Publications by authors named "Michael Ghadimi"

174 Publications

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo.

Cancers (Basel) 2021 Feb 28;13(5). Epub 2021 Feb 28.

Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany.

Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients' long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets.

Materials And Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice.

Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo.

Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.
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http://dx.doi.org/10.3390/cancers13051011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957803PMC
February 2021

NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy.

Cancers (Basel) 2021 Jan 26;13(3). Epub 2021 Jan 26.

Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, 37073 Goettingen, Germany.

Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.
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http://dx.doi.org/10.3390/cancers13030455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865718PMC
January 2021

Endoscopic internal drainage and low negative-pressure endoscopic vacuum therapy for anastomotic leaks after oncologic upper gastrointestinal surgery.

Endoscopy 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology and Gastrointestinal Oncology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris and University of Paris, Paris, France.

Background:  Endoscopic internal drainage (EID) with double-pigtail stents or low negative-pressure endoscopic vacuum therapy (EVT) are treatment options for leakage after upper gastrointestinal oncologic surgery. We aimed to compare the effectiveness of these techniques.

Methods:  Between 2016 and 2019, patients treated with EID in five centers in France and with EVT in Göttingen, Germany were included and retrospectively analyzed using univariate analysis. Pigtail stents were changed every 4 weeks; EVT was repeated every 3-4 days until leak closure.

Results:  35 EID and 27 EVT patients were included, with a median (interquartile range [IQR]) leak size of 0.75 cm (0.5-1.5). Overall treatment success was 100 % (95 % confidence interval [CI] 90 %-100 %) for EID vs. 85.2 % (95 %CI 66.3 %-95.8 %) for EVT ( = 0.03). The median (IQR) number of endoscopic procedures was 2 (2-3) vs. 3 (2-6.5;  = 0.003) and the median (IQR) treatment duration was 42 days (28-60) vs. 17 days (7.5-28;  < 0.001), for EID vs. EVT, respectively.

Conclusion:  EID and EVT provide high closure rates for upper gastrointestinal anastomotic leaks. EVT provides a shorter treatment duration, at the cost of a higher number of procedures.
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http://dx.doi.org/10.1055/a-1375-8151DOI Listing
January 2021

[Human resources management and leadership in surgery].

Chirurg 2021 Mar 25;92(3):227-231. Epub 2021 Jan 25.

Klinik für Allgemein‑, Viszeral- und Kinderchirurgie, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Deutschland.

Due to an increasing lack of qualified personnel, the German healthcare system and especially surgical departments face tremendous challenges. This shortage of qualified personnel not only results in constraints in the provision of patient care but also has a negative impact on the health of available personnel, as these are by default expected to fill the gap. The situation is aggravated by demands and expectations of the younger generation of employees, who are particularly concerned with key topics, such as leadership, working hours and work-life balance. This transformation will inevitably necessitate both chief surgeons and hospital management to re-evaluate and adapt their strategies in order to retain full operability and high quality of medical care of clinics in the future. The objective of this article is to provide a personal assessment of the current and future situation in surgical clinics in Germany with a focus on human resources and leadership.
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http://dx.doi.org/10.1007/s00104-020-01345-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832412PMC
March 2021

A rare cause of upper gastrointestinal bleeding from a submucosal tumor.

Endosc Ultrasound 2021 Jan-Feb;10(1):75-76

Department of Gastroenterology and Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

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http://dx.doi.org/10.4103/eus.eus_75_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980693PMC
January 2021

Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial.

Eur J Cancer 2021 Feb 28;144:281-290. Epub 2020 Dec 28.

Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Background: The CAO/ARO/AIO trial has shown that oxaliplatin added to preoperative chemoradiotherapy and postoperative chemotherapy significantly improved disease-free survival in locally advanced rectal cancer (LARC). Here, we present a post-hoc analysis of quality of life (QoL) in disease-free patients.

Patients And Methods: Between 2006 and 2010, 1236 patients with LARC were randomly assigned either to preoperative chemoradiotherapy followed by total mesorectal excision and postoperative chemotherapy (N = 623) or combined with oxaliplatin (N = 613). QoL questionnaires (EORTC QLQ-C30, colorectal module CR38) were completed at baseline, after postoperative chemotherapy and during follow-up. Analysis was performed according intent-to-treat.

