ABSTRACT
Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2 and LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2 and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of the mitogen-activated protein kinase-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.
Subject(s)
Carcinoma, Pancreatic Ductal , Glucose , Intramolecular Oxidoreductases , Macrophage Migration-Inhibitory Factors , Pancreatic Neoplasms , Transcription Factor AP-1 , Humans , Macrophage Migration-Inhibitory Factors/metabolism , Macrophage Migration-Inhibitory Factors/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Animals , Mice , Glucose/metabolism , Intramolecular Oxidoreductases/metabolism , Intramolecular Oxidoreductases/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Transcription Factor AP-1/metabolism , Cell Line, Tumor , MAP Kinase Signaling System , Gene Expression Regulation, Neoplastic , Hexokinase/metabolism , Hexokinase/genetics , Cell Proliferation , Signal Transduction , Metabolic ReprogrammingABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.
Subject(s)
Adaptor Proteins, Signal Transducing , Carcinoma, Pancreatic Ductal , Cell Proliferation , Gene Expression Regulation, Neoplastic , LIM Domain Proteins , Pancreatic Neoplasms , LIM Domain Proteins/metabolism , LIM Domain Proteins/genetics , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Male , Female , Cell Movement , Cell Line, Tumor , Prognosis , Middle AgedABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Cell Movement , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Cell Line, Tumor , Male , Female , Metabolome , Autophagy-Related Proteins/metabolism , Autophagy-Related Proteins/genetics , Neoplasm Invasiveness , Transcriptome , Middle Aged , Metabolic ReprogrammingABSTRACT
BACKGROUND: Pancreatic adenocarcinoma located in the pancreatic body might require a portomesenteric venous resection (PVR), but data regarding surgical risks after distal pancreatectomy (DP) with PVR are sparse. Insight into additional surgical risks of DP-PVR could support preoperative counseling and intraoperative decision making. This study aimed to provide insight into the surgical outcome of DP-PVR, including its potential risk elevation over standard DP. METHODS: We conducted a retrospective, multicenter study including all patients with pancreatic adenocarcinoma who underwent DP ± PVR (2018-2020), registered in four audits for pancreatic surgery from North America, Germany, Sweden, and The Netherlands. Patients who underwent concomitant arterial and/or multivisceral resection(s) were excluded. Predictors for in-hospital/30-day major morbidity and mortality were investigated by logistic regression, correcting for each audit. RESULTS: Overall, 2924 patients after DP were included, of whom 241 patients (8.2%) underwent DP-PVR. Rates of major morbidity (24% vs. 18%; p = 0.024) and post-pancreatectomy hemorrhage grade B/C (10% vs. 3%; p = 0.041) were higher after DP-PVR compared with standard DP. Mortality after DP-PVR and standard DP did not differ significantly (2% vs. 1%; p = 0.542). Predictors for major morbidity were PVR (odds ratio [OR] 1.500, 95% confidence interval [CI] 1.086-2.071) and conversion from minimally invasive to open surgery (OR 1.420, 95% CI 1.032-1.970). Predictors for mortality were higher age (OR 1.087, 95% CI 1.045-1.132), chronic obstructive pulmonary disease (OR 4.167, 95% CI 1.852-9.374), and conversion from minimally invasive to open surgery (OR 2.919, 95% CI 1.197-7.118), whereas concomitant PVR was not associated with mortality. CONCLUSIONS: PVR during DP for pancreatic adenocarcinoma in the pancreatic body is associated with increased morbidity, but can be performed safely in terms of mortality.
