAS mutant subclones selected under EGFR-directed therapeutic pressure.
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http://dx.doi.org/10.3389/fonc.2019.01559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985072PMC
January 2020

Current status of immunotherapy in gastrointestinal malignancies.

Z Gastroenterol 2020 Jun 4;58(6):542-555. Epub 2020 Feb 4.

Hämatologisch-Onkologische Praxis Eppendorf, University Cancer Center Hamburg, Germany.

Gastrointestinal (GI) malignant neoplasms have a high global incidence and a huge impact on cancer-associated mortality. In the past years, excitement was growing among oncologists and patients alike for the use of immunotherapy, specifically immune checkpoint inhibitors. The approval of several PD-1/PD-L1 and CTLA-4 inhibitors radically changed the treatment landscape in many cancer types and established immune-oncology as a new treatment strategy against cancer. Despite major breakthrough reports, shortcomings of immune checkpoint inhibitors (ICI) have been observed, including primary and acquired treatment resistance, especially in patients receiving ICIs as a single treatment. Several immunotherapies for the treatment of GI tumors have recently emerged; however, checkpoint inhibition has not yet shown similar success in GI malignancies compared to other solid tumors. Various phase I-III trials focusing on immunotherapies for GI tumors have found only moderate to unsatisfactory objective response rates (ORR), ranging between 10 % and 25 %. In particular, negative studies have been reported in gastric and pancreatic cancer. Nevertheless, small subsets of cancers, such as DNA mismatch repair deficient (dMMR)/microsatellite instable (MSI) cancers, among others, seem to benefit from treatment with immune checkpoint inhibition. Routine testing for the rare molecular features that can predict response should be implemented in clinical routine for all GI tumors, and large scale clinical trials to identify predictive biomarkers are needed. This article will address the current use and evidence for immunotherapy in GI malignancies and future trends in this area for clinical practice.
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http://dx.doi.org/10.1055/a-1071-8322DOI Listing
June 2020

Guidelines for Long-Term Follow-Up after Childhood Cancer: Practical Implications for the Daily Work.

Oncol Res Treat 2020 13;43(3):61-69. Epub 2020 Jan 13.

Pediatric Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany,

Background: Many childhood cancer survivors develop treatment-associated late effects emerging years or even decades after the end of treatment. Evidence-based guidelines recommend risk-adapted screening, facilitating early diagnosis and management of these sequelae. Long-term follow-up (LTFU) in specialized late effects clinics is devised to implement screening recommendations in the care of childhood cancer survivors.

Objectives: To create a practical LTFU tool for the daily practice.

Methods: Current guidelines and screening recommendations concerning LTFU in adult survivors of childhood cancer were reviewed and a comprehensive LTFU approach was developed.

Results: A risk stratification model assigning patients to three risk groups with different screening recommendations and frequencies is presented based on current LTFU guidelines. Furthermore, a model of LTFU in a clinical multidisciplinary team is proposed.

Conclusions: Although late morbidity and mortality in childhood cancer survivors have been attenuated in the last decade by reducing treatment toxicities, a high proportion of long-term survivors already is or will still be affected by treatment-associated chronic health conditions. With the knowledge of late effects and their occurrence as a consequence of specific treatment modalities, practical LTFU recommendations are essential to achieve standardized and structured LTFU care.
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http://dx.doi.org/10.1159/000504200DOI Listing
July 2020

Quality Control of Protein Complex Assembly by a Transmembrane Recognition Factor.

Mol Cell 2020 01 31;77(1):108-119.e9. Epub 2019 Oct 31.

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address:

The inner nuclear membrane (INM) is continuous with the endoplasmic reticulum (ER) but harbors a distinctive proteome essential for nuclear functions. In yeast, the Asi1/Asi2/Asi3 ubiquitin ligase complex safeguards the INM proteome through the clearance of mislocalized ER membrane proteins. How the Asi complex selectively targets mislocalized proteins and coordinates its activity with other ER functions, such as protein biogenesis, is unclear. Here, we uncover a link between INM proteome identity and membrane protein complex assembly in the remaining ER. We show that lone proteins and complex subunits failing to assemble in the ER access the INM for Asi-mediated degradation. Substrates are recognized by direct binding of Asi2 to their transmembrane domains for subsequent ubiquitination by Asi1/Asi3 and membrane extraction. Our data suggest a model in which spatial segregation of membrane protein complex assembly and quality control improves assembly efficiency and reduces the levels of orphan subunits.
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http://dx.doi.org/10.1016/j.molcel.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941229PMC
January 2020

Immunotherapy in colorectal cancer: Available clinical evidence, challenges and novel approaches.

World J Gastroenterol 2019 Aug;25(29):3920-3928

Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.
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http://dx.doi.org/10.3748/wjg.v25.i29.3920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689806PMC
August 2019