Results: Available questionnaires (baseline) were 82% (N = 512) in the control and 84% (N = 513) in the investigational group. Response rates were 49% (533 of 1086) at 1 year and 43% (403 of 928) at 3 years. Global health status (GHS) for disease-free patients was stable in both groups (range 0-100). At baseline: standard arm 62.0 (mean, SD 21.6; N = 491) versus oxaliplatin arm 63.2 (mean, SD 22; N = 503); at 3 years: 69.4 (SD 19.3; N = 187) versus 65.4 (SD 22.2; N = 202). After treatment and at 3 years, no significant differences (≥10 points) between groups were found in QoL subscales. Disease-free patients experiencing neurotoxic side-effects (grade 1-4) showed reduced GHS at 3 years versus patients without neurotoxicity (mean 59.2 versus 69.3; P < 0.001), while grade 3-4 rate was low.

Conclusion: The addition of oxaliplatin was not associated with worse overall QoL. This information is of interest to patients in many ongoing rectal cancer trials.

Trial Registration Information: NCT00349076.
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http://dx.doi.org/10.1016/j.ejca.2020.11.029DOI Listing
February 2021

Importance and Qualitative Requirements of Magnetic Resonance Imaging for Therapy Planning in Rectal Cancer - Interdisciplinary Recommendations of AIO, ARO, ACO and the German Radiological Society.

Rofo 2020 Dec 16. Epub 2020 Dec 16.

III Medical Clinic, Day Therapy Centre, Medical Faculty of the University of Heidelberg, Mannheim, Germany.

Due to its excellent intrinsic soft tissue contrast, magnetic resonance imaging allows excellent visualization and anatomical separation of therapy-relevant risk structures such as the mesorectal fascia, local lymph nodes, and vascular structures in patients with rectal carcinoma. This makes magnetic resonance imaging (MRI) a valuable evaluation method for further therapeutic stratification. In particular, MRI is indispensable for the decision to refrain from neoadjuvant therapy and to choose a primary surgical approach. In addition to the oncologically generally relevant T-, N-, and M-criteria, two further parameters are included: the extramural vascular infiltration and the circumferential resection margin. Due to the significant impact of MRI on further therapeutic decision-making, standardized MR image quality is considered essential. KEY POINTS::   · Magnetic resonance imaging is a valuable evaluation method for further therapeutic stratification.. · Critical anatomic landmarks for evaluation are circumferential resection margins.. CITATION FORMAT: · Attenberger UI, Clasen S, Ghadimi M et al. Importance and Qualitative Requirements of Magnetic Resonance Imaging for Therapy Planning in Rectal Cancer - Interdisciplinary Recommendations of AIO, ARO, ACO and the German Radiological Society. Fortschr Röntgenstr 2020; DOI: 10.1055/a-1299-1807.
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http://dx.doi.org/10.1055/a-1299-1807DOI Listing
December 2020

Vascular Heterogeneity With a Special Focus on the Hepatic Microenvironment.

Front Physiol 2020 11;11:591901. Epub 2020 Nov 11.

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

Utilizing single-cell sequencing, recent studies were able to analyze at a greater resolution the heterogeneity of the vasculature and its complex composition in different tissues. Differing subpopulations have been detected, distinguishable only by their transcriptome. Designed to provide further insight into the heterogeneity of the functional vascular tissue, endothelial cells have been the main target of those studies. This review aims to present a synopsis of the variability of the different vascular beds, their endothelial variety, and the supporting cells that allow the vessels to serve their various purposes. Firstly, we are going to chart vascular tissue heterogeneity on a cellular level, describing endothelial diversity as well as stromal microenvironmental variety and interaction in a physiological setting. Secondly, we will summarize the current knowledge of pathological vessel formation in the context of cancer. Conventional anti-tumor therapeutic targets as well as anti-angiogenetic therapy is frequently limited by poor response of the tumor tissue. Reasons for moderate response and resistance to treatment can be found through different drivers of angiogenesis, different mechanisms of blood supply, but also in poorly understood tissue diversity. Based on this, we are comparing how pathologies alter the normal structure of vascular tissues highlighting the involved mechanisms. Lastly, illustrating the concept above, we will focus on the hepatic microenvironment, an organ of frequent metastatic spreading (e.g., from colorectal, breast, and lung cancers). We will address how the hepatic vasculature usually develops and subsequently we will describe how common liver metastases vary in their vasculature and the way they supply themselves (e.g., angiogenesis versus vessel co-option).
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http://dx.doi.org/10.3389/fphys.2020.591901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686534PMC
November 2020

Precision Medicine.