ABSTRACT
PURPOSE: For primary and secondary liver tumors oncological resection remains a chance of cure. Augmentation of functional liver tissue may be necessary to preserve sufficient future liver remnant (FLR). Clinical decision-making on liver augmentation techniques and indications may differ internationally. Thus, this study aims to identify standards of liver augmentation in hepato-pancreatico-biliary (HPB) centers in Germany, Switzerland, and Austria. METHODS: Using a web-based survey, 48 hospitals in Germany, Switzerland, and Austria were invited to report their surgical indication, standard procedures, and results of liver augmentation. RESULTS: Forty (83.3%) of the hospitals invited participated. Most of the hospitals were certified liver centers (55%), performing complex surgeries such as liver transplantation (57.5%) and ALPPS (80%). The standard liver augmentation technique in all countries was portal vein embolization (PVE; 56%), followed by ALPPS (32.1%) in Germany or PVE with hepatic vein embolization (33.3%) in Switzerland and Austria. Standard procedure for liver augmentation did not correlate with certification as liver center, performance of liver transplantation or ALPPS. Surgical indication for PVE varied depending on tumor entity. Most hospitals rated the importance of PVE before resection of cholangiocarcinoma or colorectal metastases as high, while PVE for hepatocellular carcinoma was rated as low. CONCLUSION: The survey gives an overview of the clinical routine in HPB centers in Germany, Austria, and Switzerland. PVE seems to dominate as standard technique to increase the FLR. However, there is a variety in the main indication for liver augmentation. Further studies are necessary evaluating the differing PVE techniques for liver augmentation.
Subject(s)
Hepatectomy , Liver Neoplasms , Humans , Austria , Hepatectomy/methods , Switzerland , Germany , Liver Neoplasms/surgery , Liver Neoplasms/pathology , Surveys and Questionnaires , Liver Transplantation , Embolization, TherapeuticABSTRACT
The multimodal treatment of rectal cancer has differentiated considerably over the last decade depending on the characteristics of the tumor and the patient's circumstances. Surgery continues to be an important pillar of therapy, the quality of which is of prognostic relevance for affected patients. This review provides an up-to-date overview of the indications for the various surgical procedures, current developments in perioperative management and the timing of surgery.
Subject(s)
Digestive System Surgical Procedures , Rectal Neoplasms , Humans , Rectal Neoplasms/surgery , Combined Modality TherapyABSTRACT
The most common organs affected by abdominal trauma are the spleen and the liver, often in combination. Pancreatic injuries are rare. In the case of blunt abdominal trauma, which is much more common, a clinical and laboratory examination as well as sonography should be performed. In the initial assessment, the circulatory situation must be screened. If there is haemodynamic instability and presentation of free fluid, an emergency laparotomy is indicated. If the situation is stable or stabilised and a pathological sonography is present, it is essential to perform triphasic contrast enhanced computed tomography, which is also mandatory in polytraumatised patients. If a renal injury is suspected, a late venous phase should be attached. In addition to the classification of the injury, attention should be paid to possible vascular injury or active bleeding. In this case, angiography with the possibility of intervention should be performed. Endoscopic treatment is possible for injuries of the pancreatic duct. If the imaging does not reveal any intervention target and a circulation is stable, a conservative approach is possible with continuous monitoring using clinical, laboratory and sonographic controls. Most injuries can be successfully treated by non-operative management (NOM).There are various surgical options for treating the injury, such as local and resecting procedures. There is also the option of "damage control surgery" with acute bleeding control and second look. Complex surgical procedures should be performed at centres. Postoperative complications arise out of elective surgery.In the less common case of penetrating abdominal trauma, the actual extent of the injury cannot be estimated from the visible wound. Here again, the circulatory situation determines the next steps. An emergency laparotomy should be carried out in case of instability. If the condition is stable, further diagnostics should be performed using contrast enhanced computed tomography. If penetration through the peritoneum cannot be clearly excluded, diagnostic laparoscopy should be performed.
