The novel PII-interactor PirC identifies phosphoglycerate mutase as key control point of carbon storage metabolism in cyanobacteria.

Nitrogen limitation imposes a major transition in the lifestyle of nondiazotrophic cyanobacteria that is controlled by a complex interplay of regulatory factors involving the pervasive signal processor PII Immediately upon nitrogen limitation, newly fixed carbon is redirected toward glycogen synthesis. How the metabolic switch for diverting fixed carbon toward the synthesis of glycogen or of cellular building blocks is operated was so far poorly understood. Here, using the nondiazotrophic cyanobacterium Synechocystis sp. PCC 6803 as model system, we identified a novel PII interactor, the product of the sll0944 gene, which we named PirC. We show that PirC binds to and inhibits the activity of 2,3-phosphoglycerate-independent phosphoglycerate mutase (PGAM), the enzyme that deviates newly fixed CO2 toward lower glycolysis. The binding of PirC to either PII or PGAM is tuned by the metabolite 2-oxoglutarate (2-OG), which accumulates upon nitrogen starvation. In these conditions, the high levels of 2-OG dissociate the PirC-PII complex to promote PirC binding to and inhibition of PGAM. Accordingly, a PirC-deficient mutant showed strongly reduced glycogen levels upon nitrogen deprivation, whereas polyhydroxybutyrate granules were overaccumulated compared to wild-type. Metabolome analysis revealed an imbalance in 3-phosphoglycerate to pyruvate levels in the pirC mutant, confirming that PirC controls the carbon flux in cyanobacteria via mutually exclusive interaction with either PII or PGAM.

Mini-open vs. arthroscopic double tight-rope reconstruction after acute AC-joint dislocation: a comparison in functional outcome and sports activity.

INTRODUCTION: In athletes, acromioclavicular joint disruptions account for up to 50% of all shoulder injuries. In high-grade injuries, surgery is favored to ensure a correct restoration of the joint, especially in young athletes. The aim of this study was to compare the clinical, radiological and sport related outcomes of the arthroscopic stabilization with the fixation of the AC joint in a mini-open approach. MATERIALS AND METHODS: 19 patients treated arthroscopically (ASK) and 26 patients with an acute AC-joint dislocation Rockwood V who had undergone the mini-open (MO) surgery were included. Constant Murley Score (CMS), Taft Score (TS) and the Simple Shoulder Tests (SST) were evaluated. The sports activity level was determined according to Valderrabano and the athlete's recovery of their athletic activity level after surgery according to Rhee. Furthermore, all available X-ray images were analyzed. RESULTS: Patients in the ASK group achieved an average score of 11.7 ± 0.6 points in the SST, 10.3 ± 1.8 points in the TS and 91.2 ± 11.8 points in the CMS. On average, patients in the MO group achieved results of 10.5 ± 1.4 points in the SST, 11.7 ± 0.7 points in the TS and 91.6 ± 9.8 points in the CMS. The ASK group showed significant difference regarding the CC distance in side comparison (Δ = 3.6 mm), whereas no significant difference was found in the MO group (Δ = 0.8 mm). In comparison of both groups, the posterior as well as the combined translation were significantly greater in the ASK group than in the MO group (posterior: ASK: 24.8 mm, MO: 19.3 mm, combined: ASK: 29.1 mm, MO: 20.9 mm). Residual horizontal instability was greater in the ASK group (43%) than in the MO group (32%). Similar results were achieved in sports activity and the recovery of athletic activity (Valderrabano: ASK: 2.8, MO: 2.6; Rhee: ASK: 1.6, MO: 1.5). CONCLUSIONS: Both techniques prove to be effective for the stabilization of high-grade AC-joint disruptions in athletes and showed excellent clinical results. From a radiographic standpoint, the mini-open procedure appears superior to the arthroscopic technique. After mini-open surgery postoperative loss of correction is less common and greater horizontal stability is achieved. The results also suggest the mini-open technique is superior to the arthroscopic procedure when aiming to restore the athlete's original level of sports activity.

