Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer.

Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathway activated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 were expressed by the majority of human primary CRCs and metastases, which was associated with low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependent pathway controls anti-tumor immunity, revealing additional targets for immune checkpoint inhibition in microsatellite-stable CRC.

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold.

BACKGROUND AND AIMS: This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). METHODS: Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). RESULTS: EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). CONCLUSION: In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Correlation of microscopic tumor extension with tumor microenvironment in esophageal cancer patients.

OBJECTIVE: In the era of image-guided adaptive radiotherapy, definition of the clinical target volume (CTV) is a challenge in various solid tumors, including esophageal cancer (EC). Many tumor microenvironmental factors, e.g., tumor cell proliferation or cancer stem cells, are hypothesized to be involved in microscopic tumor extension (MTE). Therefore, this study assessed the expression of FAK, ILK, CD44, HIF-1α, and Ki67 in EC patients after neoadjuvant radiochemotherapy followed by tumor resection (NRCHT+R) and correlated these markers with the MTE. METHODS: Formalin-fixed paraffin-embedded tumor resection specimens of ten EC patients were analyzed using multiplex immunofluorescence staining. Since gold fiducial markers had been endoscopically implanted at the proximal and distal tumor borders prior to NRCHT+R, correlation of the markers with the MTE was feasible. RESULTS: In tumor resection specimens of EC patients, the overall percentages of FAK+, CD44+, HIF-1α+, and Ki67+ cells were higher in tumor nests than in the tumor stroma, with the outcome for Ki67+ cells reaching statistical significance (p < 0.001). Conversely, expression of ILK+ cells was higher in tumor stroma, albeit not statistically significantly. In three patients, MTE beyond the fiducial markers was found, reaching up to 31 mm. CONCLUSION: Our findings indicate that the overall expression of FAK, HIF-1α, Ki67, and CD44 was higher in tumor nests, whereas that of ILK was higher in tumor stroma. Differences in the TME between patients with residual tumor cells in the original CTV compared to those without were not found. Thus, there is insufficient evidence that the TME influences the required CTV margin on an individual patient basis. TRIAL REGISTRATION NUMBER AND DATE: BO-EK-148042017 and BO-EK-177042022 on 20.06.2022, DRKS00011886, https://drks.de/search/de/trial/DRKS00011886 .

Preoperative IL-8 levels as prognostic indicators of overall survival: an extended follow-up in a prospective cohort with colorectal liver metastases.

INTRODUCTION: CRC with liver metastases is a major contributor to cancer-related mortality. Despite advancements in liver resection techniques, patient survival remains a concern due to high recurrence rates. This study seeks to uncover prognostic biomarkers that predict overall survival in patients undergoing curative hepatic resection for CRC liver metastases. METHODS: Prospectively collected serum samples from a cohort of 49 patients who received curative hepatic resection for CRC liver metastases were studied. The patients are part of a cohort, previously analyzed for perioperative complications (see methods). Various preoperative serum markers, clinical characteristics, and factors were analyzed. Univariate and multivariate Cox regression analyses were conducted to determine associations between these variables and disease-free survival as well as overall survival. RESULTS: For disease-free survival, univariate analysis highlighted the correlation between poor outcomes and advanced primary tumor stage, high ASA score, and synchronous liver metastases. Multivariate analysis identified nodal-positive primary tumors and synchronous metastases as independent risk factors for disease-free survival. Regarding overall survival, univariate analysis demonstrated significant links between poor survival and high preoperative IL-8 levels, elevated neutrophil-lymphocyte ratio (NLR), and presence of metastases in other organs. Multivariate analysis confirmed preoperative IL-8 and having three or more liver metastases as independent risk factors for overall survival. The impact of IL-8 on survival was particularly noteworthy, surpassing the influence of established clinical factors. CONCLUSION: This study establishes preoperative IL-8 levels as a potential prognostic biomarker for overall survival in patients undergoing curative liver resection for CRC liver metastases. This study underscores the importance of incorporating IL-8 and other biomarkers into clinical decision-making, facilitating improved patient stratification and tailored treatment approaches. Further research and validation studies are needed to solidify the clinical utility of IL-8 as a prognostic marker.

Satisfaction of surgeons with the current state of training in minimally invasive surgery: a survey among German surgeons.