Subject(s)
Abdominal Injuries , Liver , Pancreas , Abdominal Injuries/surgery , Abdominal Injuries/diagnostic imaging , Abdominal Injuries/therapy , Abdominal Injuries/diagnosis , Humans , Liver/injuries , Liver/diagnostic imaging , Liver/surgery , Pancreas/injuries , Pancreas/surgery , Pancreas/diagnostic imaging , Wounds, Nonpenetrating/surgery , Wounds, Nonpenetrating/diagnostic imaging , Wounds, Nonpenetrating/therapy , Wounds, Nonpenetrating/diagnosis , Spleen/injuries , Spleen/diagnostic imaging , Tomography, X-Ray Computed , Multiple Trauma/surgery , Multiple Trauma/diagnostic imaging , Multiple Trauma/diagnosis , Laparotomy , Kidney/injuries , Kidney/diagnostic imagingABSTRACT
OBJECTIVE: The incidence for clinically relevant postoperative pancreatic fistulas (CR-POPF) in distal pancreatectomy (DP) ranges up to 25%. None of the available sealants significantly reduce CR-POPF. A new biodegradable sealant patch was able to reduce POPF and to achieve bleeding control in a preclinical porcine DP model. The aim of this first-in-human study was to assess the safety and performance of the sealant patch. METHODS: In this multicenter, single-arm study, 40 patients undergoing distal pancreatectomy were prospectively enrolled from 8 centers. Following surgical resection, the transection plane was closed according to the standard of care and manually covered with the sealant patch. As primary endpoint the incidence of CR-POPF up to 30-days postoperatively was evaluated. The secondary endpoints included the assessment of complications and device usability. RESULTS: Among 40 patients after distal pancreatectomy, CR-POPF occurred in 7 (17.5%) up to postoperative day 30. No type C POPF was observed. There was no intraoperative bleeding observed after patch application. CONCLUSION: The results of this international phase II study demonstrate promising results of a new sealant patch regarding the rate of CR-POPF. Randomized studies are now needed to confirm the superiority of the current patch as compared to the best current practice.
Subject(s)
Pancreatectomy , Pancreatic Fistula , Humans , Pancreatic Fistula/prevention & control , Pancreatic Fistula/etiology , Pancreatectomy/adverse effects , Prospective Studies , Female , Male , Middle Aged , Aged , Treatment Outcome , Adult , Time Factors , Aged, 80 and overABSTRACT
BACKGROUND: Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. METHODS: We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. RESULTS: We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. CONCLUSION: These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Humans , Endothelial Cells/pathology , Liver Neoplasms/genetics , Neovascularization, Pathologic/pathology , Colorectal Neoplasms/pathologyABSTRACT
OBJECTIVE: This NEUROmonitoring System (NEUROS) trial assessed whether pelvic intraoperative neuromonitoring (pIONM) could improve urogenital and ano-(neo-)rectal functional outcomes in patients who underwent total mesorectal excisions (TMEs) for rectal cancer. BACKGROUND: High-level evidence from clinical trials is required to clarify the benefits of pIONM. METHODS: NEUROS was a 2-arm, randomized, controlled, multicenter clinical trial that included 189 patients with rectal cancer who underwent TMEs at 8 centers, from February 2013 to January 2017. TMEs were performed with pIONM (n=90) or without it (control, n=99). The groups were stratified according to neoadjuvant chemoradiotherapy and sex, with blocks of variable length. Data were analyzed according to a modified intention-to-treat protocol. The primary endpoint was a urinary function at 12 months after surgery, assessed with the International Prostate Symptom Score, a patient-reported outcome measure. Deterioration was defined as an increase of at least 5 points from the preoperative score. Secondary endpoints were sexual and anorectal functional outcomes, safety, and TME quality. RESULTS: The intention-to-treat analysis included 171 patients. Marked urinary deterioration occurred in 22/171 (13%) patients, with significantly different incidence between groups (pIONM: n=6/82, 8%; control: n=16/89, 19%; 95% confidence interval, 12.4-94.4; P =0.0382). pIONM was associated with better sexual and ano-(neo)rectal function. At least 1 serious adverse event occurred in 36/88 (41%) in the pIONM group and 53/99 (54%) in the control group, none associated with the study treatment. The groups had similar TME quality, surgery times, intraoperative complication incidence, and postoperative mortality. CONCLUSION: pIONM is safe and has the potential to improve functional outcomes in rectal cancer patients undergoing TME.