A mixed-linkage (1,3;1,4)-ß-D-glucan specific hydrolase mediates dark-triggered degradation of this plant cell wall polysaccharide.

The presence of mixed-linkage (1,3;1,4)-ß-d-glucan (MLG) in plant cell walls is a key feature of grass species such as cereals, the main source of calorie intake for humans and cattle. Accumulation of this polysaccharide involves the coordinated regulation of biosynthetic and metabolic machineries. While several components of the MLG biosynthesis machinery have been identified in diverse plant species, degradation of MLG is poorly understood. In this study, we performed a large-scale forward genetic screen for maize (Zea mays) mutants with altered cell wall polysaccharide structural properties. As a result, we identified a maize mutant with increased MLG content in several tissues, including adult leaves and senesced organs, where only trace amounts of MLG are usually detected. The causative mutation was found in the GRMZM2G137535 gene, encoding a GH17 licheninase as demonstrated by an in vitro activity assay of the heterologously expressed protein. In addition, maize plants overexpressing GRMZM2G137535 exhibit a 90% reduction in MLG content, indicating that the protein is not only required, but its expression is sufficient to degrade MLG. Accordingly, the mutant was named MLG hydrolase 1 (mlgh1). mlgh1 plants show increased saccharification yields upon enzymatic digestion. Stacking mlgh1 with lignin-deficient mutations results in synergistic increases in saccharification. Time profiling experiments indicate that wall MLG content is modulated during day/night cycles, inversely associated with MLGH1 transcript accumulation. This cycling is absent in the mlgh1 mutant, suggesting that the mechanism involved requires MLG degradation, which may in turn regulate MLGH1 gene expression.

The difference between arterial pCO2 and etCO2 after cardiac arrest - Outcome predictor or marker of unfavorable resuscitation circumstances?

INTRODUCTION: In former studies, the arterio-alveolar carbon dioxide gradient (ΔCO2) predicted in-hospital mortality after initially survived cardiac arrest. As early outcome predictors are urgently needed, we evaluated ΔCO2 as predictor for good neurological outcome in our cohort. METHODS: We retrospectively analyzed all patients ≥18 years of age after non-traumatic in- and out of hospital cardiac arrest in the year 2018 from our resuscitation database. Patients without advanced airway management, incomplete datasets or without return of spontaneous circulation were excluded. The first arterial pCO2 after admission and the etCO2 in mmHg at the time of blood sampling were recorded from patient's charts. We then calculated ΔCO2 (pCO2 - etCO2). For baseline analyses, ΔCO2 was dichotomized into a low and high group with separation at the median. Good neurological outcome on day 30, expressed as Cerebral Performance Category 1-2, defined our primary endpoint. Survival to 30 days was used as secondary endpoint. RESULTS: Out of 302 screened patients, 128 remained eligible for analyses. ΔCO2 was lower in 30-day survivors with good neurological outcome (12.2 mmHg vs. 18.8 mmHg, p = 0.009) and in 30-day survivors (12.5 mmHg vs. 20.0 mmHg, p = 0.001). In patients with high ΔCO2, a cardiac etiology of arrest was found less often. They had a higher body mass index, longer duration of resuscitation, higher amounts of epinephrine, lower pO2 levels but both higher pCO2 and blood lactate levels, resulting in lower blood pH and HCO3- levels at admission. In a crude binary logistic regression analysis, ΔCO2 was associated with 30-day neurological outcome (OR = 1.041 per mmHg of ΔCO2, 95% CI 1.008-1.074, p = 0.014). This association persisted after the adjustment for age, sex, witnessed arrest and shockable first rhythm. However, after addition of the duration of resuscitation or the cumulative epinephrine dosage to the model, ΔCO2 lost its association. CONCLUSION: ΔCO2 at admission after a successfully resuscitated cardiac arrest is associated with 30 days survival with good neurological outcome. However, a higher ΔCO2 may rather be a surrogate for unfavorable resuscitation circumstances than an independent outcome predictor.

