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1.
Int J Colorectal Dis ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33855608

RESUMO

PURPOSE: Little is known about difference between synchronous colorectal cancer (SCRC) and metachronous colorectal cancer (MCRC) despite the relevance for this selected patient group. The aim of this retrospective review was to analyze patients with SCRC and MCRC. METHODS: All patients who underwent surgery for SCRC and MCRC between 1982 and 2019 were included in this retrospective analysis of our tertiary referral center. Clinical, histological, and molecular genetic characteristics were analyzed. The primary endpoint was cause-specific survival, evaluated by the Kaplan-Meier method. Secondary endpoints were recurrence-free survival and the identification of prognostic factors. RESULTS: Overall, 3714 patients were included in this analysis. Of those, 3506 (94.4%) had a primary unifocal colorectal cancer (PCRC), 103 (2.7%) had SCRC, and 105 (2.8%) had MCRC. SCRC occurred more frequently in elderly (p=0.009) and in male patients (p=0.027). There were no differences concerning tumor stages or grading. Patients with SCRC did not show altered recurrence or survival rates, as compared to unifocal tumors. However, MCRC had a lower rate of recurrence, compared to PCRC (24% vs. 41%, p=0.002) and a lower rate of cause-specific death (13% vs. 37%, p<0.001). Five-year cause-specific survival rates were 63±1% for PCRC, 62±6% for SCRC (p=0.588), and 88±4% for MCRC (p<0.001). Multivariable analysis revealed that MCRC were an independent favorable prognostic parameter regarding case-specific survival. CONCLUSION: Patients with SCRC seem to not have a worse prognosis compared to patients with PCRC. Noteworthy, patients with MCRC showed better survival rates in this retrospective analysis.

2.
Cancers (Basel) ; 13(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804009

RESUMO

Adenocarcinoma of the gastroesophageal junction (AEG) ranks among the most common cancers in the Western world with increasing incidence. However, the prognostic influence and applicability of the Lauren classification was not examined in detail before. The purpose of this analysis was to analyze the oncologic outcomes of GE-junction cancer related to the Lauren histotype in a large single center cohort. Data from the prospectively documented database of the Klinikum Rechts der Isar (TUM School of Medicine) for patients undergoing curatively intended oncologic resection for GE-junction cancer between 1984 and 2018 were extracted. Univariate and multivariate regression analyses were performed to identify predictors for overall survival. Kaplan-Meier analyses were done to investigate the survival rates according to the Lauren histotype. After identification of two distinct histologic categories with prognostic implications, propensity score matching (PSM) was performed to balance for confounders and evaluate its oncologic outcomes retrospectively. In the time period indicated, 1710 patients were treated for GE-junction cancer. Exclusion criteria were: R2-resections (n = 134), metastatic disease (n = 296), 30-day mortality (n = 45), Siewert type I (n = 21), and missing/incomplete data (n = 61). Finally, 1153 patients were analyzed. In a multiple variable analysis, age, UICC-stage, all Lauren histotypes, R-stage, and postoperative complications were significant predictors of overall survival. Kaplan Meier analysis demonstrated significant survival differences between intestinal, diffuse, and mixed Lauren-histotypes (p = 0.001 and p = 0.029). Survival rates were comparable between non-classifiable and intestinal Lauren-types (p = 0.16) and between diffuse and mixed types (p = 0.56). When combining non-classifiable, well, and moderately differentiated Lauren-types and combining poorly differentiated intestinal, diffuse, and mixed types, two highly prognostic groups were identified (p < 0.0001). This was confirmed after PSM for possible confounders. The Lauren histotypes demonstrate highly prognostic value after oncologic resection of GE-junction cancer (Siewert type II and type III) in a single center Western patient cohort. A simplified histotype classification based on Lauren subtypes revealed a clear distinction of prognostic groups and should be considered for further evaluation.