Subject(s)
Pelvis , Rectal Neoplasms , Male , Humans , Prospective Studies , Rectal Neoplasms/surgery , Rectal Neoplasms/radiotherapy , Rectum/surgery , Neoadjuvant Therapy/adverse effects , Treatment OutcomeABSTRACT
Proteasome inhibition represents a promising strategy of cancer pharmacotherapy, but resistant tumor cells often emerge. Here we show that the microRNA-101 (miR-101) targets the proteasome maturation protein POMP, leading to impaired proteasome assembly and activity, and resulting in accumulation of p53 and cyclin-dependent kinase inhibitors, cell cycle arrest, and apoptosis. miR-101-resistant POMP restores proper turnover of proteasome substrates and re-enables tumor cell growth. In ERα-positive breast cancers, miR-101 and POMP levels are inversely correlated, and high miR-101 expression or low POMP expression associates with prolonged survival. Mechanistically, miR-101 expression or POMP knockdown attenuated estrogen-driven transcription. Finally, suppressing POMP is sufficient to overcome tumor cell resistance to the proteasome inhibitor bortezomib. Taken together, proteasome activity can not only be manipulated through drugs, but is also subject to endogenous regulation through miR-101, which targets proteasome biogenesis to control overall protein turnover and tumor cell proliferation.
Subject(s)
MicroRNAs/genetics , MicroRNAs/metabolism , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Proteasome Inhibitors/metabolism , 3' Untranslated Regions , Animals , Apoptosis , Boronic Acids/pharmacology , Bortezomib , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor Proteins/metabolism , Drug Resistance, Neoplasm/genetics , Estrogen Receptor alpha/metabolism , Female , Gene Knockdown Techniques , HCT116 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Mice , Molecular Chaperones/antagonists & inhibitors , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Pyrazines/pharmacology , RNA, Small Interfering/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
PURPOSE: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a "watch and wait" strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. EXPERIMENTAL DESIGN: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. RESULTS: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76). CONCLUSION: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a "watch and wait" strategy. TRANSLATIONAL RELEVANCE: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for "watch and wait".
Subject(s)
Chemoradiotherapy , Rectal Neoplasms , Biopsy , Clinical Trials as Topic , Humans , Neoadjuvant Therapy , Rectal Neoplasms/genetics , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Treatment OutcomeABSTRACT
BACKGROUND: Endoscopic internal drainage (EID) with double-pigtail stents or low negative-pressure endoscopic vacuum therapy (EVT) are treatment options for leakage after upper gastrointestinal oncologic surgery. We aimed to compare the effectiveness of these techniques. METHODS: Between 2016 and 2019, patients treated with EID in five centers in France and with EVT in Göttingen, Germany were included and retrospectively analyzed using univariate analysis. Pigtail stents were changed every 4 weeks; EVT was repeated every 3-4 days until leak closure. RESULTS: 35 EID and 27 EVT patients were included, with a median (interquartile range [IQR]) leak size of 0.75âcm (0.5-1.5). Overall treatment success was 100â% (95â% confidence interval [CI] 90â%-100â%) for EID vs. 85.2â% (95â%CI 66.3â%-95.8â%) for EVT (Pâ=â0.03). The median (IQR) number of endoscopic procedures was 2 (2-3) vs. 3 (2-6.5; Pâ=â0.003) and the median (IQR) treatment duration was 42 days (28-60) vs. 17 days (7.5-28; Pâ<â0.001), for EID vs. EVT, respectively. CONCLUSION: EID and EVT provide high closure rates for upper gastrointestinal anastomotic leaks. EVT provides a shorter treatment duration, at the cost of a higher number of procedures.
