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BACKGROUND: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Leucovorina , Compostos Organoplatínicos , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Masculino , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Adulto , Metástase Neoplásica , Biomarcadores Tumorais/sangueAssuntos
Di-Hidrouracila Desidrogenase (NADP) , Fluoruracila , Haplótipos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Di-Hidrouracila Desidrogenase (NADP)/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody-drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.
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Neoplasias dos Genitais Femininos , Infecções por Papillomavirus , Neoplasias Vulvares , Humanos , Feminino , Neoplasias Vulvares/genética , Neoplasias Vulvares/terapia , Neoplasias Vulvares/patologia , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Medicina de Precisão , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Estudos Retrospectivos , BiomarcadoresRESUMO
BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Gencitabina , Linhagem Celular Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Smad3/metabolismoRESUMO
Receptor tyrosine kinase erythroblastic oncogene B2 (ERBB2), also known as human epidermal growth factor receptor 2 (HER2), represents an oncogenic driver and has been effectively targeted in breast and gastric cancer. Recently, next-generation sequencing (NGS) discovered ERBB2 as a promising therapeutic target in metastatic colorectal cancer (mCRC), where it is altered in 3-5% of patients, but no therapies are currently approved for this use. Herein, we present the experience of a single center in diagnosing actionable genetic ERBB2 alterations using NGS and utilizing the latest therapeutic options. Between October 2019 and December 2022, a total of 107 patients with advanced CRC underwent molecular analysis, revealing actionable ERBB2 mutations in two patients and ERBB2 amplifications in two other patients. These findings correlated with immunohistochemical (IHC) staining. Of these four patients, two were treated with trastuzumab-deruxtecan (T-DXd). We present two exemplary cases of patients with actionable ERBB2 alterations to demonstrate the effectiveness of T-DXd in heavily pretreated ERBB2-positive mCRC patients and the need for early molecular profiling. To fully exploit the potential of this promising treatment, earlier molecular profiling and the initiation of targeted therapies are essential.
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The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, and comparison of oncological outcomes in PVR patients. We retrieved n = 90 patients from a prospectively collected data bank who underwent pancreas surgery between 2012 and 2019 at the University Medical Centre Göttingen (Germany) and showed a histologically confirmed pancreatic ductal adenocarcinoma (PDAC). While 50 patients (55.6%) underwent pancreatic resection combined with PVR, 40 patients (44.4%) received standard pancreatic surgery. Patients with distal pancreatectomy or a tumor other than PDAC were excluded. PVR was performed either as local excision or circular resection of the portal vein. Clinical/patient data and follow-ups were retrieved. The median follow-up period was 20.5 months. Regarding the oncological outcome, a statistically poorer CSS (p = 0.04) was observed in PVR patients. There was no difference (p = 0.18) in patients' outcomes between tangential and complete PVR, while n = 21 (42% of PVR patients) showed portal vein infiltration. The correlation between performed PVR and resection status was statistically significant: 48.6% of PVR patients achieved R0 resections compared to 75% in non-PVR patients (p = 0.03). Patients who underwent PDAC surgery with PVR show a significantly poorer outcome regardless of PVR type. Tumor size and R-status remain two important variables significantly associated with outcome. Since there is a lack of standardization for the indication of PVR, it remains unknown if the need for resection of vein structures during pancreatic resection represents the biological aggressiveness of the tumor or is biased by the experience of the surgeon.
