Quantitative analysis of trabecular bone tissue cryosections via a fully automated neural network-based approach.

Cryosectioning is known as a common and well-established histological method, due to its easy accessibility, speed, and cost efficiency. However, the creation of bone cryosections is especially difficult. In this study, a cryosectioning protocol for trabecular bone that offers a relatively cheap and undemanding alternative to paraffin or resin embedded sectioning was developed. Sections are stainable with common histological dying methods while maintaining sufficient quality to answer a variety of scientific questions. Furthermore, this study introduces an automated protocol for analysing such sections, enabling users to rapidly access a wide range of different stainings. Therefore, an automated 'QuPath' neural network-based image analysis protocol for histochemical analysis of trabecular bone samples was established, and compared to other automated approaches as well as manual analysis regarding scattering, quality, and reliability. This highly automated protocol can handle enormous amounts of image data with no significant differences in its results when compared with a manual method. Even though this method was applied specifically for bone tissue, it works for a wide variety of different tissues and scientific questions.

Cold Atmospheric Plasma Is a Promising Alternative Treatment Option in Case of Split Skin Graft Failure.

Cold atmospheric plasma (CAP) has shown promising potential in promoting wound healing. This case report presents the successful application of CAP in a 42-year-old female patient with extensive wound healing disorders and superinfections following the excision of an abscess in the left thoracic region. After several failed split skin graft attempts, the implementation of CAP led to significant improvements in wound healing. This report highlights the wound healing-promoting effects of CAP and discusses its potential mechanisms of action.

[Surgical strategy for hiatal hernias]. / Operative Strategie bei Hiatushernien.

The indications for surgical treatment of hiatus hernias differentiate between type I and types II, III and IV hernias. The indications for a type I hernia should include a proven reflux disease but the indications for surgical treatment of types II, III and IV hernias are mandatory due to the symptoms with problems in the passage of food and due to the sometimes very severe possible complications. The primary aims of surgery are the repositioning of the herniated contents and a hiatoplasty, which includes a surgical narrowing of the esophageal hiatus by suture implantation. In addition, depending on the clinical situation other procedures, such as hernia sac removal, mesh implantation, gastropexy and fundoplication can be considered. There are various approaches to the repair, all of which have individual advantages and disadvantages. An adaptation to the specific needs situation of the patient and the expertise of the surgeon is therefore essential.

The role of intraoperative swab during appendectomy in patients with uncomplicated and complicated appendicitis.

INTRODUCTION: Bacteria play an important role not only in pathogenesis of appendicitis but also in the postoperative course of patients. However, the usefulness of an intraoperative swab during appendectomy is controversial. The primary aim of this study was to investigate the impact of intraoperative swab during appendectomy on the postoperative outcome in patients with uncomplicated and complicated appendicitis. METHODS: A retrospective analysis was conducted on a consecutive series of 1570 adult patients who underwent appendectomy for acute appendicitis at the University Hospital Erlangen between 2010 and 2020. Data regarding the intraoperative swab were collected and analyzed for the entire cohort as well as for patients with uncomplicated and complicated appendicitis. RESULTS: An intraoperative swab was taken in 29% of the cohort. The bacterial isolation rate in the obtained intraoperative swabs was 51%, with a significantly higher rate observed in patients with complicated appendicitis compared to those with uncomplicated appendicitis (79% vs. 35%, p < 0.001). The presence of a positive swab was significantly associated with worse postoperative outcomes, including higher morbidity, increased need for re-surgery, and longer hospital stay, when compared to patients without a swab or with a negative swab. A positive swab was an independent risk factor for postoperative morbidity (OR 9.9 (95% CI 1.2-81.9), p = 0.034) and the need for adjustment of postoperative antibiotic therapy (OR 8.8 (95% CI 1.1-72.5), p = 0.043). However, a positive swab resulted in postoperative antibiotic therapy adjustment in only 8% of the patients with bacterial isolation in the swab. CONCLUSION: The analysis of swab samples obtained during appendectomy for acute appendicitis can help identify patients at a higher risk of a worse postoperative outcome. However, the frequency of antibiotic regime changes based on the swab analysis is low.