3.
JCI Insight ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33764904

RESUMO

BACKGROUND AND AIMS: Pancreatic cancer is one of the deadliest cancers, still with low long term survival rates. Despite recent advances in treatment, it is extremely important to screen high-risk individuals in order to establish preventive and early detection measures and, in some cases, molecular driven therapeutic options. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are known to be related with an increased risk and might offer novel screening and therapy options. In this study, our goal was to discover the identity of a familial pancreatic cancer gene in two members of a family with FPC. METHODS: Whole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry was used to characterize PALLD expression. RESULTS: A germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer. The identical PALLD mutation was identified in the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the two sisters. Apart from the PALLD mutation, commonly mutated genes that characterize PDAC (KRAS and CDKN2A) were found in both tumor samples. However, the two patients harbored different somatic KRAS mutations (respectively G12D in the index patient and G12V in the index patient's sister). Analysis for PALLD mutation in the healthy siblings of the two sisters was negative, indicating that the identified PALLD mutation might have a disease specific impact. Of note, compartment-specific gene expression data and IHC suggested a predominant role in cancer associated fibroblasts (CAFs). CONCLUSION: We identified a germline mutation of the palladin (PALLD) gene in two siblings in Europe, affected by familial pancreatic cancer, with a predominant function in the tumor stroma.

4.
Histol Histopathol ; : 18332, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769550

RESUMO

BACKGROUND: Tumor regression grading (TRG) based on histopathology is the main tool to assess therapy effects after neoadjuvant therapy (NAT) of pancreatic ductal adenocarcinoma (PDAC). However, reliable markers to distinguish therapy effects from pre-existing tumor features are lacking. The aim of this study was the characterization of PDAC after NAT, focusing on the stroma. MATERIAL AND METHODS: Tissue samples from patients resected for PDAC after NAT (n=27) were analyzed. TRG was assessed using the Royal North Shore (RNS) system. Stromal composition was evaluated by Movat's stain. Immunohistochemistry (IH) for Ki-67 and five previously established stroma markers (alpha-Crystallin B, alpha-Smooth muscle actin (alpha-SMA), Neurotrophin-3 (NT-3), SPARC and Tenascin C) was also performed. Results were compared with therapy-naïve PDACs (n=10). RESULTS: Most cases showed a moderate response (RNS 2; 74%), while 15% displayed a poor response (RNS 3), and 11% a good response (RNS 1). No complete response was observed. Poor regression was associated with mucin-rich stroma, while good regression was associated with collagen-rich stroma. Cases with poorer therapy response had significantly higher proliferation. Higher peritumoral staining intensity for alpha-SMA and Tenascin C also showed a trend towards an association with poor regression. CONCLUSIONS: Similar to the stroma in therapy-naïve PDAC, the stroma of PDAC after NAT is heterogeneous. Distinguishing between desmoplastic stroma and therapy-induced fibrosis by single markers is not possible. Movat's pentachrome stain, IH for Ki-67, and to some extent for Tenascin C and alpha-SMA, can help detect poor histopathological response to NAT.

5.
Dig Surg ; 38(2): 158-165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33640885

RESUMO

BACKGROUND: This survey aimed to register changes determined by the COVID-19 pandemic on pancreatic surgery in a specific geographic area (Germany, Austria, and Switzerland) to evaluate the impact of the pandemic and obtain interesting cues for the future. METHODS: An online survey was designed using Google Forms focusing on the local impact of the pandemic on pancreatic surgery. The survey was conducted at 2 different time points, during and after the lockdown. RESULTS: Twenty-five respondents (25/56) completed the survey. Many aspects of oncological care have been affected with restrictions and delays: staging, tumor board, treatment selection, postoperative course, adjuvant treatments, outpatient care, and follow-up. Overall, 60% of respondents have prioritized pancreatic cancer patients according to stage, age, and comorbidities, and 40% opted not to operate high-risk patients. However, for 96% of participants, the standards of care were guaranteed. DISCUSSION/CONCLUSIONS: The first wave of the COVID-19 pandemic had an important impact on pancreatic cancer surgery in central Europe. Guidelines for prompt interventions and prevention of the spread of viral infections in the surgical environment are needed to avoid a deterioration of care in cancer patients in the event of a second wave or a new pandemic. High-volume centers for pancreatic surgery should be preferred and their activity maintained. Virtual conferences have proven to be efficient during this pandemic and should be implemented in the near future.