Maximizing PHB content in Synechocystis sp. PCC 6803: a new metabolic engineering strategy based on the regulator PirC.

BACKGROUND: PHB (poly-hydroxy-butyrate) represents a promising bioplastic alternative with good biodegradation properties. Furthermore, PHB can be produced in a completely carbon-neutral fashion in the natural producer cyanobacterium Synechocystis sp. PCC 6803. This strain has been used as model system in past attempts to boost the intracellular production of PHB above ~ 15% per cell-dry-weight (CDW). RESULTS: We have created a new strain that lacks the regulatory protein PirC (product of sll0944), which exhibits a higher activity of the phosphoglycerate mutase resulting in increased PHB pools under nutrient limiting conditions. To further improve the intracellular PHB content, two genes involved in PHB metabolism, phaA and phaB, from the known producer strain Cupriavidus necator, were introduced under the control of the strong promotor PpsbA2. The resulting strain, termed PPT1 (ΔpirC-REphaAB), produced high amounts of PHB under continuous light as well under a day-night regime. When grown in nitrogen and phosphorus depleted medium, the cells produced up to 63% per CDW. Upon the addition of acetate, the content was further increased to 81% per CDW. The produced polymer consists of pure PHB, which is highly isotactic. CONCLUSION: The amounts of PHB achieved with PPT1 are the highest ever reported in any known cyanobacterium and demonstrate the potential of cyanobacteria for a sustainable, industrial production of PHB.

PHB is Produced from Glycogen Turn-over during Nitrogen Starvation in Synechocystis sp. PCC 6803.

Polyhydroxybutyrate (PHB) is a polymer of great interest as a substitute for conventional plastics, which are becoming an enormous environmental problem. PHB can be produced directly from CO2 in photoautotrophic cyanobacteria. The model cyanobacterium Synechocystis sp. PCC 6803 produces PHB under conditions of nitrogen starvation. However, it is so far unclear which metabolic pathways provide the precursor molecules for PHB synthesis during nitrogen starvation. In this study, we investigated if PHB could be derived from the main intracellular carbon pool, glycogen. A mutant of the major glycogen phosphorylase, GlgP2 (slr1367 product), was almost completely impaired in PHB synthesis. Conversely, in the absence of glycogen synthase GlgA1 (sll0945 product), cells not only produced less PHB, but were also impaired in acclimation to nitrogen depletion. To analyze the role of the various carbon catabolic pathways (EMP, ED and OPP pathways) for PHB production, mutants of key enzymes of these pathways were analyzed, showing different impact on PHB synthesis. Together, this study clearly indicates that PHB in glycogen-producing Synechocystis sp. PCC 6803 cells is produced from this carbon-pool during nitrogen starvation periods. This knowledge can be used for metabolic engineering to get closer to the overall goal of a sustainable, carbon-neutral bioplastic production.

Metastatic Spread Emerging From Liver Metastases of Colorectal Cancer: Does the Seed Leave the Soil Again?