Visc Med 2020 Oct 2;36(5):407-410. Epub 2020 Oct 2.

Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

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http://dx.doi.org/10.1159/000511534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590746PMC
October 2020

TIM-3 Genetic Variants Are Associated with Altered Clinical Outcome and Susceptibility to Gram-Positive Infections in Patients with Sepsis.

Int J Mol Sci 2020 Nov 6;21(21). Epub 2020 Nov 6.

Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany.

: Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. : Patients with sepsis ( = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. : Kaplan-Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and infections, and rs10515746 CC homozygotes presented more infections. : The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.
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http://dx.doi.org/10.3390/ijms21218318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664272PMC
November 2020

Assessment of esophageal motility disorders by real-time MRI.

Eur J Radiol 2020 Nov 12;132:109265. Epub 2020 Sep 12.

Department of Diagnostic and Interventional Radiology, University Medical Center Göttingen, Germany.

Purpose: To investigate imaging findings of esophageal motility disorders on dynamic real-time.

Material And Methods: 102 patients with GERD-like symptoms were included in this retrospective study between 2015-2018. Dynamic real-time MRI visualized the transit of a 10 mL pineapple juice bolus through the esophagus and EGJ with a temporal resolution of 40 ms. Dynamic and anatomic parameters were measured by consensus reading. Imaging findings were compared to HRM utilizing the Chicago classification of esophageal motility disorders, v3.0.

Results: All 102 patients completed real-time MRI in a median examination time of 15 min. On HRM, 14 patients presented with disorders with EGJ outlet obstruction (EGJOO) (13.7 %), 7 patients with major disorders of peristalsis (6.9 %), and 32 patients with minor disorders of peristalsis (31.4 %). HRM was normal in 49 patients (48.0 %). Incomplete bolus clearance was significantly more frequent in patients with esophageal motility disorders on HRM than in patients with normal HRM (p = 0.0002). In patients with motility disorders with EGJOO and major disorders of peristalsis, the esophageal diameter tended to be wider (23.6 ± 8.0 vs. 21.2 ± 3.5 mm, p = 0.089) and the sphincter length longer (19.7 ± 7.3 vs. 16.7 ± 3.0 mm, p = 0.091) compared to patients with normal HRM. 3/7 patients with achalasia type II were correctly identified by real-time MRI and one further achalasia type II patient was diagnosed with a motility disorder on MRI films. The other 3/7 patients presented no specific imaging features.

Conclusion: Real-time MRI is an auxiliary diagnostic tool for the assessment of swallowing events. Imaging parameters may assist in the detection of esophageal motility disorders.
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http://dx.doi.org/10.1016/j.ejrad.2020.109265DOI Listing
November 2020

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer.

PLoS One 2020 1;15(10):e0239806. Epub 2020 Oct 1.

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

Introduction: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing.

Materials And Methods: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens.

Results: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis.

Conclusions: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529221PMC
November 2020

The long-term influence of hospital and surgeon volume on local control and survival in the randomized German Rectal Cancer Trial CAO/ARO/AIO-94.

Surg Oncol 2020 Dec 26;35:200-205. Epub 2020 Aug 26.

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

Background: The association of treatment volume and oncological outcome of rectal cancer patients undergoing multidisciplinary treatment is subject of an ongoing debate. Prospective data on long-term local control and overall survival (OS) are not available so far. This study investigated the long-term influence of hospital and surgeon volume on local recurrence (LR) and OS in patients with locally advanced rectal cancers.

Methods: In a post-hoc analysis of the randomized phase III CAO/ARO/AIO-94 trial after a follow-up of more than 10 years, 799 patients with stage II/III rectal cancers were evaluated. LR-rates and OS were stratified by hospital recruitment volume (≤20 vs. 21-90 vs. >90 patients) and by surgeon volume (≤10 vs. 11-50 vs. >50 procedures).

Results: Patients treated in high-volume hospitals had a longer OS than those treated in hospitals with medium or low treatment volume (p = 0.03). The surgeon volume was adversely associated with LR (p = 0.01) but had no influence on overall survival. The positive effect of neoadjuvant chemoradiation (CRT) on local control was the strongest in patients being operated by medium-volume surgeons, less in patients being operated by high-volume surgeons and missing in those being operated by low-volume surgeons.