Assuntos
/prevenção & controle , Acesso aos Serviços de Saúde/tendências , Pancreatectomia/tendências , Neoplasias Pancreáticas/cirurgia , Padrões de Prática Médica/tendências , Assistência ao Convalescente/métodos , Assistência ao Convalescente/normas , Assistência ao Convalescente/tendências , Atitude do Pessoal de Saúde , Europa (Continente)/epidemiologia , Pesquisas sobre Serviços de Saúde , Acesso aos Serviços de Saúde/normas , Humanos , Controle de Infecções/métodos , Controle de Infecções/tendências , Estadiamento de Neoplasias , Pancreatectomia/normas , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Pandemias , Aceitação pelo Paciente de Cuidados de Saúde , Assistência Perioperatória/métodos , Assistência Perioperatória/normas , Assistência Perioperatória/tendências , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Tempo para o Tratamento/normas , Tempo para o Tratamento/tendências
6.
Artigo em Inglês | MEDLINE | ID: mdl-33590974

RESUMO

BACKGROUND: Cachexia, a devastating syndrome in cancer patients, critically determines survival and life quality. It is characterized by impaired homeostasis of multiple organs including the liver, involves tissue wasting, and is conventionally diagnosed and classified by weight loss (WL). However, recent studies pointed at the problem that WL is not sufficient for precise classification of cancer patients according to disease severity (i.e. prognosis). Tissue inhibitor of metalloproteinases-1 (TIMP-1) is an easily accessible cachexia-associated biomarker in the blood, known to alter liver homeostasis. Here, we investigated the value of combining blood levels of TIMP-1 with parameters of liver functionality towards establishment of a cachexia-associated clinical score, which predicts survival of cancer patients, reflects the clinical manifestation of cachexia, and is easily accessible in the clinic. METHODS: The TIMP-1/liver cachexia (TLC) score, expressed as numerical value ranging from 0 to 1, was calculated by categorizing the blood levels of TIMP-1 and parameters of liver functionality (C-reactive protein, ferritin, gamma-glutamyl transferase, albumin, and total protein) for each patient as below/above a certain risk threshold. The TLC score was tested in a cohort of colorectal cancer (CRC) patients (n = 82, 35.4% women, 64.6% men, median age: 70 years) and validated in a cohort of pancreatic cancer (PC) patients (n = 84, 54.8% women, 45.2% men, median age: 69 years). RESULTS: In CRC patients, the TLC score positively correlated with presence of cachexia-related symptoms (WL, impaired liver function), predicted survival [P < 0.001, hazard ratio (HR): 96.91 (9.85-953.90)], and allowed classification of three prognostically distinct patient subpopulations [low (LO)-risk, intermediate (IM)-risk, and high (HI)-risk groups; LO vs. IM: P = 0.003, LO vs. HI: P < 0.001, IM vs. HI: P = 0.029]. The prognostic power of the cachexia-associated TLC score [P < 0.001, HR: 7.37 (2.80-19.49)] and its application to define risk groups (LO vs. IM: P = 0.032, LO vs. HI: P < 0.001, IM vs. HI: P = 0.014) was confirmed in a cohort of PC patients. The prognostic power of the TLC score was independent of presence of liver metastases in CRC or PC patients and was superior to clinically established staging classifications. CONCLUSIONS: The TLC score, a result of straightforward determination of blood parameters, is an objective cachexia-associated clinical tool for precise survival prediction of gastrointestinal cancer patients.

7.
Dtsch Arztebl Int ; 118(Forthcoming)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33634785

RESUMO

BACKGROUND: Appendectomy is the gold standard for treatment of acute appendicitis. However, recent studies favor primary antibiotic therapy. The aim of this observational study was to explore changes in the numbers of operations for acute appendicitis in the period 2010-2017, paying special attention to disease severity. METHODS: Data from diagnosis-related group statistics were used to analyze the trends, mortality, and complication rates in the surgical treatment of appendicitis in Germany between 2010 and 2017. All cases of appendectomy after a diagnosis of appendicitis were included. RESULTS: Altogether, 865 688 inpatient cases were analyzed. The number of appendectomies went down by 9,8%, from 113 614 in 2010 to 102 464 in 2017, while the incidence fell from 139/100 000 in 2010 to 123/100 000 in 2017 (standardized by age group). This decrease is due to the lower number of operations for uncomplicated appendicitis (79 906 in 2017 versus 93 135 in 2010). Hospital mortality decreased both in patients who underwent surgical treatment of complicated appendicitis (0.62% in 2010 versus 0.42% in 2017) and in those with a complicated clinical course (5.4% in 2010 versus 3.4% in 2017). CONCLUSION: Decisions on the treatment of acute appendicitis in German hospitals follow the current trend towards non-surgical management in selected patients. At the same time, the care of acute appendicitis has improved with regard to overall hospital morbidity and hospital mortality.

8.
Gastroenterology ; 160(5): 1755-1770.e17, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33388318

RESUMO

BACKGROUND & AIMS: Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. RESULTS: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. CONCLUSIONS: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.

