Gregor Kocher - Academia.edu (original) (raw)

Papers by Gregor Kocher

AME surgical journal, Apr 1, 2023

Supplementary Figure Legends for S1-5 and Table S6 shows the primary antibodies used in this study.

Supplementary Table S1. Human kinome sgRNA library used in this study. Supplementary Table S2. PC... more Supplementary Table S1. Human kinome sgRNA library used in this study. Supplementary Table S2. PCR primers used in this study. Supplementary Table S3. NGS data of sgRNAs in chemotherapy- and vehicle-treated MESO-1 cells. Supplementary Table S4. Kinase candidates scored in negative selection CRISPR screening. Supplementary Table S5. Sequences of WEE1-specific sgRNAs and negative control sgRNAs.

MSTO-211H Vehicle Chemo (0.1+0.5μM AZD1775 (0.1μM AZD1775 (0.2μM) Combi 2 Combi 1 H28 Vehicle Che... more MSTO-211H Vehicle Chemo (0.1+0.5μM AZD1775 (0.1μM AZD1775 (0.2μM) Combi 2 Combi 1 H28 Vehicle Chemo (0.1+0.5μM) AZD1775 (0.1μM AZD1775 (0.2μM) Combi 2 Combi 1 MESO-4 Vehicle Chemo (0.1+0.5μM AZD1775 (0.1μM AZD1775 (0.5μM) Combi 2 Combi 1

AME surgical video database, 2022

Research Square (Research Square), Jan 24, 2022

Once considered a waste product of anaerobic cellular metabolism, lactate has been identi ed as a... more Once considered a waste product of anaerobic cellular metabolism, lactate has been identi ed as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of nonsmall cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) mutant (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate

British Journal of Surgery, May 1, 2021

Objective The management of malignant pleural effusion is a common problem in thoracic surgery. P... more Objective The management of malignant pleural effusion is a common problem in thoracic surgery. Patients are often polymorbid and are usually referred at a terminal stage of their oncological disease. Our objective was to compare the efficiency and outcomes after different treatment strategies of malignant pleural effusion. Methods We retrospectively reviewed the charts of a total of 416 patients treated during the period of 2010 to 2020 who underwent thoracoscopic pleurodesis with or without implantation of tunneled pleural catheter (TPC) as well as patients who underwent the implantation of TPC alone. Primary outcome was postoperative survival and secondary outcome was length of stay (LOS). In addition, we documented the recurrence of ipsilateral pleural effusion and the need for reintervention as well as the pulmonary reexpansion of the lung on postoperative chest x-ray. Inclusion criteria were malignant pleural effusion and documented follow-up until time of death. Exclusion criteria were treatment for mesothelioma, pneumothorax and emphysema. Results A total of 199 patients were included for analysis. Median LOS of patients treated with implantation of TPC alone in analgosedation (n = 28) was 1 day (range:1-4 days). Median LOS of patients who received video-assisted talcum pleurodesis (n = 65) without implantation of a TPC was 6 days (range 1-38 days). Median LOS of patients who received VATS talcum pleurodesis and TPC (n = 106) was 3 days (range 1-34 day). The difference in LOS was statistically significant (p < 0.05). Median overall survival was 108 days (range 3-3001 days). There was no statistically significant difference in survival between the different treatment groups (p = 0.47). Conclusion The primary goal when treating patients with malignant pleural effusion is relief of dyspnea and/or pain and to keep the duration of the inpatient treatment to a minimum. In patients with a considerable surgical risk due to comorbidities and their underlying oncological disease and who don’t require the sampling of histological material, a conservative treatment option with implantation of a TPC can be sufficient. The additional insertion of a TPC not only reduces the length of stay, but also has a positive effect on the efficacy of the pleurodesis in terms of less recurrence. We therefore recommend the routine use of TPC when performing VATS talcum pleurodesis in patients with malignant pleural effusion.