Conclusions: Patients with locally advanced rectal cancers might benefit from treatment in specialized high-volume hospitals. In particular, the surgeon volume had significant influence on long-term local tumour control. The effect of neoadjuvant CRT on local tumour control may likewise depend on the surgeon volume.
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http://dx.doi.org/10.1016/j.suronc.2020.08.021DOI Listing
December 2020

[Surgical treatment of esophageal cancer-Indicators for quality in diagnostics and treatment].

Chirurg 2021 Apr;92(4):350-360

Klinik für Allgemein‑, Viszeral‑, Tumor- und Transplantationschirurgie, Universitätsklinikum Köln, Köln, Deutschland.

Background: Within the framework of the quality initiative of the German Society for General and Visceral Surgery (DGAV) a review article was compiled based on a systematic literature search. Recommendations for the current diagnostics and treatment of esophageal cancer were also elaborated.

Methods: The systematic literature search was carried out in March 2019 according to the PRISMA criteria using the MEDLINE databank. The recommendations were formulated based on a consensus in the DGAV.

Results And Conclusion: Operations below the currently valid minimum quantity threshold should no longer be carried out. There are many indications that the minimum quantity in Germany should be raised to ≥20 resections/year/hospital in order to comprehensively improve the quality. Prehabilitation programs with endurance, strength and intensive breathing training as well as nutritional therapy improve patient outcome. The current treatment of esophageal cancer is stage-dependent and incorporates endoscopic resection of (sub)mucosal low-risk tumors (T1m1-3 or T1sm1 low risk), primary esophagectomy of submucosal high-risk tumors (T1a), submucosal cancer (T1sm2-3) and T2N0 tumors, multimodal treatment with neoadjuvant chemoradiotherapy or perioperative chemotherapy and operations for advanced stages. Esophagectomy is nowadays carried out in one stage as a so-called hybrid procedure (laparoscopy and muscle-preserving thoracotomy) or as a total minimally invasive operation (laparoscopy and thoracoscopy).
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http://dx.doi.org/10.1007/s00104-020-01267-8DOI Listing
April 2021

Association of Treatment Adherence With Oncologic Outcomes for Patients With Rectal Cancer: A Post Hoc Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 09;6(9):1416-1421

Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.

Importance: Despite numerous published phase 3 trials, the association of treatment adherence with outcomes for patients with rectal cancer remains largely unexplored.

Objective: To analyze the association of treatment adherence with disease-free survival (DFS) among patients with rectal cancer in the CAO/ARO/AIO-04 trial.

Design, Setting, And Participants: This post hoc analysis of a phase 3 randomized clinical trial was conducted from July 25, 2006, to February 26, 2010, among 1232 patients from 80 centers with T3 to T4 or node-positive rectal adenocarcinoma. Statistical analysis was performed from May 5, 2019, to February 2, 2020.

Interventions: A total of 625 patients received neoadjuvant fluorouracil-based chemoradiotherapy (nCRT), and a total of 607 patients received fluorouracil-based nCRT with addition of oxaliplatin. Of the 1126 patients who underwent curative surgery, 439 started fluorouracil-based adjuvant chemotherapy and 419 started fluorouracil-based adjuvant chemotherapy with oxaliplatin.

Main Outcomes And Measures: The association of adherence with nCRT and adjuvant chemotherapy with DFS was assessed in both groups in the as-treated population.

Results: Among the 625 patients (442 men; mean age, 63.0 years) who received fluorouracil nCRT and the 607 patients (430 men; mean age, 63.0 years) who received fluorouracil-based nCRT with addition of oxaliplatin, after a median follow-up of 50 months (interquartile range, 38-61 months), 3-year DFS in the as-treated population was 71.1% in the fluorouracil group and 75.8% in the fluorouracil-oxaliplatin group (hazard ratio [HR], 0.803; 95% CI, 0.651-0.990; P = .04). Overall, 419 patients in the fluorouracil nCRT group (67.0%) and 434 patients in the fluorouracil-oxaliplatin nCRT group (71.5%) received full doses of preoperative nCRT. Likewise, 253 of 439 patients in the fluorouracil group (57.6%) and 134 of 419 patients in the fluorouracil-oxaliplatin group (32.0%) received full doses of adjuvant chemotherapy. Adherence to nCRT was associated with 3-year DFS in both the fluorouracil group (complete vs near complete: HR, 1.325; 95% CI, 0.959-1.832; P = .09; complete vs reduced: HR, 1.877; 95% CI, 1.147-3.072; P = .01) and the fluorouracil-oxaliplatin group (complete vs near complete: HR, 1.501; 95% CI, 0.980-2.299; P = .06; complete vs reduced: HR, 1.724; 95% CI, 1.144-2.596; P = .009) in multivariable analyses. In contrast, adjuvant chemotherapy was not associated with DFS in both the fluorouracil group (complete vs near complete: HR, 0.900; 95% CI, 0.559-1.448; P = .66; complete vs incomplete: HR, 1.057; 95% CI, 0.807-1.386; P = .69) and the fluorouracil-oxaliplatin group (complete vs near complete: HR, 1.155; 95% CI, 0.716-1.866; P = .56; complete vs incomplete: HR, 1.073; 95% CI, 0.790-1,457; P = .65).