9.
Chirurg ; 2021 Jan 26.
Artigo em Alemão | MEDLINE | ID: mdl-33496813

RESUMO

Minimally invasive surgical techniques with respect to the treatment of gastric cancer have progressed rapidly over the last few years. Especially in Asia, where the incidence of gastric cancer is ten times higher than in Europe, surgery for gastric cancer is steadily evolving, especially regarding laparoscopic and robot-assisted procedures. This review first discusses the different options for reconstruction of the gastrointestinal passage after gastrectomy, ranging from Billroth procedures to the latest developments, such as the double tract reconstruction. In particular, the possibility of function-preserving partial gastrectomy, such as proximal and distal gastric resection and the corresponding reconstruction techniques are presented. The latest studies and technical developments are presented, especially with respect to laparoscopically assisted, completely laparoscopic and robot-assisted gastrectomies.

10.
Inflamm Bowel Dis ; 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33512505

RESUMO

BACKGROUND: Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis. METHODS: Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative recovery and anastomotic healing were evaluated using the disease activity index, histological healing scores, and weight monitoring. Ultimately, whole-genome RNA sequencing of the anastomotic tissue was performed to unravel underlying molecular mechanisms. RESULTS: Anxa1-knockout exacerbated the inflammatory response in the healing anastomosis. Treatment with Ac2-26-NPs improved preoperative colitis activity (P < 0.045), postoperative healing scores (P < 0.018), and weight recovery (P < 0.015). Whole-genome RNA sequencing revealed that the suppression of proinflammatory cytokine and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was associated with the treatment effects and a phenotypic switch toward anti-inflammatory M2 macrophages. CONCLUSIONS: Proresolving therapy with Ac2-26-NPs promises to be a potent perioperative therapy because it improves colitis activity and even intestinal anastomotic healing by the suppression of proinflammatory signaling.

11.
Clin Epigenetics ; 13(1): 18, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33499904

RESUMO

BACKGROUND: Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. METHODS: A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. RESULTS: We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. CONCLUSIONS: This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

12.
Expert Rev Anticancer Ther ; : 1-11, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33355020

RESUMO

INTRODUCTION: To date, all efforts to fight gastrointestinal cancer, regardless of its origin and entity, have resulted in complex therapeutic regimens involving a combination of systemic therapy, radiation therapy and surgery. It is generally accepted across all disciplines that not one, but the combination and the proper timing of all modalities result in the best oncologic outcome. AREAS COVERED: Here, we provide insight into the current and future value of multimodal therapeutic approaches for upper and lower gastrointestinal cancer. Various aspects of treatment as well as open questions regarding indication and timing of multimodal strategies are addressed in this review. EXPERT OPINION: In order to further improve the survival and quality of life of patients with gastrointestinal tumors in the future, scientifically proven multimodal therapy concepts are needed first and foremost. In addition, markers are pivotal to assign individual patients to a specific concept and to monitor the success of therapy. The main question is in which situation a neoadjuvant, perioperative or adjuvant radio-, chemo- or immunotherapy is superior. In fact, almost every curatively intended concept still contains surgical resection. Thus, improvement in surgical technique is also critical for multimodality concepts.

13.
Lancet Gastroenterol Hepatol ; 6(2): 128-138, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33338442

RESUMO

BACKGROUND: The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. METHODS: In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. FINDINGS: Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. INTERPRETATION: Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. FUNDING: Celgene.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/uso terapêutico , Esquema de Medicação , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Quimioterapia de Indução , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Pancreatectomia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento , Adulto Jovem
14.
BMC Surg ; 20(1): 313, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33272227