Risk Factors for Conversion from Laparoscopic to Open Appendectomy.

(1) Background: Since its introduction in the 1990s, laparoscopic appendectomy has become established over the years and is today considered the standard therapy for acute appendicitis. In some cases, however, a conversion to the open approach is still necessary. The primary aim of this study was to identify risk factors for the need to convert from the laparoscopic to an open approach during appendectomy for acute appendicitis. (2) Methods: A retrospective analysis of 1220 adult patients who underwent laparoscopic appendectomy for acute appendicitis from 2010 to 2020 at the University Hospital Erlangen was performed. Data, including patient demographics and pre-, intra-, and postoperative findings, were collected and compared between patients with and without conversion. (3) Results: The conversion rate in our cohort was 5.5%. A higher preoperative WBC count and CRP (OR 1.9, p = 0.042, and OR 2.3, p = 0.019, respectively), as well as the presence of intraoperative perforation, necrosis or gangrene, perityphlitic abscess and peritonitis (OR 3.2, p = 0.001; OR 2.3, p = 0.023; OR 2.6, p = 0.006 and OR 2.0, p = 0.025, respectively) were identified as independent risk factors for conversion from the laparoscopic to the open approach. Conversion was again independently associated with higher morbidity (OR 2.2, p = 0.043). (4) Conclusion: The laparoscopic approach is feasible and safe in the majority of patients with acute appendicitis. Only increased inflammatory blood markers could be detected as the preoperative risk factors potentially influencing the choice of surgical approach but only with low specificity and sensitivity. For the decision to convert, intraoperative findings are additionally crucial. However, patients with conversion should receive special attention in the postoperative course, as these have an increased risk of developing complications.

A contemporary assessment of total neoadjuvant therapy (TNT) protocols for locally advanced rectal cancer: adoption and expert perspectives at German Cancer Society (DKG)-certified colorectal cancer centers.

PURPOSE: The treatment paradigm for locally advanced rectal cancer (LARC) is shifting toward the total neoadjuvant therapy (TNT) concept, which administered systemic chemotherapy in the neoadjuvant setting, either before or after chemoradiotherapy (CRT) or short-course radiotherapy (SCRT). First results have shown higher pathologic complete response (pCR) rates and a favorable impact on disease-free survival (DFS). Our study aimed to evaluate the current clinical practice and expert opinion regarding TNT for locally advanced rectal cancer across DKG (German Cancer Society)-certified colorectal cancer centers. METHODS: A comprehensive online questionnaire, constituted of 14 TNT-focused queries targeting patients with locally advanced rectal cancer, was conducted among DKG-certified colorectal cancer centers registered within the database of the Addz (Arbeitsgemeinschaft Deutscher Darmzentren) between December 2022 and January 2023. RESULTS: A significant majority (68%) indicated that they treated between 0 and 10 patients using a TNT protocol. Only a third (36%) of these centers participated in patient enrollment for a TNT study. Despite this, 84% of centers reported treating patients in a manner analogous to a TNT study, with the RAPIDO regimen being the most prevalent approach, employed by 60% of the respondents. The decision to adopt a TNT approach was primarily influenced by factors, such as the lower third of the rectum (93% of centers), cT4 stage (86% of centers), and a positive circumferential resection margin (80% of centers). Regarding concerns, 65% of the survey respondents expressed no reservations about the TNT concept, while 35% had concerns. In particular, there appears to be disagreement and uncertainty in regard to a clinical complete response and the "Watch and Wait" approach. While some centers adopt the watch-and-wait approach (42%), others only utilize it when extirpation is otherwise necessary (39%), and a portion still proceeds with surgery as initially planned (19%). The survey also addressed unmet needs, which were elaborated in the free-text responses. Overall, there was high interest in participating in planned observational studies. CONCLUSIONS: This study presents an overview of current clinical practice and unmet needs within DKG-certified German colorectal cancer centers. It is noteworthy that total neoadjuvant therapy (TNT) is predominantly performed outside of clinical trials. Moreover, across the centers, there is significant heterogeneity in handling clinical complete response and adopting the "watch and wait" approach. Further research is needed to establish standardization in the care of locally advanced rectal cancer.