Conclusions And Relevance: To our knowledge, this is the first analysis of a phase 3 trial to assess the association of treatment adherence with some clinical outcomes for patients with rectal cancer. The findings emphasize the need for appropriate trial design with optimized nCRT dose and schedule and supportive strategies to facilitate good adherence and precision delivery, especially for intensified nCRT.

Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.
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http://dx.doi.org/10.1001/jamaoncol.2020.2394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349129PMC
September 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

Editorial zum Themenschwerpunkt Liposarkome.

Zentralbl Chir 2020 04 8;145(2):138-139. Epub 2020 Apr 8.

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http://dx.doi.org/10.1055/a-1071-3649DOI Listing
April 2020

Real-time MRI for dynamic assessment of gastroesophageal reflux disease: Comparison to pH-metry and impedance.

Eur J Radiol 2020 Apr 29;125:108856. Epub 2020 Jan 29.

Department of Diagnostic and Interventional Radiology, University Medical Center, Göttingen, 37075, Germany.

Purpose: To evaluate the diagnostic potential of real-time MRI for dynamic assessment of gastroesophageal reflux in patients with GERD (gastroesophageal reflux disease)-like symptoms compared to pH-metry and impedance.

Methods: Patients who underwent real-time MRI and pH-metry between 2015-2018 were included in this retrospective study. Real-time MRI at 3 T was achieved by undersampled radial FLASH acquisitions with iterative image reconstruction by NLINV. Real-time MRI visualized transit of pineapple juice through the gastroesophageal junction and during Valsalva maneuver. MRI results were compared to 24 h pH-metry to assess acidic reflux (following Lyon Consensus guidelines) and to impedance to assess non-acidic reflux. A standard 2 × 2 table was chosen to calculate diagnostic performance.

Results: 91/93 eligible patients fulfilled inclusion criteria (male n = 49; female n = 42; median age 55 y). All MRI studies were successfully completed without adverse events at a mean examination time of 15 min. On real-time MRI, reflux was evident in 60 patients (66 %). pH-metry revealed reflux in 41 patients (45 %), and impedance in 54 patients (59 %). Compared to pH-metry and impedance, real-time MRI sensitivity was 0.78 (95 % CI: 0.66-0.87), specificity 0.67 (95 % CI: 0.45-0.84) and PPV 0.87 (95 % CI: 0.75-0.94).

Conclusion: Real-time MRI is an imaging method for assessment of gastroesophageal reflux in patients with GERD-like symptoms. Considering its high positive predictive value, real-time MRI can accurately identify patients in which further invasive testing with pH-metry and impedance might be considered.
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http://dx.doi.org/10.1016/j.ejrad.2020.108856DOI Listing
April 2020

Impact of Endoscopic Vacuum Therapy with Low Negative Pressure for Esophageal Perforations and Postoperative Anastomotic Esophageal Leaks.

Digestion 2020 Feb 11:1-11. Epub 2020 Feb 11.

Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany,

Introduction: Management of esophageal anastomotic leaks (AL) and esophageal perforations (EP) remains difficult and often requires an interdisciplinary treatment modality. For primary endoscopic management, self-expanding metallic stent (SEMS) placement is often considered first-line therapy. Recently, endoscopic vacuum therapy (EVT) has emerged as an alternative or adjunct for management of these conditions. So far, data for EVT in the upper gastrointestinal-tract is restricted to single centre, non-randomized trials. No studies on optimal negative pressure application during EVT exist. The aim of our study is to describe our centre's experience with low negative pressure (LNP) EVT for these indications over the past 5-years.