RESUMO

BACKGROUND: During the first wave of the COVID-19 pandemic, German health care centres were restructured for the treatment of COVID-19 patients. This was accompanied by the suspension of the surgical programme. The aim of the survey was to determine the effects of COVID-19 on surgical care in non-university hospitals in Germany. METHODS: This cross-sectional study was based on an anonymous online survey, which was accessible from April 24th to May 10th, 2020 for surgeons of the Konvent der leitenden Krankenhauschirurgen (Convention of leading Hospital Surgeons) in Germany. The analysis comprised of 22.8% (n = 148/649) completed surveys. RESULTS: Communication and cooperation with authorities, hospital administration and other departments were largely considered sufficient. In the early phase of the COVID-19 pandemic, 28.4% (n = 42/148) of the respondents complained about a short supply of protective equipment available for the hospital staff. 7.4% (n = 11/148) of the participants stated that emergency operations had to be postponed or rescheduled. A decreased quantity of emergency surgical procedures and a decreased number of surgical emergency patients treated in the emergency room was reported in 43.9% (n = 65/148) and 63.5% (n = 94/148), respectively. Consultation and treatment of oncological patients in the outpatient clinic was decreased in 54.1% (n = 80/148) of the surveyed hospitals. To increase the capacity for COVID-19 patients, a reduction of bed and operating room occupancy of 50.8 ± 19.3% and 54.2 ± 19.1% were reported, respectively. Therefore, 90.5% (n = 134/148) of all participants expected a loss of revenue of 28.2 ± 12.9% in 2020. CONCLUSION: The first wave of the COVID-19 pandemic had a significant impact on surgical care in Germany. The reduction in the bed and the operating room capacity may have lead to considerable delays in urgent and semi-elective surgical interventions. In addition to the risk of worsening patient care, we anticipate severe financial damage to the clinics in 2020 and beyond. National and supranational planning is urgently needed to ensure the surgical care of patients during the ongoing COVID-19 pandemic.

15.
J Exp Clin Cancer Res ; 39(1): 289, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33357230

RESUMO

BACKGROUND: Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. METHODS: We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. RESULTS: We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. CONCLUSION: For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

16.
Medicine (Baltimore) ; 99(50): e23642, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327343

RESUMO

Malnutrition and cachexia affects the majority of cancer patients and significantly worsens their quality of life and prognosis. However, the diagnostic criteria of malnutrition and cachexia remain a topic under constant debate. To overcome this hurdle, diagnostic tools to objectively detect and quantify the loss of muscle and fat mass are needed. Computed tomography (CT)-based measurement is currently considered the golden standard. Bioelectrical impedance analysis (BIA) is an economical, non-invasive tool but it is seen controversial in patients with cancer and malnutrition because of possible estimation errors.BIA and CT-based analysis of body mass compartments were performed 172 times in 118 cancer patients, within the nutrition program of our institution. Prevalence of malnutrition was determined according to the global leadership initiative on malnutrition criteria. Data obtained for muscle and fat mass from both BIA and CT were correlated using Pearson's ρ. All analyses were performed with an explorative significance level of 5%.45.7% of the cohort were classified as "malnourished." No significant differences were observed between the 2 groups regarding demographic data. Median body mass index, Karnofsky performance status, and nutritional risk score were lower in the malnourished group. Values for muscle and fat mass by BIA and CT were significantly lower in malnourished patients. Correlation of the measured parameters were highly significant between CT-based and BIA measurement. In the overall cohort, correlation of measured muscle mass values by CT and BIA was significant with Pearson's ρ = 0.794 (P < .01). Looking at patients without malnutrition only, Pearson's ρ was 0.754 (P < .01). The correlation of measured fat mass values was equally significant, with Pearson's ρ of 0.748 (P < .01) in the overall cohort and 0.771 (P < .01) in patients with malnutrition.To our knowledge, this is the first study comparing BIA to CT-based body mass analysis in a large cohort of cancer patients with malnutrition. The results suggest that BIA is a valid diagnostic tool for the assessment of muscle and fat mass, even in patients with malnutrition, and could be implemented for the early detection and short-term follow-up of malnutrition and cachexia.


Assuntos
Índice de Massa Corporal , Caquexia/diagnóstico , Impedância Elétrica , Desnutrição/diagnóstico , Neoplasias/complicações , Tomografia Computadorizada por Raios X/normas , Adulto , Fatores Etários , Idoso , Composição Corporal/fisiologia , Caquexia/etiologia , Caquexia/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Desnutrição/etiologia , Desnutrição/patologia , Pessoa de Meia-Idade , Estado Nutricional , Índice de Gravidade de Doença , Fatores Sexuais
18.
Expert Opin Ther Targets ; : 1-9, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33246383