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BACKGROUND: We evaluated the feasibility of a chick chorioallantoic membrane (CAM) tumor model for preclinical research on tumor radiofrequency ablation (RFA). METHODS: Fertilized chicken eggs were incubated and divided into five cohorts: RFA for 30 s (n = 5), RFA for 60 s (n = 5), RFA for 120 s (n = 4), sham (n = 8), and controls (n = 6). Xenografting using pancreatic neuroendocrine tumor cells of the BON-1 cell line was performed on embryonic day (ED) 8. The RFA was performed on ED 12. Survival, stereomicroscopic observations, and histological observations using hematoxylin-eosin (H&E) and Ki67 staining were evaluated. RESULTS: The survival rates in the 30-s, 60-s, and 120-s, sham and control cohort were 60%, 60%, 0%, 100%, and 50%, respectively. Signs of bleeding and heat damage were common findings in the evaluation of stereomicroscopic observations. Histological examination could be performed in all but one embryo. Heat damage, bleeding, thrombosis, and leukocyte infiltration and hyperemia were regular findings in H&E-stained cuts. A complete absence of Ki67 staining was recorded in 33.3% and 50% of embryos in the 30-s and 60-s cohorts that survived until ED 14, respectively. CONCLUSIONS: The CAM model is a feasible and suiting research model for tumor RFA with many advantages over other animal models. It offers the opportunity to conduct in vivo research under standardized conditions. Further studies are needed to optimize this model for tumor ablations in order to explore promising but unrefined strategies like the combination of RFA and immunotherapy. RELEVANCE STATEMENT: The chick chorioallantoic membrane model allows in vivo research on tumor radiofrequency ablation under standardized conditions that may enable enhanced understanding on combined therapies while ensuring animal welfare in concordance with the "Three Rs." KEY POINTS: ⢠The chorioallantoic membrane model is feasible and suiting for tumor radiofrequency ablation. ⢠Radiofrequency ablation regularly achieved reduction but not eradication of Ki67 staining. ⢠Histological evaluation showed findings comparable to changes in humans after RFA. ⢠The chorioallantoic membrane model can enable studies on combined therapies after optimization.
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Galinhas , Neoplasias Pancreáticas , Humanos , Animais , Membrana Corioalantoide , Estudos de Viabilidade , Antígeno Ki-67 , Amarelo de Eosina-(YS)RESUMO
Maintaining cancer patients' exercise capacity and therefore patients' ability to live a self-determined life is of huge importance, but little is known about major determinants. We sought to identify determinants of exercise capacity in patients with a broad spectrum of cancer types, who were already receiving cancer treatment or about to commence such therapy. Exercise capacity was assessed in 253 consecutive patients mostly suffering from advanced cancer using the 6-min walk test (6-MWT). All patients underwent echocardiography, physical examination, resting electrocardiogram, hand grip strength (HGS) measurement, and laboratory assessments. Patients were divided into two groups according to the median distance in the 6-MWT (459 m). Patients with lower exercise capacity were older, had significantly lower HGS and haemoglobin and higher values of high sensitive (hs) Troponin T and NT-proBNP (all p < 0.05). Whilst the co-morbidity burden was significantly higher in this group, no differences were detected for sex, body mass index, tumor type, or cachexia (all p > 0.2). Using multivariable logistic regression, we found that the presence of anaemia (odds ratio (OR) 6.172, 95% confidence interval (CI) 1.401-27.201, p = 0.016) as well as an increase in hs Troponin T (OR 3.077, 95% CI 1.202-5.301, p = 0.019) remained independent predictors of impaired exercise capacity. Increasing HGS was associated with a reduced risk of a lower exercise capacity (OR 0.896, 95% CI 0.813-0.987, p = 0.026). Screening patients for elevated hs troponin levels as well as reduced HGS may help to identify patients at risk of lower exercise capacity during cancer treatment.
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Tolerância ao Exercício , Neoplasias , Humanos , Força da Mão , Troponina T , Índice de Massa CorporalRESUMO
BACKGROUND: The PanaMa trial demonstrated significant benefit in progression-free survival with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. Here, we report health-related quality of life (HRQOL) analyses from the PanaMa trial. METHODS: HRQOL outcomes were evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression/death. HRQOL outcomes were mean and individual changes in EORTC QLQ-C30 from baselines (before induction therapy and before maintenance therapy) to each cycle of treatment. Comparative analyses were performed by randomisation status and treatment arm for induction- and maintenance-therapy, respectively. The trial is registered with clinicaltrials.gov (NCT01991873). RESULTS: At least one HRQOL questionnaire was completed by a total of 349/377 (93%) patients who received induction therapy, and by 237/248 (96%) patients who were randomised and received maintenance therapy. During induction therapy, most HRQOL dimensions remained stable or showed improvement, while appetite loss and diarrhoea significantly deteriorated. During maintenance therapy, HRQOL dimensions remained stable, while those that deteriorated during induction therapy showed significant improvement, without significant differences between the treatment arms. CONCLUSION: Maintenance therapy improves HRQOL dimensions that initially deteriorated during induction therapy while stabilising HRQOL in other dimensions. The addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer prolongs progression-free survival without negative impact on HRQOL.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Panitumumabe , Leucovorina/uso terapêutico , Qualidade de Vida , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fluoruracila/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Endometrial carcinomas are the most common female genital malignancies. They are very rare in pregnancy and worldwide less than 60 cases associated with pregnancy are published. No clear cell carcinoma has been described in a pregnancy with a live birth. CASE PRESENTATION: We present the course of a 43-year-old Uyghur female patient with the diagnosis of endometrial carcinoma with a deficiency in the DNA mismatch repair system in the pregnancy. The malignancy with clear cell histology was confirmed by biopsy following the delivery via caesarean section due to preterm birth of a fetus with sonographically suspected tetralogy of Fallot. Earlier whole exome sequencing after amniocentesis had shown a heterozygous mutation in the MSH2 gene, which was unlikely to be related to the fetal cardiac defect. The uterine mass was initially deemed an isthmocervical fibroid by ultrasound and was confirmed as stage II endometrial carcinoma. The patient was consequently treated with surgery, radiotherapy and chemotherapy. Six months after the adjuvant therapy, re-laparotomy was performed due to ileus symptoms and an ileum metastasis was found. The patient is currently undergoing immune checkpoint inhibitor therapy with pembrolizumab. CONCLUSION: Rare endometrial carcinoma should be included in the differential diagnosis of uterine masses in pregnant women with risk factors.