Current challenges in thoracic surgery, Jun 1, 2023

Patients who have undergone previous pneumonectomy may develop new or second primary cancers, sec... more Patients who have undergone previous pneumonectomy may develop new or second primary cancers, secondary cancers (metastases) or even recurrent malignant disease in the remaining single lung. It is a common misbelief that additional pulmonary resection in a single lung is not feasible. These cases should not be deemed unresectable solely due to the fact of new lesions in the remaining lung after contralateral pneumonectomy. Individual treatment approaches should be based on a multidisciplinary case discussion in specialized centers with high patient volume following meticulous preoperative evaluation and cardiopulmonary assessment. In patients with sufficient cardiopulmonary reserves, an aggressive approach with limited sublobar resection (segmentectomy or wedge resection) can be beneficial and provide good functional and oncological outcome as well as maintenance of quality of life. In this narrative review the evaluation, the management as well as the outcome of additional pulmonary resection after contralateral pneumonectomy with benefits of using extracorporeal membrane oxygenation (ECMO) during these surgical procedures is discussed. In addition, a patient that we encountered in our clinical work is dissected in further detail. This case elucidates numerous critical considerations that the interdisciplinary team must make and the challenging decision-making process in balancing feasibility, individual risks and expected benefits. The surgical methodology employed and the outcomes are also highlighted.

PubMed, Dec 1, 2016

Introduction: Robot-assisted surgery emerged and evolved in order to increase the surgical precis... more Introduction: Robot-assisted surgery emerged and evolved in order to increase the surgical precision and due to the need to overcome the drawbacks of conventional minimally invasive surgery. In thoracic surgery the first reported use of a robotic device was in a series of 12 patients with different lung pathologies with the assistance of the DaVinci Robotic Surgical System in 2002. The DaVinci system has been used for various procedures in the field of thoracic surgery since then. While its advantages for the resection of early stage thymoma have been well documented, its role in the treatment of lung cancer and other pathologies is still under investigation. Evidence acquisition: A systematic literature search was performed on the following medical databases: Medline, EMBASE and Cochrane Library. The search was performed in June 2016 and was limited to material published since the first report of a robotic system for a surgical procedure in 1985. Evidence synthesis: The results for various thoracic surgical procedures were analyzed with focus on the benefits and limitations of the robotic system compared to open and thoracoscopic or video-assisted techniques. Conclusions: Although numerous studies have shown the feasibility and safety of robotic surgery for various procedures, they were not able to show superior postoperative outcomes in terms of morbidity and mortality in exchange for the higher costs of robotic surgery compared to conventional video-assisted thoracic surgery (VATS), except for early-stage thymoma resection. Therefore, randomized control trials comparing robotic particularly with VATS, but also with open procedures are required to further evaluate this crucial topic.

EBioMedicine, Nov 1, 2021

Background: Although T cell abundance in solid tumours is associated with better outcomes, it als... more Background: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFb1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown. Methods: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival. In an independent cohort of NSCLC samples, we used flow cytometry to identify mesenchymal subsets and ex vivo functional studies to characterize their immune regulatory function. Findings: We observed a high enrichment in a core set of genes defining an IA gene expression signature in NSCLC across TCGA Pan-cancer cohort. High IA signature score correlates with enrichment of ECM/stromal gene signature across TCGA NSCLC datasets. Importantly, a higher ratio of ECM/stromal to IA gene signature score was associated with shorter overall survival. In tumours resected from a separate cohort of NSCLC patients, we identified CD90+CD73+ peritumoral cells that were enriched in the ECM/stromal gene signature, which was amplified by TGFb1. IFNg and TNFa-primed peritumoral CD90+CD73+ cells upregulate immune checkpoint molecules PD-L1 and IDO1 and secrete an array of cytokines/chemokines including TGFb1. Finally, immune primed peritumoral CD90+CD73+ cells suppress T cell function, which was relieved following combined blockade of PD-L1 and TGFb1 with IDO1 inhibition but not PD-L1 or anti-CD73 alone. Interpretation: Our findings suggest that targeting PD-L1 together with independent biological features of the stroma may enhance host antitumor immunity in NSCLC.