CCR4 Blockade Diminishes Intratumoral Macrophage Recruitment and Augments Survival of Syngeneic Pancreatic Cancer-Bearing Mice.

Pancreatic cancer is known for its tumor microenvironment (TME), which is rich in stromal and immune cells supporting cancer growth and therapy resistance. In particular, tumor-associated macrophages (TAMs) are known for their angiogenesis- and metastasis-promoting properties, which lead to the failure of conventional therapies for pancreatic cancer. Hence, treatment options targeting TAMs are needed. The C-C chemokine receptor type 4 (CCR4) is critical for immune cell recruitment into the TME, and in this paper we explore the effects of its genetic or immunotherapeutic blockade in pancreatic-cancer-bearing mice. Murine PDA6606 pancreatic cancer cells and murine peritoneal macrophages were used for in vitro migration assays. In vivo, a syngeneic, orthotropic pancreatic cancer model was established. Tumor growth and survival were monitored under prophylactic and therapeutic application of a CCR4 antagonist (AF-399/420/18025) in wildtype (CCR4wt) and CCR4-knockout (CCR4-/-) mice. Immune infiltration was monitored in tumor tissue sections and via flow cytometry of lysed tumors. PDA6606 cells induced less migration in CCR4-/- than in CCR4wt macrophages in vitro. Pancreatic TAM infiltration was higher, and survival was reduced in CCR4wt mice compared to CCR4-/- mice. Antagonizing CCR4 in wildtype mice revealed similar results as in CCR4-/- mice without antagonization. Prophylactic CCR4 antagonist application in wildtype mice was more efficient than therapeutic antagonization. CCR4 seems to be critically involved in TAM generation and tumor progression in pancreatic cancer. CCR4 blockade may help prolong the relapse-free period after curative surgery in pancreatic cancer and improve prognosis.

Narrowing the therapeutic window?-A case-control study on the influence of the COVID-19 pandemic on the primary UICC stage of NSCLC.

Background: General clinical perception suggests a decline in the diagnosis and treatment of lung cancer during the SARS-CoV-2 pandemic. Early diagnosis of non-small cell lung cancer (NSCLC) is crucial in therapeutic regimes as early stages are potentially curable by operation alone or with combined therapy. Pandemic-triggered overload of the healthcare system may have prolonged the diagnosis of NSCLC, possibly leading to higher tumor stages at first diagnosis. This study aims to identify how COVID-19 affected the distribution of the Union for International Cancer Control (UICC) stage in NSCLC at first diagnosis. Methods: A retrospective case-control study was conducted, including all patients receiving their first diagnosis of NSCLC in the regions of Leipzig and Mecklenburg-Vorpommern (MV) between January 2019 and March 2021. Patient data were retrieved from the clinical cancer registries of the city of Leipzig and the federal state of MV. Ethical approval for this retrospective evaluation of archived, anonymized patient data was waived by the Scientific Ethical Committee at the Medical Faculty, Leipzig University. Three investigation periods were defined to study the effects of high incidences of SARS-COV-2: the curfew period as an enacted security measure, the period of high incidence rates and the period of the aftermath of high incidences. Differences in the UICC stages between these pandemic periods were studied by Mann-Whitney-U-Test. Pearson's correlation was calculated to examine changes in operability. Results: The number of patients diagnosed with NSCLC dropped substantially during investigation periods. There was a significant difference in the UICC status in the aftermath of high incidences and imposed security measures in Leipzig (P=0.016). N-status differed significantly in the aftermath of high incidences and imposed security measures (P=0.022) with a decrease of N0- and an increase of N3-status, respectively, while N1- and N2-status remained relatively unaffected. No pandemic phase showed a significant difference in operability. Conclusions: The pandemic led to a delay in the diagnosis of NSCLC in the two examined regions. This resulted in higher UICC stages upon diagnosis. However, no increase in inoperable stages was shown. It remains to be seen, how this will affect the overall prognosis of the involved patients.

Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association.

In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.

Risk factors for postoperative morbidity, prolonged length of stay and hospital readmission after appendectomy for acute appendicitis.

PURPOSE: The aim of the present study was to identify risk factors associated with postoperative morbidity and major morbidity, with a prolonged length of hospital stay and with the need of readmission in patients undergoing appendectomy due to acute appendicitis. METHODS: We performed a retrospective analysis of 1638 adult patients who underwent emergency appendectomy for preoperatively suspected acute appendicitis from 2010 to 2020 at the University Hospital Erlangen. Data including patient demographics, pre-, intra-, and postoperative findings were collected and compared between different outcome groups (morbidity, major morbidity, prolonged length of postoperative hospital stay (LOS) and readmission) from those patients with verified acute appendicitis (n = 1570). RESULTS: Rate of negative appendectomies was 4%. In patients with verified acute appendicitis, morbidity, major morbidity and readmission occurred in 6%, 3% and 2%, respectively. Mean LOS was 3.9 days. Independent risk factors for morbidity were higher age, higher preoperative WBC-count and CRP, lower preoperative hemoglobin, longer time to surgery and longer duration of surgery. As independent risk factors for major morbidity could be identified higher age, higher preoperative CRP, lower preoperative hemoglobin and longer time to surgery. Eight parameters were independent risk factors for a prolonged LOS: higher age, higher preoperative WBC-count and CRP, lower preoperative hemoglobin, need for conversion, longer surgery duration, presence of intraoperative complicated appendicitis and of postoperative morbidity. Presence of malignancy and higher preoperative WBC-count were independent risk factors for readmission. CONCLUSION: Among patients undergoing appendectomy for acute appendicitis, there are relevant risk factors predicting postoperative complications, prolonged hospital stays and readmission. Patients with the presence of the identified risk factors should receive special attention in the postoperative course and may benefit from a more individualized therapy.

Disseminated Intravascular Coagulation (DIC): Old player creates new perspectives on the polymicrobial sepsis model of CASP.

BACKGROUND: Disseminated Intravascular Coagulation (DIC) is a life-threatening complication of sepsis. In surgical ICUs, DIC is frequently caused by abdominal sepsis, and the disarranged coagulation and complications often lead to death. The severity of sepsis is associated with a higher DIC score according to the parameters proposed by the International Society of Hemostasis and Thrombosis (ISTH) in 2001: platelet count, bleeding time (Quick), D-dimer, and fibrinogen. One problem in studying DIC is finding an adequate animal model that reflects the clinical situation of polymicrobial overwhelming infection. AIMS AND METHODS: We investigated whether a well-established polymicrobial sepsis model of colon ascendens stent peritonitis (CASP) is suited to investigate the complexity of DIC. For this purpose, CASP-operated mice were examined 20 h after the operation with regard to coagulation parameters using cell counts, bleeding times, rotational thromboelastometry (ROTEM), ELISAs for D-dimer and fibrinogen, and platelet accumulation in affected organs via immunohistochemistry to see if the mice develop a coagulation disorder that meets the definition of DIC proposed by the ISTH 2001 consensus conference. RESULTS: Herein, we showed that the CASP model is an all-encompassing animal model to analyze the complexity of systemic DIC in murine abdominal sepsis. There is highly reproducible thrombocytopenia, a significant prolongation of the bleeding time, and a loss of fibrinogen in plasma. We also observed microvascular thrombosis due to platelet accumulation in the microcirculation of the liver. CONCLUSION: The CASP model seems superior to other artificial models, e.g., injecting substances, for inducing DIC. CASP is one of the best true-to-life models for analyzing the complexity of disseminated intravascular coagulation in polymicrobial sepsis.