BACKGROUND: Minimally invasive surgery (MIS) requires intense education and training with structured supervision and feedback. However, a standardized training structure is lacking in Germany. This nationwide survey aimed to assess the current state of minimally invasive surgery (MIS) training and factors impacting surgeons' satisfaction. METHODS: Between July and October 2021, an online survey was conducted among general, abdominal, and thoracic surgeons in Germany. The survey collected data on department size, individual operative experience, availability of MIS training equipment and curricula, and individual satisfaction with training. A linear regression analysis was conducted to investigate factors influencing the surgeons' satisfaction with the MIS training. RESULTS: A total of 1008 surgeons participated in the survey, including residents (26.1%), fellows (14.6%), attendings (43.8%), and heads of departments (15.2%). Of the respondents, 57.4% reported having access to MIS training equipment, 29.8% and 26% had a curriculum for skills lab MIS training and intraoperative MIS training, respectively. In multivariate linear regression analysis, strongest predictors for surgeons' satisfaction with skills lab MIS training and intraoperative training were the availability of respective training curricula (skills lab: ß 12.572; p < 0.001 & intraoperative: ß 16.541; p < 0.001), and equipment (ß 5.246; p = 0.012 & ß 4.295; p = 0.037), and experience as a first surgeon in laparoscopy (ß 12.572; p < 0.001 & ß 3.748; p = 0.007). Additionally, trainees and teachers differed in their satisfaction factors. CONCLUSION: Germany lacks standardized training curricula and sufficient access to MIS training equipment. Trainees and teachers have distinct factors influencing their satisfaction with MIS training. Standardized curricula, equipment accessibility, and surgical experience are crucial for improving surgeons' satisfaction with training.

Can you feel the force just right? Tactile force feedback for training of minimally invasive surgery-evaluation of vibration feedback for adequate force application.

BACKGROUND: Tissue handling is a crucial skill for surgeons and is challenging to learn. The aim of this study was to develop laparoscopic instruments with different integrated tactile vibration feedback by varying different tactile modalities and assess its effect on tissue handling skills. METHODS: Standard laparoscopic instruments were equipped with a vibration effector, which was controlled by a microcomputer attached to a force sensor platform. One of three different vibration feedbacks (F1: double vibration > 2 N; F2: increasing vibration relative to force; F3: one vibration > 1.5 N and double vibration > 2 N) was applied to the instruments. In this multicenter crossover trial, surgical novices and expert surgeons performed two laparoscopic tasks (Peg transfer, laparoscopic suture, and knot) each with all the three vibration feedback modalities and once without any feedback, in a randomized order. The primary endpoint was force exertion. RESULTS: A total of 57 subjects (15 surgeons, 42 surgical novices) were included in the trial. In the Peg transfer task, there were no differences between the tactile feedback modalities in terms of force application. However, in subgroup analysis, the use of F2 resulted in a significantly lower mean-force application (p-value = 0.02) among the student group. In the laparoscopic suture and knot task, all participants exerted significantly lower mean and peak forces using F2 (p-value < 0.01). These findings remained significant after subgroup analysis for both, the student and surgeon groups individually. The condition without tactile feedback led to the highest mean and peak force exertion compared to the three other feedback modalities. CONCLUSION: Continuous tactile vibration feedback decreases the mean and peak force applied during laparoscopic training tasks. This effect is more pronounced in demanding tasks such as laparoscopic suturing and knot tying and might be more beneficial for students. Laparoscopic tasks without feedback lead to increased force application.

The development of tissue handling skills is sufficient and comparable after training in virtual reality or on a surgical robotic system: a prospective randomized trial.

BACKGROUND: Virtual reality is a frequently chosen method for learning the basics of robotic surgery. However, it is unclear whether tissue handling is adequately trained in VR training compared to training on a real robotic system. METHODS: In this randomized controlled trial, participants were split into two groups for "Fundamentals of Robotic Surgery (FRS)" training on either a DaVinci VR simulator (VR group) or a DaVinci robotic system (Robot group). All participants completed four tasks on the DaVinci robotic system before training (Baseline test), after proficiency in three FRS tasks (Midterm test), and after proficiency in all FRS tasks (Final test). Primary endpoints were forces applied across tests. RESULTS: This trial included 87 robotic novices, of which 43 and 44 participants received FRS training in VR group and Robot group, respectively. The Baseline test showed no significant differences in force application between the groups indicating a sufficient randomization. In the Midterm and Final test, the force application was not different between groups. Both groups displayed sufficient learning curves with significant improvement of force application. However, the Robot group needed significantly less repetitions in the three FRS tasks Ring tower (Robot: 2.48 vs. VR: 5.45; p < 0.001), Knot Tying (Robot: 5.34 vs. VR: 8.13; p = 0.006), and Vessel Energy Dissection (Robot: 2 vs. VR: 2.38; p = 0.001) until reaching proficiency. CONCLUSION: Robotic tissue handling skills improve significantly and comparably after both VR training and training on a real robotic system, but training on a VR simulator might be less efficient.