Patients And Methods: Between January 2014 and December 2018, 30 patients were endoscopically treated for AL (n = 23) or EP (n = 7). All patients were primarily treated with EVT and LNP between -20 and -50 mm Hg. Additional endoscopic treatment was added when EVT failed. Procedural and peri-procedural data, as well as clinical outcomes including morbidity and mortality, were analysed.

Results: Clinical successful endoscopic treatment of EP and AL was achieved in 83.3% (n = 25/30), with 73.3% success using EVT alone (n = 22/30). Mean treatment duration until leak closure was 16.1 days (range 2-58 days). Additional treatment modalities for complete leak resolution was necessary in 10% (n = 3/30), including SEMS placement and fibrin glue injection. Mean hospital stay for patients with EP was shorter with 33.7 days compared to AL with 54.4 days (p = 0.08). Estimated preoperative 10-year overall survival (Charlson comorbidity score) was 39.4% in patients with AL and 59.9% in patients with EP (p = 0.26). A mean of 5.1 EVT changes (range 1-12) was needed in EP and 3.6 changes (range 1-13) in AL to achieve complete closure, switch to other treatment modality, or reach endoscopic failure (p = 0.38).

Conclusion: LNP EVT enables effective minimally - invasive endoluminal leak closure from anastomotic esophageal leaks and EP in high-morbid patients. In this study, EVT was combined with other endoscopic treatment options such as SEMS placement or fibrin glue injection in order to achieve leak or perforation closure in the vast majority of patients (83.3%). Low aspiration pressures led to slower but still sufficient clinical results.
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http://dx.doi.org/10.1159/000506101DOI Listing
February 2020

CA19-9 for detecting recurrence of pancreatic cancer.

Sci Rep 2020 Jan 28;10(1):1332. Epub 2020 Jan 28.

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

CA19-9 values are regularly measured in patients with pancreatic cancer. Certainly, its potential as a biomarker has been compromised by false negative results in CA19-9 negative patients and false positive results in benign pancreatico-biliary diseases. For detection of PDAC recurrence, however, CA19-9 might play an important role. The aim of this study is to analyze the accuracy of CA19-9 for detecting recurrence of pancreatic cancer. All included patients were treated either at the University Medical Center Goettingen, or at the Department of Interdisciplinary Oncology and Pneumonology, DRK-Kliniken Nordhessen, Kassel. We analyzed data of 93 patients with pancreatic cancer in the training set and 41 in the validation set, both retrospectively. Pre- and postoperative CA19-9 values and results of imaging techniques were compared. We performed ROC-analysis. The association between longitudinally measured CA19-9 values and relapse was studied with a joint model between a random effects model for the longitudinal CA19-9 measurements and a Cox proportional hazards models for the survival data. In the test set (n = 93 patients) the median follow-up time was 644 days (22 months). Overall, 71 patients (76.3%) developed recurrence during follow-up. Patients with CA19-9 values of <10kU/l were considered as CA19-9 negative patients (n = 11) and excluded from further analysis. Among the rest, approximately 60% of the patients showed significantly elevated CA19-9 prior to detection of recurrence by imaging techniques. Recurrence was shown by 2.45 times elevated CA19-9 values with 90% positive predictive value. In the validation set, 2.45 times elevated CA19-9 values showed recurrence with 90% sensitivity and 83,33% specificity, with an area under the curve of 95%. Based on measured CA19-9 values during follow-up care, the joint model estimates in recurrence-free patients the probability of recurrence-free survival. CA19-9 elevation is an early and reliable sign for PDAC recurrence. On the strength of a very high accuracy in CA19-9 positive patients, it should be considered to use CA19-9 for therapy decision even without a correlate of imaging technics. Using the joint model, follow-up care of PDAC patients after curative therapy can be stratified.
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http://dx.doi.org/10.1038/s41598-020-57930-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987233PMC
January 2020

Intensified Histopathological Work-Up after Pancreatic Head Resection Reveals Relevant Prognostic Markers.

Digestion 2021 21;102(2):265-273. Epub 2020 Jan 21.

Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany,

Introduction: Local recurrence remains a major problem after pancreatic head resection. Intensified histopathological work-up of surgical specimens after pancreatic head resection has revealed an increased number of incomplete resections (R1) depending on tumor infiltration front at the resection margins (RMs). It remains unclear to which extent the increased R1 resection rate has a clinical relevance for the patients' prognosis.