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Neoplasias do Endométrio , Nascimento Prematuro , Neoplasias Uterinas , Recém-Nascido , Gravidez , Feminino , Humanos , Adulto , Instabilidade de Microssatélites , Cesárea , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/patologiaRESUMO
Introduction: Multi-professional interdisciplinary tumor boards (ITB) are essential institutions to discuss all newly diagnosed, relapsed or complex cancer patients in a team of specialists to find an optimal cancer care plan for each individual patient with regard to national and international clinical practice guidelines, patient´s preference and comorbidities. In a high-volume cancer center, entity-specific ITBs take place at least once a week discussing a large number of patients. To a high level of expertise and dedication, this also requires an enormous amount of time for physicians, cancer specialists and administrative support colleagues, especially for radiologists, pathologists, medical oncologists and radiation oncologists, who must attend all cancer-specific boards according to certification requirements. Methods: In this 15-month prospective German single-center analysis, we examined the established structures of 12 different cancer-specific ITBs at the certified Oncology Center and demonstrate tools helping to optimize processes before, during and after the boards for optimal, time-saving procedures. Results: By changing pathways, introducing revised registration protocols and new digital supports we could show that the workload of preparation by radiologists and pathologists could be reduced significantly by 22.9% (p=<0.0001) and 52.7% (p=<0.0001), respectively. Furthermore, two questions were added to all registration forms about the patient´s need for specialized palliative care support that should lead to more awareness and early integration of specialized help. Discussion: There are several ways to reduce the workload of all ITB team members while maintaining high quality recommendations and adherence to national and international guidelines.
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An aorto-esophageal fistula (AEF) is a rare and life-threatening situation, associated with aneurysms, foreign bodies, infiltrating tumors, and radiotherapy. The ideal management is unclear. Open surgery of AEF has a high mortality and morbidity. Thoracic endovascular aortic repair (TEVAR) of an AEF is an effective and safe emergency treatment for these patients. We describe a case of AEF due to esophageal cancer successfully treated the first time by total percutaneous TEVAR (pTEVAR). A 70-year-old male patient presented with massive hematemesis at the emergency department. The patient had a known history of esophageal cancer previously treated by radiochemotherapy which was completed 3 days before. Emergency upper gastrointestinal endoscopy failed to stop the bleeding. Subsequent contrast-enhanced computed tomography revealed an aorto-esophageal fistula and emergency pTEVAR was performed. The bleeding stopped directly after stent graft placement and the patient was discharged after 10 days later. He died 3 months after pTEVAR from cancer progression. pTEVAR is an effective and safe treatment option for AEF. It can be applied as a first-line treatment and offers the potential to improve survival in the emergency setting.
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OBJECTIVE: The objective of this study is to examine the performance of new generation protection aprons as alternative to conventional lead aprons regarding their radiation protection effectiveness. METHOD AND MATERIALS: Radiation protection aprons made of lead-containing and lead-free materials from a total of seven companies were compared. Furthermore, different lead equivalent values of 0.25, 0.35 and 0.5 mm were compared. For quantitative assessment, radiation attenuation was determined with increasing voltage in steps of 20 kV from 70 kV up to 130 kV. RESULTS: New generation aprons and conventional protection lead aprons showed a similar shielding performance at lower tube voltages below 90 kVp. When tube voltage was increased above 90 kVp, significant (p < 0.05) differences between the three apron types were observed, with conventional lead material as best shielding performer over lead composite and lead-free aprons. CONCLUSION: We observed a similar radiation protection performance between conventional lead aprons and new generation aprons at low intensity radiation workplaces, with lead aprons being dominant for all energies. Only new generation aprons of 0.5 mm thickness would adequately replace 0.25 and 0.35 mm conventional lead aprons. For healthy radiation protection, the possibility of using weight-reduced X-ray aprons is very limited.