Impact of dehydration on laparoscopic performance: a prospective, open-label, randomized cross-over trial.

INTRODUCTION: During laparoscopic surgery, surgeons may experience prolonged periods without fluid intake, which might impact surgical performance, yet there are no objective data investigating this issue. Therefore, the aim of this study was to elucidate the effect of prolonged dehydration on laparoscopic surgical performance and tissue handling. METHODS: A total of 51 laparoscopic novices participated in a single-center, open-label, prospective randomized cross-over trial. All participants were trained to proficiency using a standardized laparoscopic training curriculum. Afterward, all participants performed four different laparoscopic tasks twice, once after 6 h without liquid intake (dehydrated group) and once without any restrictions (control group). Primary endpoints were tissue handling defined by force exertion, task time, and error rate. The real hydration status was assessed by biological parameters, like heart rate, blood pressure, and blood gas analysis. RESULTS: 51 laparoscopic novices finished the curriculum and completed the tasks under both hydrated and dehydrated conditions. There were no significant differences in mean non-zero and peak force between the groups. However, dehydrated participants showed significantly slower task times in the Peg transfer task (hydrated: 139.2 s vs. dehydrated: 147.9 s, p = 0.034) and more errors regarding the precision in the laparoscopic suture and knot task (hydrated: 15.7% accuracy rate vs. dehydrated: 41.2% accuracy rate, p < 0.001). CONCLUSION: Prolonged periods of dehydration do not appear to have a substantial effect on the fundamental tissue handling skills in terms of force exertion among surgical novices. Nevertheless, the observed impact on speed and precision warrants attention.

Preoperative anaemia in distal pancreatectomy: a propensity-score matched analysis.

BACKGROUND: Preoperative anaemia is a prevalent morbidity predictor that adversely affects short- and long-term outcomes of patients undergoing surgery. This analysis aimed to investigate preoperative anaemia and its detrimental effects on patients after distal pancreatectomy. MATERIAL AND METHODS: The present study was a propensity-score match analysis of 286 consecutive patients undergoing distal pancreatectomy. Patients were screened for preoperative anaemia and classified according to WHO recommendations. The primary outcome measure was overall morbidity. The secondary endpoints were in-hospital mortality and rehospitalization. RESULTS: The preoperative anaemia rate before matching was 34.3% (98 patients), and after matching a total of 127 patients (non-anaemic 42 vs. anaemic 85) were included. Anaemic patients had significantly more postoperative major complications (54.1% vs. 23.8%; p < 0.01), a higher comprehensive complication index (26.2 vs. 4.3; p < 0.01), and higher in-hospital mortality rate (14.1% vs. 2.4%; p = 0.04). Multivariate regression analysis confirmed these findings and identified preoperative anaemia as a strong independent risk factor for postoperative major morbidity (OR 4.047; 95% CI: 1.587-10.320; p < 0.01). CONCLUSION: The current propensity-score matched analysis strongly considered preoperative anaemia as a risk factor for major complications following distal pancreatectomy. Therefore, an intense preoperative anaemia workup should be increasingly prioritised.

Differences in Physicians' Ratings of Work Stressors and Resources Associated With Digital Transformation: Cross-Sectional Study.

BACKGROUND: The emergence of the COVID-19 pandemic rapidly accelerated the need and implementation of digital innovations, especially in medicine. OBJECTIVE: To gain a better understanding of the stress associated with digital transformation in physicians, this study aims to identify working conditions that are stress relevant for physicians and differ in dependence on digital transformation. In addition, we examined the potential role of individual characteristics (ie, age, gender, and actual implementation of a digital innovation within the last 3 years) in digitalization-associated differences in these working conditions. METHODS: Cross-sectional web-based questionnaire data of 268 physicians (mean age 40.9, SD 12.3 y; n=150, 56% women) in Germany were analyzed. Physicians rated their chronic stress level and 11 relevant working conditions (ie, work stressors such as time pressure and work resources such as influence on sequence) both before and after either a fictional or real implementation of a relevant digital transformation at their workplace. In addition, a subsample of individuals (60; n=33, 55% women) submitted self-collected hair samples for cortisol analysis. RESULTS: The stress relevance of the selected working conditions was confirmed by significant correlations with self-rated chronic stress and hair cortisol levels (hair F) within the sample, all of them in the expected direction (P values between .01 and <.001). Multilevel modeling revealed significant differences associated with digital transformation in the rating of 8 (73%) out of 11 working conditions. More precisely, digital transformation was associated with potentially stress-enhancing effects in 6 working conditions (ie, influence on procedures and complexity of tasks) and stress-reducing effects in 2 other working conditions (ie, perceived workload and time pressure). Younger individuals, women, and individuals whose workplaces have implemented digital innovations tended to perceive digitalization-related differences in working conditions as rather stress-reducing. CONCLUSIONS: Our study lays the foundation for future hypothesis-based longitudinal research by identifying those working conditions that are stress relevant for physicians and prone to differ as a function of digital transformation and individual characteristics.