OBJECTIVE: To investigate whether liver metastases contribute to metastatic spread of colorectal cancer (CRC) by shedding intact tumor cells. BACKGROUND: Metastases represent the primary cause of death in CRC. Understanding the metastatic activity of metastases and which patients are at high risk for tumor cell dissemination may, therefore, have significant influence on cancer care in the future. METHODS: Circulating tumor cells (CTCs) were detected in the hepatic inflow (portal venous blood [PVB]) and outflow compartment (hepatic venous blood [HVB]) of a training (n = 55) and validation (n = 50) set using the CellSearch system. Isolated CTC from the HVB were subjected to gene expression analyses by quantitative polymerase chain reaction. RESULTS: CTC detection rate (37.2% vs 19.6%; P = 0.04) and count (mean: 12.7, SEM: ±â€Š5.9 vs 1.9; ±â€Š1.2; P = 0.01) were significantly higher in HVB compared to PVB. The increased CTC detection rate (54% vs 11.4%; P < 0.001) and CTC count (14.7 ±â€Š5.1 vs 1.1 ±â€Š0.6; P < 0.001) in the HVB compared to the PVB compartment was confirmed in the validation cohort. Expression of epithelial markers and genes involved in cell-to-cell and cell-to-matrix adhesion was reduced in CTC compared to tumor cells in liver metastases. Metastasis size greater than 5 cm was associated with CTC shedding from established liver metastases in the training and validation cohorts. CONCLUSIONS: Colorectal liver metastases shed intact tumor cells with an invasive phenotype. Metastasis size serves as a surrogate marker for metastatic activity of colorectal liver metastases.

Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients.

BACKGROUND: Matrixmetalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases which are involved in angiogenesis, tumor invasion and metastatic formation. Up to date, the prognostic relevance of MMPs in serum of patients with colon cancer remains unknown. Thus, we wanted to assess an expression pattern of MMPs in a homogenous cohort of colon cancer patients to assess their potential as prognostic biomarkers. METHODS: Differences in the expression pattern of MMP7, MMP10 and MMP12 in 78 serum specimens of patients with an adenocarcinoma of the colon and serum specimens of a healthy control group were assessed using Luminex-100 technologies. Subsequently, we correlated these results with histopathological and clinical data of the patients. RESULTS: Luminex based expression analysis revealed a significant overexpression of MMP7 and an overexpression of MMP10 and MMP12 in the sera of colon cancer patients compared to the healthy control group. Patients with vascular invasion showed a significantly higher MMP12 expression than V0-staged patients. Moreover overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera displayed a significantly impaired overall survival. Multivariate analysis revealed high MMP10 serum levels to be an independent adverse prognostic marker in colon cancer patients. CONCLUSIONS: Expression patterns of MMP7, MMP10 and MMP12 in colon cancer patients´ sera are different compared to serum specimens of healthy individuals. Furthermore, overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera correlates with a dismal prognosis and may help to stratify patients into different risk groups.

Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer.

Exosomes are small vesicles (50-150 nm) of endocytic origin that are released by many different cell types. Exosomes in the tumor microenvironment may play a key role in facilitating cell-cell communication. Exosomes are reported to predominantly contain RNA and proteins. In this study, we investigated whether exosomes from pancreatic cancer cells and serum from patients with pancreatic ductal adenocarcinoma contain genomic DNA. Our results provide evidence that exosomes contain >10-kb fragments of double-stranded genomic DNA. Mutations in KRAS and p53 can be detected using genomic DNA from exosomes derived from pancreatic cancer cell lines and serum from patients with pancreatic cancer. In addition, using whole genome sequencing, we demonstrate that serum exosomes from patients with pancreatic cancer contain genomic DNA spanning all chromosomes. These results indicate that serum-derived exosomes can be used to determine genomic DNA mutations for cancer prediction, treatment, and therapy resistance.

Overexpression of SIX1 is an independent prognostic marker in stage I-III colorectal cancer.