Subject(s)
Anastomotic Leak , Negative-Pressure Wound Therapy , Anastomotic Leak/etiology , Anastomotic Leak/surgery , Drainage , Esophagectomy , Humans , Retrospective StudiesABSTRACT
BACKGROUND: Rectal cancer remains a complex disease and a relevant global health issue, increasingly affecting also younger patients. This update review summarizes the current standard of care and discusses the individualized treatment approaches taking into consideration individual tumor characteristics and patients preferences. SUMMARY: Remaining "gray zones" of rectal cancer therapy warranting further prospective studies are identified including surgical approaches for rectal cancer, e.g., minimally invasive surgical techniques and lateral lymph node dissection for low rectal cancers. The emerging concept of a watch-and-wait strategy upon clinical complete response after chemoradiotherapy is discussed, also considering the still limited evidence and the clinical challenges arising from individualized patient management. KEY MESSAGES: Finally, currently conducted clinical trials of the German Rectal Cancer Study Group are described, aiming to further individualize multimodal treatment according to risk profiles and strict MRI criteria.
Subject(s)
Neoadjuvant Therapy , Rectal Neoplasms , Chemoradiotherapy/methods , Humans , Neoadjuvant Therapy/methods , Neoplasm Recurrence, Local , Prospective Studies , Rectal Neoplasms/surgery , Treatment Outcome , Watchful Waiting/methodsABSTRACT
BACKGROUND: Liver metastases (LM) occur in about 50% of patients with colorectal cancer. Besides the multimodal treatment of the primary tumor, the only way to cure patients with colorectal LM (CRLM) is complete resection. Different surgical procedures for this purpose are available depending on location, size, and number of LM. Additional concepts for patients with primary unresectable LM exist, ranging from Chemotherapy to induction of liver hypertrophy and even liver transplantation. This review intends to provide an overview of the surgical approach. SUMMARY: Surgical options in the treatment of CRLM are defined and limited by their intraparenchymal location and their proximity to major vessels and intrahepatic bile ducts. Lesions located in the periphery can be excised in a parenchymal sparing fashion with a small tumor-surrounding resection margin of healthy liver parenchyma. If this is not possible, anatomical resections based on segmental boundaries are performed. In these cases, a sufficient functional volume of liver parenchyma after resection (future liver remnant volume [FLRV]) has to be preserved. This FLRV depends on various factors such as bodyweight and possible preexisting liver damage, such as cirrhosis, fibrosis, or chemotherapy-induced liver impairment. Liver hypertrophy via partial occlusion of the portal venous system is a standard procedure for patients with primary unresectable LM to increase FLRV. Furthermore, discussion of liver transplantation in cases of unresectable LM is gaining importance again. A combination of surgery and adjuvant and/or neoadjuvant chemotherapy may be indicated in individual cases, but general evidence-based recommendations cannot be given without further studies. KEY MESSAGES: Surgical removal of all metastases represents the only option of a potentially curative treatment of UICC stage IV colorectal carcinoma with liver involvement. An interdisciplinary approach consisting of chemotherapeutical downsizing and hypertrophy of the FLRV offers potential curative treatment for patients with initially unresectable metastases. For all others, liver transplantation is seeing a revival showing promising results in overall survival compared to chemotherapy alone.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Colorectal Neoplasms/pathology , Hepatectomy , Humans , Hypertrophy/surgery , Liver Neoplasms/pathologyABSTRACT
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.