Materials And Methods: Pancreatic head resections between 2006 and 2012 were histologically intensively worked-up by a previously described protocol. The distance between the tumor infiltration front and the resection planes or organ surfaces was documented. The impact of the size of the tumor and an additional portal vein resection was analyzed. The effect of a R1 resection status on development and type of recurrence was evaluated.

Results: A total of 203 pancreatic head resections were evaluated. Different definitions of R1 resection were applied. These led to significantly different prognosis for patients. A greater distance between the tumor infiltration front and the resection plane or organ surface was associated with a better outcome for the patients. For the ventral surface, the mesopancreas and the pancreatic body these differences were statistically significant comparing the different R1 definitions. For the dorsal surface, a significant difference in prognosis was found if the tumor was >2 mm away from the resection surface. A tumor size of 3 cm was identified to play a relevant role for the prognosis. Patients who had a portal vein resection without a histologically proven infiltration showed a statistically significant higher overall survival. Patients with R1 resection were at highest risk for developing local recurrence as well as distant metastasis.

Conclusion: Intensified histopathological work-up with an increased number of R1 resections has a clinical relevance for patients' prognosis. Tumors with a smaller size or with a greater distance to the organ surface or RM have a better outcome.
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http://dx.doi.org/10.1159/000504648DOI Listing
January 2020

Favorable 90-Day Mortality in Obese Caucasian Patients with Septic Shock According to the Sepsis-3 Definition.

J Clin Med 2019 Dec 24;9(1). Epub 2019 Dec 24.

Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany.

Septic shock is a frequent life-threatening condition and a leading cause of mortality in intensive care units (ICUs). Previous investigations have reported a potentially protective effect of obesity in septic shock patients. However, prior results have been inconsistent, focused on short-term in-hospital mortality and inadequately adjusted for confounders, and they have rarely applied the currently valid Sepsis-3 definition criteria for septic shock. This investigation examined the effect of obesity on 90-day mortality in patients with septic shock selected from a prospectively enrolled cohort of septic patients. A total of 352 patients who met the Sepsis-3 criteria for septic shock were enrolled in this study. Body-mass index (BMI) was used to divide the cohort into 24% obese (BMI ≥ 30 kg/m) and 76% non-obese (BMI < 30 kg/m) patients. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality (31% vs. 43%; = 0.0436) in obese patients compared to non-obese patients. Additional analyses of baseline characteristics, disease severity, and microbiological findings outlined further statistically significant differences among the groups. Multivariate Cox regression analysis estimated a significant protective effect of obesity on 90-day mortality after adjustment for confounders. An understanding of the underlying physiologic mechanisms may improve therapeutic strategies and patient prognosis.
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http://dx.doi.org/10.3390/jcm9010046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019854PMC
December 2019

The prognostic capacities of CBP and p300 in locally advanced rectal cancer.

World J Surg Oncol 2019 Dec 19;17(1):224. Epub 2019 Dec 19.

Department of General, Visceral and Pediatric Surgery, University Medical Center, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

Background: CREB-binding protein (CBP) and p300 represent histone acetyltransferases (HATs) and transcriptional coactivators that play essential roles in tumour initiation and progression. Both proteins are generally thought to function as tumour suppressors, although their distinct roles in colorectal cancer (CRC) remain inconsistent and ambiguous. Thus, we analysed the expression of these two HATs in human tissue samples from patients with locally advanced rectal cancer via immunohistochemistry and evaluated their potential impacts on future CRC diagnosis and treatment.

Methods: In our analysis, we included ninety-three (n = 93) patients diagnosed with adenocarcinoma in the upper third of the rectum. None of the patients received preoperative chemoradiotherapy, but the patients did undergo primary resection of the tumour within the phase II GAST-05 trial. By using H-scores, the expression of both proteins was visualised via immunohistochemistry in resected specimens from the patients. CBP and p300 expression were correlated with clinical and follow-up data.

Results: Our analysis showed that high expression of CBP was significantly associated with prolonged cancer-specific survival (CSS; p = 0.002). In univariate analysis, CBP was an independent prognostic parameter for CSS (p = 0.042). High nuclear CBP expression was observed in two-thirds of patients. In contrast, we could not find any significant correlation between the expression of p300 and cancer-specific survival in this cohort of patients (p = 0.09). We did not observe any cooperation between CBP and p300 in our analysis.