Epithelial-to-mesenchymal transition (EMT) contributes significantly to tumor progression and metastasis. The assessment of EMT-associated transcription factors could be a promising approach to identify biomarkers and potential therapeutic targets in colorectal cancer. In our study, we focused on the transcription factor "Sine oculis homeobox" (SIX) 1, which is a member of the superfamily of the homeobox genes and has been described to promote EMT in different types of tumors. Immunohistochemistry against SIX1 was performed on colorectal mucosa, adenomas, carcinomas-in situ and primary adenocarcinomas. An expression score was developed and subsequently assessed for its prognostic value in two independent cohorts. Cohort 1 consisted of 128 patients with stage I-III colorectal cancer; cohort 2 included 817 patients with stage I-III colorectal cancer who had participated in the DACHS study. HCT-116 cells were transfected with SIX1 plasmids and subjected to migration and colony formation assays. The expression of SIX1 increases gradually from mucosa to colorectal adenocarcinomas (p > 0.0001). Univariate and multivariate analyses reveal that high expression of SIX1 is associated with decreased overall survival (cohort 1: HR: 4.01, CI: 1.20-14.07, p = 0.025; cohort 2: HR: 1.43, CI: 1.014-2.02, p = 0.047). Overexpression of SIX1 induces a more mesenchymal-like phenotype in HCT-116 cells and enhances tumor migration. High expression of SIX1 is an independent prognostic marker in colorectal cancer. It might be a promising biomarker to stratify patients into different risk groups. Moreover, targeting SIX1 might be a novel therapeutic approach in patients with colorectal cancer.

Potential of fecal microbiota for early-stage detection of colorectal cancer.

Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late-stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor-related host-microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.

Expressional STAT3/STAT5 Ratio is an Independent Prognostic Marker in Colon Carcinoma.

BACKGROUND: Signal transducer and activator of transcription proteins (STATs) are crucial regulators of cell growth and differentiation; however, their specific prognostic impact in human colon cancer has only been studied to limited extent. We aimed to assess the prognostic significance of specific STAT expression patterns in colon carcinoma. METHODS: Protein expression patterns of activated STAT1, STAT3, STAT4, and STAT5 in human colon carcinoma tissue and corresponding healthy mucosa (n = 104) were assessed using multiplex bead-based immunoassay technologies. Expression patterns were correlated with clinical and survival data. Immunohistochemistry was performed to assess spatial expression of STAT3 and STAT5. RESULTS: STAT3 was underexpressed whereas STAT4 and STAT5 were overexpressed in colon carcinoma tissue. Primary tumors from patients with distant metastases (M1) displayed significantly increased expression of STAT1 and STAT3 but decreased expression of STAT4 and STAT5. Increased tumor expression of STAT1 or STAT3 was associated with impaired patient survival, whereas increased expression of STAT4 or STAT5 correlated with improved survival. Multivariate analysis identified an increased STAT3/STAT5 expressional ratio as an adverse prognostic marker in colon cancer patients. CONCLUSIONS: The tumor progression-associated transcription factors STAT3, STAT4, and STAT5 are differently expressed in colon carcinoma tissue and colon mucosa. Moreover, the STAT3/STAT5 expression ratio is an independent prognostic marker in colon cancer patients.

Staged resection of bilobar colorectal liver metastases: surgical strategies.

BACKGROUND: Radical resection is the treatment of choice for colorectal liver metastases (CLM). Unfortunately, only about 20 % of patients present with initially resectable disease, in most cases due to bilobar disease. In the last two decades, major achievements have been made to extend surgical indications to patients with bilobar CLM, such as two-stage hepatectomy with or without portal vein occlusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). PURPOSE: The purpose of this review article was to summarize current surgical approaches and their safety and efficacy for patients with initially unresectable bilobar CLM. CONCLUSION: In selected patients, two-stage hepatectomy and ALPPS are efficient and safe to convert unresectable to resectable CLM. Further studies are required to evaluate long-term outcome of these procedures.

Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy.