Subject(s)
Neuroendocrine Tumors , Pancreatic Neoplasms , Vipoma , Humans , Vipoma/diagnosis , Vipoma/drug therapy , Pancreatic Neoplasms/pathology , Octreotide/therapeutic use , Somatostatin/therapeutic use , Neuroendocrine Tumors/therapyABSTRACT
BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare abdominal tumors. Pretreatment biopsies may be used to diagnose a GIST and enable tailored treatment. Some experts are skeptical about biopsies because they fear tumor cell seeding. The objective of this study was to determine if pretreatment biopsy is associated with increased tumor recurrence. METHODS: We performed a systematic literature search and included studies assessing the oncological outcome of GIST patients who underwent a pre-treatment core needle biopsy or fine needle aspiration. We assessed methodological quality with the Newcastle-Ottawa-Scale for non-randomized studies. This review was registered in the PROSPERO database (CRD42021170290). RESULTS: Three non-randomized studies and eight case reports comprising 350 patients were eligible for inclusion. No prospective study designed to answer the review question was found. One case of needle tract seeding after percutaneous core needle biopsy of GIST was reported. None of the studies reported an increased rate of abdominal recurrence in patients with pretreatment biopsy. CONCLUSIONS: The existing evidence does not indicate a relevant risk of needle tract seeding or abdominal recurrence after pre-treatment biopsy of GIST. Biopsy can safely be done to differentiate GIST from other tumors and to select the most appropriate treatment.
Subject(s)
Gastrointestinal Stromal Tumors , Abdomen/pathology , Biopsy, Fine-Needle , Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Stromal Tumors/pathology , Humans , Prospective StudiesABSTRACT
BACKGROUND: Non-resectability is common in patients with pancreatic ductal adenocarcinoma (PDAC) due to local invasion or distant metastases. Then, biliary or gastroenteric bypasses or both are often established despite associated morbidity and mortality. The current study explores outcomes after palliative bypass surgery in patients with non-resectable PDAC. METHODS: From the prospectively maintained German StuDoQ|Pancreas registry, all patients with histopathologically confirmed PDAC who underwent non-resective pancreatic surgery between 2013 and 2018 were retrospectively identified, and the influence of the surgical procedure on morbidity and mortality was analyzed. RESULTS: Of 389 included patients, 127 (32.6%) underwent explorative surgery only, and a biliary, gastroenteric or double bypass was established in 92 (23.7%), 65 (16.7%) and 105 (27.0%). After exploration only, patients had a significantly shorter stay in the intensive care unit (mean 0.5 days [SD 1.7] vs. 1.9 [3.6], 2.0 [2.8] or 2.1 [2.8]; P < 0.0001) and in the hospital (median 7 days [IQR 4-11] vs. 12 [10-18], 12 [8-19] or 12 [9-17]; P < 0.0001), and complications occurred less frequently (22/127 [17.3%] vs. 37/92 [40.2%], 29/65 [44.6%] or 48/105 [45.7%]; P < 0.0001). In multivariable logistic regression, biliary stents were associated with less major (Clavien-Dindo grade ≥ IIIa) complications (OR 0.49 [95% CI 0.25-0.96], P = 0.037), whereas-compared to exploration only-biliary, gastroenteric, and double bypass were associated with more major complications (OR 3.58 [1.48-8.64], P = 0.005; 3.50 [1.39-8.81], P = 0.008; 4.96 [2.15-11.43], P < 0.001). CONCLUSIONS: In patients with non-resectable PDAC, biliary, gastroenteric or double bypass surgery is associated with relevant morbidity and mortality. Although surgical palliation is indicated if interventional alternatives are inapplicable, or life expectancy is high, less invasive options should be considered.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Retrospective Studies , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/surgery , Pancreas/pathology , Palliative Care , Registries , Pancreatic NeoplasmsABSTRACT
Neuroendocrine neoplasia of the pancreas (pNEN) has an increasing incidence and is therefore becoming increasingly clinically relevant. In addition to hormonally inactive pNEN, there are hormone-producing tumours and both inactive and active pNEN can be either sporadic or hereditary. Treatment is not only based on tumour-associated factors, but also on the individual patient's own circumstances. Treatment must be based on individual, tailor-made concepts that consider the respective factors and circumstances.