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Proteção Radiológica , Protetores contra Radiação , Humanos , Doses de Radiação , Proteção Radiológica/métodos , Raios X , Roupa de ProteçãoRESUMO
BACKGROUND: Granulomatous diseases as sarcoidosis can impair the staging of metastatic diseases since metastasis are hard to distinguish from granulomas in standard imaging. This case report describes the diagnostic workup and therapy in a patient with simultaneous sarcoidosis and rectal cancer with hepatic metastasis and how a curative stadium was achieved. CASE DESCRIPTION: A 71-year old male patient was diagnosed with an adenocarcinoma of the rectum after presenting with involuntary weight loss and anemia. Further diagnostics raised strong suspicion of hepatic, pulmonary and splenic metastasis. Histology after bronchoscopy surprisingly discovered non-caseating granulomas, leading to the diagnosis of sarcoidosis. Due to an obstructive tumor, a rectum resection was performed. Due to a high suspicion of splenic metastasis during surgery, the spleen was removed. Histology revealed no metastasis in the spleen but multiple granulomas due to sarcoidosis. After surgery, biopsy of a suspicious lesion in the liver revealed both metastasis and sarcoidosis in the same sample. The patient was treated with a pseudo(neo)adjuvant chemotherapy with 5-Fluorouracil, Leukovorin, Oxaliplatin (FOLFOX) and Panitumumab (Anti-EGF-antibody). After treatment, CT scan revealed two hepatic lesions decreasing in size, while all other lesions were metrically stable. A right hemihepatectomy followed and histology revealed both sarcoidosis and metastasis. The curated patient was sent to aftercare and there is no suspicion for a relapse (13 month after last surgery). DISCUSSION: The simultaneous appearance of metastatic tumors and sarcoidosis creates a diagnostic dilemma since both manifestations can barely be distinguished in regular imaging technologies. This case report demonstrates that the histological work-up of affected organs with consecutive resections can cure a patient of a metastatic tumor disease, even in the context of simultaneous sarcoidosis.
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Carcinoma , Neoplasias Retais , Sarcoidose , Neoplasias Esplênicas , Masculino , Humanos , Idoso , Recidiva Local de Neoplasia , Sarcoidose/diagnóstico , Neoplasias Retais/diagnóstico , Neoplasias Retais/terapia , GranulomaRESUMO
AIMS: Maintaining quality of life (QoL) in patients with cancer has gathered significant interest, but little is known about its major determinants. We sought to identify determinants of QoL in patients undergoing cancer treatment as well as in treatment-naïve patients about to commence such therapy. METHODS AND RESULTS: QoL was assessed in 283 patients with cancer using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire. All patients underwent a battery of tests including physical examination, resting electrocardiogram, hand grip strength, and biochemistry assessment. Using multivariable logistic regression, we found that age [odds ratio (OR) 0.954, 95% confidence interval (CI) 0.916-0.994], resting heart rate (OR 1.036, 95% CI 1.004-1.068), hand grip strength (OR 0.932, 95% CI 0.878-0.990), and the presence of cachexia (OR 4.334, 95% CI 1.767-10.631) and dyspnoea (OR 3.725, 95% CI 1.540-9.010; all P < 0.05) remained independently predictive of reduced QoL. CONCLUSIONS: Therefore, it may be reasonable to address circumstances that are affecting muscle mass, body weight, and heart rate to maintaining QoL; however, prospective studies to test these endpoints are required.