Conclusions: High expression of CBP was significantly associated with improved oncological outcomes. This finding could help to stratify patients in the future for CRC treatment. Histone deacetylase (HDAC) inhibitors are increasingly playing a role in oncological treatment and could additionally become therapeutic options in CRC. Our findings need to be further evaluated and verified in future clinical analyses.
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http://dx.doi.org/10.1186/s12957-019-1764-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923994PMC
December 2019

Kompetenzorientiertes Lehren in der Chirurgie.

Zentralbl Chir 2019 12 11;144(6):530-531. Epub 2019 Dec 11.

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http://dx.doi.org/10.1055/a-1028-0107DOI Listing
December 2019

Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression.

Digestion 2021 6;102(2):227-235. Epub 2019 Nov 6.

Institute of Pathology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany.

Background: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities.

Patients And Methods: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial.

Results: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts.

Conclusion: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC.
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http://dx.doi.org/10.1159/000504093DOI Listing
November 2019

[The Joy of Being a Surgeon - How to Generate Enthusiasm in Undergraduate Medical Education - A Local Example: The "Göttinger Aufschneidertag"].

Zentralbl Chir 2019 Dec 22;144(6):614-615. Epub 2019 Oct 22.

Klinik für Allgemein-, Viszeral- und Kinderchirurgie, Universitätsmedizin Göttingen.

Offering a full-day program including practical courses and the possibility of direct exchange between medical students and university teachers, the "Göttinger Aufschneidertag" was launched to generate enthusiasm for surgery. Workshops comprising four surgical disciplines enable participants to gain insight into the craft of surgery. The program aims to create interest in surgery among medical students at an early point of their studies and to make them enjoy their profession.
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http://dx.doi.org/10.1055/a-1007-2062DOI Listing
December 2019

NO /RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer.

Int J Cancer 2020 06 19;146(11):3160-3169. Epub 2019 Nov 19.

Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase;
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http://dx.doi.org/10.1002/ijc.32733DOI Listing
June 2020

The impact of preoperative biliary stenting in pancreatic cancer: A case-matched study from the German nationwide pancreatic surgery registry (DGAV StuDoQ|Pancreas).

Pancreatology 2019 Oct 18;19(7):985-993. Epub 2019 Sep 18.

Department of Surgery, University Medical Center Luebeck, Germany; DGAV STuDoQ|Pancreas Registry of the German Association for General and Visceral Surgery, Germany.

Background/objective: The impact of preoperative biliary stenting (PBS) before pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) is controversial.

Methods: Patients undergoing PD with or without PBS for PDAC were identified from the German DGAV-StuDoQlPancreas registry. The impact of PBS on perioperative complications was analyzed.

Results: 1133 patients undergoing PD for PDAC were identified from the registry. After matching, 480 PBS patients vs. 480 patients without PBS were analyzed. Postoperative complications Clavien-Dindo classification (CDC) grade IIIa-IVb were higher in PBS patients (PBS 27% vs. no PBS 22%, p = 0.027). 320 PBS patients (66%) had no history of jaundice. In these patients, PBS was associated with higher morbidity. In contrast, PBS was not associated with higher complication rates in patients with history of jaundice. Serum bilirubin levels of 15 mg/dl and higher lead to more CDC IIIa-IVb (24% vs. 28%, p = 0.053) and higher mortality (3% vs. 7%, p < 0.001). PBS in patients with serum bilirubin levels of >15 mg/dl increased CDC IIa-IVb complications (21% vs. 50%, p = 0.001), mortality was equivalent.

Conclusion: Most PBS procedures were performed in patients with no history of jaundice and increased morbidity. Serum bilirubin levels >15 mg/dl lead to higher morbidity and mortality. PBS correlated with higher complication rates in these patients.
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http://dx.doi.org/10.1016/j.pan.2019.09.007DOI Listing
October 2019

Combined targeting of HER-2 and HER-3 represents a promising therapeutic strategy in colorectal cancer.

BMC Cancer 2019 Sep 5;19(1):880. Epub 2019 Sep 5.

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany.

Background: Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptors HER-2 and HER-3 in the three cell lines LS513, LS1034 and SW837.

Methods: Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation.

Results: The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5-fluorouracil and oxaliplatin. Finally, high expression of HER-3 was detected in 121 of 172 locally advanced rectal cancers (70.3%). In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors' mode of action, as targeting HER-2 alone is not sufficient.

Conclusion: Since HER-2 and HER-3 are expressed in a relevant number of patients, targeting both receptors may represent a promising therapeutic strategy for CRC.
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http://dx.doi.org/10.1186/s12885-019-6051-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727342PMC
September 2019