Gas plasma-oxidized sodium chloride acts via hydrogen peroxide in a model of peritoneal carcinomatosis.

Gas plasma technology generates reactive oxygen and nitrogen species (ROS/RNS), inducing lethal oxidative damage in tumor cells. The transfer of gas plasma-derived ROS/RNS into liquids has been proposed as an innovative anti-cancer strategy targeting peritoneal carcinomatosis (PC). However, the mechanism of action is under debate. To this end, we compared gas plasma-oxidized medical-grade sodium chloride (oxNaCl) with a concentration-matched control (cmc) of NaCl enriched with equivalent concentrations of H2O2 and NO3- in several cell lines and models of PC. Strikingly, oxNaCl and cmc performed equally well in oxidation and cytotoxic activity in tumor cells in two-dimensional cultures, three-dimensional (3D) tumor spheroids, vascularized 3D tumors grown on chicken-embryo chorioallantoic membranes, and a syngeneic PC mouse model in vivo. Given the importance of immunotherapies in oncology today, we focused on immunological consequences of the treatment. Again, to a similar extent, oxNaCl and cmc increased tumor cell immunogenicity and enhanced uptake by and maturation of peripheral blood monocyte-derived dendritic cells together with an inflammatory secretion profile. Furthermore, NanoString gene expression profiling revealed immune system processes and unfolded protein response-related pathways as being linked to the observed anti-tumor effects for both oxNaCl and cmc. In conclusion, gas plasma-generated oxNaCl and cmc showed equal therapeutic efficacy in our PC-related models. In light of the many promising anti-cancer studies of gas plasma-oxidized liquids and the convenient production of corresponding cmcs in large quantities as needed in clinics, our findings may spur research lines based on low-dose oxidants in peritoneal cancer therapy.

The use of single-stapling techniques reduces anastomotic complications in minimal-invasive rectal surgery.

BACKGROUND: Leakage of rectal anastomoses is one of the most important and feared complications in colorectal surgery. Apart from patient-specific risk factors, technical aspects may influence the occurrence of anastomotic complications. This study investigated whether using single-stapling techniques (SST) instead of the double-stapling technique (DST) for minimal-invasive rectal anastomosis is associated with a lower rate of anastomotic complications. METHODS: A retrospective review of 272 patients who received a minimally invasive stapled rectal anastomosis (3-16 cm from the anal verge) at our institution from 2015 to 2020 was performed. In 131 patients, rectal anastomosis was created by SST (SST group), while 141 patients received a rectal anastomosis with crossing stapler lines (DST group). The impact of the anastomotic technique on patient outcomes was determined by uni- and multivariate analyses. RESULTS: Overall anastomotic leakage rate was 6%. Patients with SST anastomoses had a lower leakage rate than patients with DST anastomoses (3% vs. 9% in the DST group, p = 0.045). The rate of anastomotic stenosis was lower in the SST group than in the DST group (1% vs. 6%, p = 0.037). Overall morbidity and mortality did not differ between the two groups. Multivariate analysis showed that single-stapling techniques significantly reduce the risk of anastomotic leakage (OR 3.5 [1.0-11.5], p = 0.043). CONCLUSION: The use of SST for rectal anastomosis may help to reduce anastomotic complications. This finding should be confirmed by a randomized controlled trial.

Continuous or interrupted suture technique for hepaticojejunostomy during pancreatoduodenectomy (HEKTIK trial): study protocol of a randomized controlled multicenter trial.