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Neoplasias , Qualidade de Vida , Humanos , Estudos Prospectivos , Força da Mão , Neoplasias/terapia , CaquexiaRESUMO
BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is the treatment option of choice for almost all pathologies of the descending thoracic aorta. The aim of the present study was to determine the impact of aortic pathology on the occurrence of postimplantation syndrome (PIS) after TEVAR. METHODS: Seventy-four patients undergoing TEVAR for aortic dissection (TAD, 25), aortic aneurysm (TAA, 26), and aortic rupture or perforated ulcer (TAR/PAU, 23) were included in this retrospective study. The clinical outcome measures were persistent inflammation at hospital discharge and in-hospital mortality. RESULTS: PIS was assessed in 22.97% of all patients, predominantly in the TAD group (P=0.03). CRP increased after TEVAR (156.6±94.5, P<0.001; 108.1±57.7, P<0.01 and 117.8±70.4, P<0.05) vs. baseline (58.1±77.5, 31.94±52.1 and 31.9±52.1 mg/L, in TAD, TAA and TAR/PAU, respectively) and this increase was more accentuated in TAD group (P<0.05). Stent-length was similar in all groups (P=0.226) but correlated with postoperative CRP only in TAD (R=0.576, P=0.013). Fresh parietal thrombus correlated with CRP (R=0.4507, P=0.0005) and is (OR=1.0883, P=0.0001), together with the pathology of aortic dissection (OR=6.2268, P=0.0288), a predictor of PIS after TEVAR. Whereas mortality (5.4%) did not correlate with PIS (P=0.38) either with aortic pathology (P=0.225), hospital stay after TEVAR was significantly prolonged by PIS (P=0.03). CONCLUSIONS: Aortic dissection is associated with more inflammation after TEVAR than aortic aneurysm, rupture or perforated ulcer, with the amount of fresh parietal thrombus playing the most significant role in the occurrence of PIS. Importantly, PIS prolongs hospital stay but not mortality after TEVAR.
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Aneurisma da Aorta Torácica , Aneurisma Aórtico , Dissecção Aórtica , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Estudos Retrospectivos , Úlcera/diagnóstico por imagem , Úlcera/cirurgia , Úlcera/complicações , Procedimentos Endovasculares/efeitos adversos , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Aneurisma Aórtico/cirurgia , Inflamação/complicações , Inflamação/cirurgia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/complicações , Resultado do TratamentoRESUMO
BACKGROUND: In vivo gene editing of somatic cells with CRISPR nucleases has facilitated the generation of autochthonous mouse tumors, which are initiated by genetic alterations relevant to the human disease and progress along a natural timeline as in patients. However, the long and variable, orthotopic tumor growth in inner organs requires sophisticated, time-consuming and resource-intensive imaging for longitudinal disease monitoring and impedes the use of autochthonous tumor models for preclinical studies. METHODS: To facilitate a more widespread use, we have generated a reporter mouse that expresses a Cre-inducible luciferase from Gaussia princeps (GLuc), which is secreted by cells in an energy-consuming process and can be measured quantitatively in the blood as a marker for the viable tumor load. In addition, we have developed a flexible, complementary toolkit to rapidly assemble recombinant adenoviruses (AVs) for delivering Cre recombinase together with CRISPR nucleases targeting cancer driver genes. RESULTS: We demonstrate that intratracheal infection of GLuc reporter mice with CRISPR-AVs efficiently induces lung tumors driven by mutations in the targeted cancer genes and simultaneously activates the GLuc transgene, resulting in GLuc secretion into the blood by the growing tumor. GLuc blood levels are easily and robustly quantified in small-volume blood samples with inexpensive equipment, enable tumor detection already several months before the humane study endpoint and precisely mirror the kinetics of tumor development specified by the inducing gene combination. CONCLUSIONS: Our study establishes blood-based GLuc monitoring as an inexpensive, rapid, high-throughput and animal-friendly method to longitudinally monitor autochthonous tumor growth in preclinical studies.
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Copépodes , Neoplasias Pulmonares , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Copépodes/genética , Copépodes/metabolismo , Edição de Genes , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Neoplasias Pulmonares/genética , CamundongosRESUMO
Introduction: The risk for metastasis at primary diagnosis of breast cancer is about 4%. The German guidelines give clear indications on when, who, and how to stage breast cancer patients. Ideally, this should be done via computerized axial tomography (CAT) scan of the thorax and abdomen and an additional bone scan. But daily practice shows that the way health-care providers handle staging recommendations can vary. To objectify adherence to guidelines we started a nation-wide survey. Methods: Between July and September 2020, we sent out a survey via email to all certified and noncertified breast centers and in addition to all Departments of Obstetrics and Gynecology in Germany. We asked for timing of staging, conditions that cause staging, and the applied method. In case we did not get any reply, we sent out a reminder. Results: A total of 220 certified breast centers, 28 noncertified breast centers, and 48 Departments of Obstetrics and Gynecology who care for breast cancer patients took part in our survey. A general pretherapeutic staging was performed in 16.4%, 39.3%, and 66.7% of all institutions and a general postoperative staging was performed in 4.1%, 0%, and 6.3% of each institutional type, respectively. In terms of the applied method, 75% of all certified breast centers used a CAT scan and bone scan, while 23.3% primarily used chest X-ray, ultrasound of the abdomen (27.7%), or MRI. As a potential reason for using X-ray and ultrasound, the presence of a "low-risk" breast cancer was mentioned. Summary: Although certified breast centers show the highest adherence to current guidelines, some still perform a general staging or do not use the recommended staging method. The low probability of primary metastatic breast cancer and the use of a reasonable exposure to radiation warrant a critical discussion.