Cancer Research, Mar 8, 2021

Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to d... more Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell-cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance antiproliferative effects and drove cancer cell death in vitro and in vivo through activation of the gH2AX-CHK-E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer. Significance: The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other FGFR1-amplified cancers.

PubMed, Jun 1, 1982

A case of orbital aspergillosis presenting as a steroid response of optic neuropathy is presented... more A case of orbital aspergillosis presenting as a steroid response of optic neuropathy is presented. The invasive and aggressive nature of this infection in the presence of systemic corticosteroids is documented by serial CT scans and necropsy examination. The authors urge inclusion of aspergilloma in the differential diagnosis of a steroid responsive optic neuropathy.

Translational lung cancer research, Sep 1, 2022

Background: With the exception of very early-stage small cell lung cancer (SCLC), surgery is not ... more Background: With the exception of very early-stage small cell lung cancer (SCLC), surgery is not typically recommended for this disease; however, incidental resection still occurs. After incidental resection, adjuvant salvage therapy is widely offered, but the evidence supporting its use is limited. This study aimed to explore proper adjuvant therapy for these incidentally resected SCLC cases. Methods: Patients incidentally diagnosed with SCLC after surgery at the Shanghai Pulmonary Hospital in China from January 2005 to December 2014 were included in this study. The primary outcome was overall survival. Patients were classified into different group according to the type of adjuvant therapy they received and stratified by their pathological lymph node status. Patients' survival was analyzed using a Kaplan-Meier analysis and Cox regression analysis. Results: A total of 161 patients were included in this study. Overall 5-year survival rate was 36.5%. For pathological N0 (pN0) cases (n=70), multivariable analysis revealed that adjuvant chemotherapy (adchemo) was associated with reduced risk of death [hazard ratio (HR): 0.373; 95% confidence interval (CI): 0.141-0.985, P=0.047] compared to omission of adjuvant therapy. For pathological N1 or N2 (pN1/2) cases (n=91), taking no adjuvant therapy cases as a reference, the multivariable analysis showed that ad-chemo was not associated with a lower risk of death (HR: 0.869; 95% CI: 0.459-1.645, P=0.666), while adjuvant chemo-radiotherapy (ad-CRT) was associated with a lower risk of death (HR: 0.279; 95% CI: 0.102-0.761, P=0.013). Conclusions: Patients who incidentally receive surgical resection and are diagnosed with limited disease SCLC after resection should be offered adjuvant therapy as a salvage treatment. For incidentally resected pN0 cases, ad-chemo should be considered and for pN1/2 cases, ad-CRT should be received.

Current challenges in thoracic surgery, 2021

Lung cancer is the second most common cancer in males, after prostate cancer, and the third in fe... more Lung cancer is the second most common cancer in males, after prostate cancer, and the third in females after breast and colorectal malignancies. Incidence of cancer increases with ageing and, because of the increase of life expectancy, the incidence of lung cancer in the elderly is becoming increasingly important. Even if lung cancer has a high prevalence among patients older than 65 years, geriatric patients are often at risk for insufficient treatment because of lack of data on outcomes after multimodality treatment. The supposed impact of age in geriatric population is probably very overestimated and therefore several trials have included no patients older than 65. In our current society, the population is getting older worldwide and simultaneously the surgical demand of elderly patients is becoming increasingly pressing. Patients with stage IIIA disease are a heterogeneous group requiring often a multimodality treatment tailored to each patient. A multidisciplinary approach to select patients and plan the best treatments is nowadays a cornerstone in order to have good surgical outcomes and reduce morbidity and mortality rates. Improve the selection of elderly patients who can benefit from multimodal treatment in stage IIIA non-small cell lung cancer (NSCLC) will be a challenge of the future.