BACKGROUND: Despite introduction of effective chemotherapy protocols, it has remained uncertain, if patients with colorectal cancer (CRC) liver metastases should receive adjuvant therapy. Clinical or molecular predictors may help to select patients at high risk for disease recurrence and death who obtain a survival advantage by adjuvant chemotherapy. METHODS: A total of 297 patients with potentially curative resection of CRC liver metastases were analyzed. These patients had no neoadjuvant therapy, no extrahepatic disease and negative resection margins. The primary endpoint was overall survival. Patients' risk status was evaluated using the Memorial Sloan-Kettering Cancer Center clinical risk score (MSKCC-CRS). Multivariable analyses were performed using Cox proportional hazard models. RESULTS: A total of 137 (43%) patients had a MSKCC-CRS > 2. Adjuvant chemotherapy was administered to 116 (37%) patients. Patients who received adjuvant chemotherapy were of younger age (p = 0.03) with no significant difference in the presence of multiple metastases (p = 0.72) or bilobar metastases (p = 0.08). On multivariate analysis adjuvant chemotherapy was associated with improved survival in the entire cohort (Hazard ratio 0.69; 95% confidence interval 0.69-0.98). It improved survival markedly in high-risk patients with a MSKCC-CRS > 2 (HR 0.40; 95% CI 0.23-0.69), whereas it was of no benefit in patients with a MSKCC-CRS ≤ 2 (HR 0.90; 95% CI 0.57-1.43). CONCLUSIONS: The MSKCC-CRS offers a tool to select patients for adjuvant therapy after resection of CRC liver metastases. Validation in independent patient cohorts is required.

Comparison of various surgical approaches for extensive bilateral colorectal liver metastases.

PURPOSE: Tailored operative strategies have been proposed for patients with bilobar colorectal liver metastases (CLM). The aim of the study was to evaluate the long-term outcome, safety and efficacy, including cancer-specific survival, morbidity, and mortality, of three different surgical strategies for extensive bilateral CLM. METHODS: This is a retrospective study of a prospective database of 356 consecutive patients, who underwent hepatic resection due to CLM between January 2003 and January 2009. Fifty-nine patients underwent three different therapeutic approaches: 22 patients with portal vein embolization (PVE) + staged resections, 11 patients with staged resections solely, and 26 patients with an extensive liver resection and simultaneous or subsequent radiofrequency ablation (RFA). RESULTS: The three groups were comparable regarding their general patient characteristics. The overall morbidity and mortality rates were 27.1 and 1.7 %, respectively. There were no significant differences in morbidity, mortality, or survival between the three groups. The median survival of all patients was 48 months, with a recurrence-free survival of 30 months. CONCLUSIONS: The clearance of bilobar CLM can be achieved by various strategies, all of them providing an acceptable mortality rate and survival for the patients. Therefore, patients with bilobar liver metastases should receive a procedure tailored for their individual extent of disease.

T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer.

High-level microsatellite-unstable (MSI-H) colorectal carcinomas (CRC) represent a distinct subtype of tumors commonly characterized by dense infiltration with cytotoxic T cells, most likely due to expression of MSI-H-related frameshift peptides (FSP). The contribution of FSP and classical antigens like MUC1 and CEA to the cellular immune response against MSI-H CRC had not been analyzed so far. We analyzed tumor-infiltrating and peripheral T cells from MSI-H (n = 4 and n = 14, respectively) and microsatellite-stable (MSS) tumor patients (n = 26 and n = 17) using interferon gamma ELISpot assays. Responses against 4 FSP antigens and peptides derived from MUC1 to CEA were compared with and without depletion of regulatory T cells, and the results were related to the presence of the respective antigens in tumor tissue. Preexisting FSP-specific T cell responses were detected in all (4 out of 4) tumor-infiltrating and in the majority (10 out of 14) of peripheral T cell samples from MSI-H CRC patients, but rarely observed in MSS CRC patients. Preexisting T cell responses in MSI-H CRC patients were significantly more frequently directed against FSP tested in the present study than against peptides derived from classical antigens MUC1 or CEA (p = 0.049). Depletion of regulatory T cells increased the frequency of effector T cell responses specific for MUC1/CEA-derived peptides and, to a lesser extent, T cell responses specific for FSP. Our data suggest that the analyzed FSP may represent an immunologically relevant pool of antigens capable of eliciting antitumoral effector T cell responses.

Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis to investigate the prognostic value of tumor cells in blood (circulating tumor cells [CTCs]) or bone marrow (BM) (disseminated tumor cells) of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer (CRC). MATERIALS AND METHODS: The following databases were searched in May 2011: MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cochrane Library. Studies that investigated the association between tumor cells in blood or BM and long-term outcome in patients with metastatic CRC were included. We extracted hazard ratios (HRs) and confidence intervals (CIs) from the included studies and performed random-effects meta-analyses for survival outcomes. RESULTS: The literature search yielded 16 studies representing 1,491 patients. The results of 12 studies representing 1,329 patients were suitable for pooled analysis. The overall survival (HR, 2.47; 95 % CI 1.74-3.51) and progression-free survival (PFS) (HR, 2.07; 95 % CI 1.44-2.98) were worse in patients with CTCs. The subgroup of studies with more than 35 % CTC-positive patients was the only subgroup with a statistically significant worse PFS. All eight studies that performed multivariable analysis identified the detection of CTCs as an independent prognostic factor for survival. CONCLUSION: The detection of CTCs in peripheral blood of patients with resectable colorectal liver metastases or widespread metastatic CRC is associated with disease progression and poor survival.

Neoadjuvant radiotherapy for rectal cancer: meta-analysis of randomized controlled trials.

BACKGROUND: Although neoadjuvant radiotherapy may improve local control of rectal cancer, its clinical value requires further evaluation as a result of potential side effects and advances in surgical technique. A meta-analysis was performed to assess effectiveness and safety of neoadjuvant radiotherapy in the management of rectal cancer. METHODS: The following databases were searched: the Cochrane Library, Biosis, Web of Science, Embase, ASCO Abstracts and WHO International Clinical Trials Registry Platform. Randomized controlled trials on the following comparisons were included: (1) neoadjuvant therapy versus surgery alone and (2) neoadjuvant chemoradiotherapy versus neoadjuvant radiotherapy. RESULTS: We identified 17 and 5 relevant trials that enrolled 8,568 and 2,393 patients, respectively. Neoadjuvant radiotherapy improved local control (hazard ratio 0.59; 95 % confidence interval 0.48-0.72) compared to surgery alone even after total mesorectal excision, whereas its benefit in overall survival just failed to reach statistical significance (0.93; 0.85-1.00). However, it was associated with increased perioperative mortality (1.48; 1.08-2.03), in particular if a dose of 5 Gy per fraction was administered (1.85; 1.23-2.78). Chemoradiotherapy improved local control as opposed to radiotherapy (0.53; 0.39-0.72), with no impact on perioperative outcome and long-term survival. CONCLUSIONS: Neoadjuvant radiotherapy improves local control in patients with rectal cancer, particularly when chemoradiotherapy is administered. The question if the use of more effective chemotherapy protocols improves overall survival warrants further investigation.

Laparoscopic surgery of liver tumors.

INTRODUCTION: Despite initial concerns regarding safety and oncological adequacy, the use of laparoscopic liver resections for benign and malignant diseases has spread worldwide. As in open liver surgery, anatomical orientation and the ability to control intraoperative challenges as bleeding have to be combined with expertise in advanced laparoscopic techniques. METHODS: In this review, we provide an overview regarding the literature on laparoscopic liver resection for benign and malignant liver tumors with the aim to discuss the current standards and define remaining challenges. Although numerous case series and meta-analyses have addressed the evolving field of laparoscopic liver surgery recently, data from randomized controlled trials are still not available. RESULTS AND CONCLUSIONS: Laparoscopic liver resection is feasible and safe in selected patients and experienced hands. Even major liver resections can be performed laparoscopically. The minimal invasive approach offers benefits in perioperative short-term outcome without compromising oncological outcomes compared to open liver resections. Further randomized trials are needed to formally prove these statements and to define the optimal indication and techniques for the individual patient.

In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction.

T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (DeltaTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proinflammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell-suppressive properties. IL6 and IL17 are not needed in this process.