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PURPOSE: VIPoma belongs to the group of neuroendocrine neoplasms. These tumours are located mostly in the pancreas and produce high levels of vasoactive intestinal peptide (VIP). In most cases, a metastatic state has already been reached at the initial diagnosis, with high levels of VIP leading to a wide spectrum of presenting symptoms. These symptoms include intense diarrhoea and subsequent hypopotassaemia but also cardiac complications, with life-threatening consequences. Treatment options include symptomatic therapy, systemic chemotherapy and targeted therapy, as well as radiation and surgery. Due to the low incidence of VIPoma, there are no prospective studies or evidence-based therapeutic standards to date. METHODS: To evaluate the possible impact of different therapy strategies, we performed literature research using PubMed. RESULTS: All possible treatment modalities for VIPoma have at least one of two therapy goals: antisecretory effects (symptom control) and antitumoural effects (tumour burden reduction). Symptomatic therapy is the most important in the emergency setting to rehydrate, balance electrolytes and stabilise the patient. Symptomatic therapy is also of great importance perioperatively. Somatostatin analogues play a major role in symptom control, although their efficiency is often limited. Chemotherapy may be effective in reaching stable disease for a certain time period, although its impact on symptom control is limited and often delayed. Among targeted therapy options, the usage of sunitinib appears to be the most effective in terms of symptom control and showing antitumoural effects at the same time. Experience with radiation is still limited; however, local ablative procedures seem to be promising options. Peptide receptor radiotherapy (PRRT) with radiolabelled somatostatin analogues (SSAs, 177Lu-DOTATATE) offers a targeted approach, especially in patients with high somatostatin receptor density. Surgery is the first-line therapy for nonmetastatic VIPoma. Additionally, if the resection of all visible tumour lesions is possible, the surgical approach seems preferable to other strategies in highly symptomatic patients. The role of surgery in very advanced stages where only tumour debulking is possible remains debatable. However, a high rate of immediate symptom control can be achieved by tumour debulking followed by somatostatin therapy, although the impact on survival remains unclear. CONCLUSION: Surgery is the only curative option for nonmetastatic VIPoma. Additionally, surgery should be a first-line therapy option for highly symptomatic patients, especially if the resection of all tumour lesions (primary tumour and metastasis) is achievable. In frail patients, other modalities can be used.
Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Vipoma , Humanos , Vipoma/diagnóstico , Vipoma/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Octreotida/uso terapêutico , Somatostatina/uso terapêutico , Tumores Neuroendócrinos/terapiaRESUMO
Tumor grading is a robust prognostic predictor in patients with neuroendocrine neoplasms (NEN) and guides therapy, especially in tumors with high proliferation. NEN can be separated into well-differentiated and poorly differentiated types. The more aggressive NEN have been further separated into neuroendocrine tumors (NET G3) with a better prognosis and neuroendocrine carcinomas (NEC) with a worse prognosis. Despite this distinction's tremendous clinical and therapeutic relevance, optimal diagnostic biomarkers are still lacking. In this study, we analyzed the protein expression and prognostic impact of Enhancer of Zeste Homolog 2 (EZH2) by immunohistochemistry in 219 tissue samples of gastroenteropancreatic (GEP-NEN) and pulmonary NEN (P-NEN). EZH2 was almost exclusively expressed in NEN with a proliferation rate above 20% (G3), while all low-grade tumors were nearly negative. Among high-grade NEN, 65% showed high and 35% low expression of EZH2. In this group, the high expression of EZH2 was significantly associated with poor overall survival and NEC histology. Interestingly, EZH2 seems to act independently of Polycomb Repressive Complex 2 (PRC2) in NEN. In conclusion, we propose EZH2 as a robust biomarker for distinguishing between NET G3 and NEC among gastroenteropancreatic and pulmonary NEN.