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancer entities, which is characterized by abundant desmoplastic stroma. The stroma consists of extracellular matrix, infiltrating immune cells, cancer-associated fibroblasts (CAFs) and others. Depending on environmental cues, CAFs can be highly heterogeneous and play context-dependent roles in PDAC progression. AREAS COVERED: In this article, we discuss the biological significance of CAFs heterogeneity (oncogenic vs. tumor-suppressive) in pancreatic carcinogenesis. In particular, the complex interaction between CAFs and infiltrating immune cells has a determinant role in defining the stromal composition. A subset of PDAC patients may benefit from anti-CAFs therapy. EXPERT OPINION: Co-defined by CAFs and infiltrating immune cells, the prognostic stroma signature is clinically relevant in a subset of human PDAC. This is the patient population which may benefit from future anti-stroma or anti-CAFs therapies. To consider CAF heterogeneity is crucial for designing anti-stroma studies. Here, reliable and traceable subtype-specific markers for CAFs are urgently needed to dissect the biological impact of CAF heterogeneity on PDAC development spatiotemporally. Given the significant contribution of CAFs to immunosuppressive microenvironment of PDAC, it is conceivable to combine anti-CAFs therapy with immunotherapy. To implement a CAF-subtype specific therapy is crucially important to improve the effectiveness of current treatments including chemotherapies and immunotherapy.

19.
Pancreatology ; 20(8): 1770-1778, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33121847

RESUMO

OBJECTIVE: Postoperative pancreatic fistula/POPF is the most feared complication in pancreatic surgery. Although several systematic reviews investigated the impact of somatostatin analogues on POPF, no stratification was performed regarding type of pancreatic resection (pancreaticoduodenectomy/PD; distal pancreatectomy/DP) and different somatostatin analogues. METHODS: This study was planed according to the Preferred-Reporting-Items-for-Systematic -Review-and-Meta-Analysis/PRISMA-guidelines. After screening databases for randomized controlled trials/RCT, studies were stratified into pancreatic resection techniques and data were pooled in meta-analyses containing subgroups of octreotide, somatostatin, lanreotide, pasireotide and vapreotide. RESULTS: The meta-analysis of studies with a mixed cohort of patients after pancreatic resection revealed a protective effect of somatostatin analogues for morbidity (RR: 0.71, p < .00001) but not for mortality (RR: 1.07, = 0.78) or intra-abdominal abscesses (RR: 1.00, p = 1.00). Moreover, no effect was visible for mortality (RR: 1.57, p = .15), morbidity (RR: 0.87, p = .15) and intra-abdominal abscesses (RR: 0.92, p = .48) after PD. The meta-analysis of patients after PD revealed no impact of somatostatin analogues on POPF (RR: 0.87, p = .19) and clinically relevant POPF (RR: 0.69, p = .30). However, treatment with somatostatin analogues in the mixed cohort showed less POPF (RR: 0.60, p < .00001) and clinically relevant POPF (RR: 0.47, p = .02), which was also the case after DP (RR: 0.41, p = .03). CONCLUSION: Somatostatin analogues did not affect POPF and clinically relevant POPF after PD, but seemed to be associated with less POPF after DP. As no sufficiently powered RCT could be identified by the systematic review, further RCTs are urgently needed to investigate the effect of somatostatin analogues after DP. STUDY REGISTRATION: CRD42018099808.

20.
Liver Int ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32997886

RESUMO

BACKGROUND: Tumour recurrence is common after resection of intrahepatic cholangiocarcinoma (ICC). Repeated resection is a potential curative treatment, but outcomes are not well-defined thus far. The aim of this retrospective multicentre cohort study was to show the feasibility and survival of repeated resection of ICC recurrence. METHODS: Data were collected from 18 German hepato-pancreatico-biliary centres for patients who underwent repeated exploration of recurrent ICC between January 2008 and December 2017. Primary end points were overall (OS) and recurrence-free survival from the day of primary and repeated resection. RESULTS: Of 156 patients who underwent repeated exploration for recurrent ICC, 113 underwent re-resection. CA19-9 prior to primary resection, R status of first liver resection, and median time to recurrence were significant determinants of repeated resectability. Median OS in the repeated resection group was 65.2 months, with consecutive 1-, 3-, and 5-year OS of 98%, 78%, and 57%, respectively. After re-exploration, median OS from primary resection was 46.7 months, with a consecutive 1-, 3-, and 5-year OS of 95%, 55%, and 22%, respectively. From the day of repeated resection, the median OS was 36.8 months, with a consecutive 1-, 3-, and 5-year OS of 86%, 51%, and 34%, respectively. Minor morbidity (grade I+II) was present in 27%, grade IIIa-IVb morbidity in 20%, and mortality in 3.5% of patients. CONCLUSION: Repeated resection of ICC has acceptable morbidity and mortality and seems to be associated with improved long-term survival. Structured follow-up after resection of ICC is necessary for early identification of these patients.

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