BACKGROUND: Hepaticojejunostomy is commonly performed in hepato-bilio-pancreatic surgery, particularly during pancreaticoduodenectomy. The purpose of this study is to evaluate the safety and efficiency of two commonly applied suture techniques (the interrupted versus the continuous suture technique) in patients undergoing a hepaticojejunostomy during pancreatoduodenectomy. METHODS: The HEKTIK trial is a multicenter, randomized controlled, patient-blinded surgical explorative trial with two parallel study groups. An adaptive sample size design was chosen: First, 100 patients scheduled for surgery including a hepaticojejunostomy will be randomized 1:1 either to the interrupted suture technique or the continuous suture technique after informed consent. Based on this data, needed sample size will be adjusted. The primary endpoint will be the occurrence of anastomotic leakage of hepaticojejunostomy, defined as bilirubin concentration in the drain fluid at least 3 times the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis (according to the definition of ISGLS). Further perioperative parameters like other morbidities as well as duration and costs of the hepaticojejunostomy will be analyzed as secondary outcomes. DISCUSSION: Until now there are no randomized controlled comparative data of these two suture techniques for hepaticojejunostomy. The HEKTIK trial will investigate the yet unanswered question of whether the interrupted suture or the continuous suture technique has advantages performing a hepaticojejunostomy during pancreatoduodenectomy. TRIAL REGISTRATION: German Clinical Trials Register DRKS00024395 . Registered on 01 February 2021.

Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study.

BACKGROUND & AIMS: To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts. METHODS: We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets. RESULTS: Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified. CONCLUSIONS: Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.

A faecal microbiota signature with high specificity for pancreatic cancer.

BACKGROUND: Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. OBJECTIVE: To explore the faecal and salivary microbiota as potential diagnostic biomarkers. METHODS: We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. RESULTS: Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. CONCLUSION: Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.

NCR, an Inflammation and Nutrition Related Blood-Based Marker in Colon Cancer Patients: A New Promising Biomarker to Predict Outcome.

Background: Colorectal carcinoma (CRC) is a heterogeneous disease, and differences in outcomes have been reported among patients diagnosed with the same disease stage. Prognostic and predictive biomarkers provide information for patient risk stratification and guide treatment selection. Although numerous studies have analyzed the effects of systemic inflammatory factors on CRC outcomes, clinical significance remains to be elucidated. In particular, the treatment strategy of colon cancer patients is different from that of rectal cancer due to outcome and recurrence differences. The identification of patients with a poor prognosis who might benefit from intensive treatment approaches is clinically necessary. Methods: This study aimed to evaluate the value of different blood-based markers and assess the significance of our newly developed inflammatory-nutrition-related biomarker (NCR = BMI × albumin/CRP) in patients with colon cancer. A two-stage design was used with 212 patients with colon cancer (CC) in the discovery cohort (n = 159) and in an external validation cohort (n = 53). Results: A lower preoperative NCR level was significantly correlated with a worse prognosis, sidedness, undifferentiated histology, nodal involvement, and advanced UICC stage. We compared the NCR with other established prognostic indices and showed that the NCR is a more reliable indicator of a poor prognosis for patients with CC. Patients with low NCR levels experienced a significantly shorter Overall Survival (OS) than patients with high levels. Multivariate analysis confirmed preoperative NCR levels as an independent predictor for overall survival with a hazard ratio of 3.3 (95% confidence interval 1.628−6.709, p < 0.001). Finally, we confirmed the predictive value of the NCR in an independent validation cohort and confirmed NCR as an independent prognostic factor for OS. Conclusion: Taken together, we discovered a new prognostic index (NCR) based on BMI, albumin, and CRP levels as an independent prognostic predictor of OS in patients with colon cancer. In all UICC stages, our newly developed NCR marker is able to distinguish patients with better and worse prognoses. We, therefore, propose that NCR may serve as a supplement to the TNM staging system to optimize the risk stratification in CC patients towards personalized oncology. In particular, NCR can be used in clinical trials to stratify patients with UICC II and III tumors and help better select patients who might benefit from adjuvant treatment.

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results.

OBJECTIVE: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. PATIENTS AND METHODS: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. RESULTS: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. CONCLUSION: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.