Ultra-sensitive CTC-based liquid biopsy for pancreatic cancer enabled by large blood volume analysis.

The limited sensitivity of circulating tumor cell (CTC) detection in pancreatic adenocarcinoma (PDAC) stems from their extremely low concentration in the whole circulating blood, necessitating enhanced detection methodologies. This study sought to amplify assay-sensitivity by employing diagnostic leukapheresis (DLA) to screen large blood volumes. Sixty patients were subjected to DLA, with a median processed blood volume of ~ 2.8 L and approximately 5% of the resulting DLA-product analyzed using CellSearch (CS). Notably, DLA significantly increased CS-CTC detection to 44% in M0-patients and 74% in M1-patients, yielding a 60-fold increase in CS-CTC enumeration. DLA also provided sufficient CS-CTCs for genomic profiling, thereby delivering additional genomic information compared to tissue biopsy samples. DLA CS-CTCs exhibited a pronounced negative prognostic impact on overall survival (OS), evidenced by a reduction in OS from 28.6 to 8.5 months (univariate: p = 0.002; multivariable: p = 0.043). Additionally, a marked enhancement in sensitivity was achieved (by around 3-4-times) compared to peripheral blood (PB) samples, with positive predictive values for OS being preserved at around 90%. Prognostic relevance of CS-CTCs in PDAC was further validated in PB-samples from 228 PDAC patients, consolidating the established association between CTC-presence and reduced OS (8.5 vs. 19.0 months, p < 0.001). In conclusion, DLA-derived CS-CTCs may serve as a viable tool for identifying high-risk PDAC-patients and aiding the optimization of multimodal treatment strategies. Moreover, DLA enables comprehensive diagnostic profiling by providing ample CTC material, reinforcing its utility as a reliable liquid-biopsy approach. This high-volume liquid-biopsy strategy presents a potential pathway for enhancing clinical management in this malignancy.

The Role of Adjuvant Therapy in Duodenal Adenocarcinoma and Intestinal Subtype Ampullary Carcinoma after Curative Resection.

OBJECTIVE: Defining the role of adjuvant therapy in duodenal adenocarcinoma (DAC) and intestinal subtype ampullary carcinoma (iAC). SUMMARY BACKGROUND DATA: DAC and iAC share a similar histological differentiation but the benefit of adjuvant therapy remains unclear. METHODS: Patients undergoing curative-intent surgical resection for DAC and iAC between 2010 and 2021 at five high-volume centers were included. Patient baseline, perioperative and long-term oncological outcomes were evaluated. Statistical testing was performed with SPSS 25 (IBM). RESULTS: A total of 136 patients with DAC and 171 with iAC were identified. Patients with DAC had more advanced tumors than those with iAC. Median overall survival (OS) in DAC patients was 101 months versus 155 months for iAC patients (P=0.098). DAC had a higher rate of local (14.1% vs. 1.2%, P<0.001) and systemic recurrence (30.4% vs. 3.5%, P<0.001). Adjuvant therapy failed to improve overall survival in all patients with DAC and iAC. For DAC, patients with perineural invasion, but not other negative prognostic factors had improved OS rates with adjuvant therapy (72 m vs. 44 m, P=0.044). IAC patients with N+ (190 m vs. 57 m, P=0.003), T3-4 (177 m vs. 59 m, P=0.050) and perineural invasion (150 m vs. 59 m, P=0.019) had improved OS rates with adjuvant therapy. CONCLUSION: While adjuvant therapy fails to improve OS in all patients with DAC and iAC in the current study, it improved overall survival in DAC patients with perineural invasion and in iAC patients with T3-4 tumors, positive lymph nodes, and perineural invasion.

A Simple Classification of Pancreatic Duct Size and Texture Predicts Postoperative Pancreatic Fistula: A classification of the International Study Group of Pancreatic Surgery.

OBJECTIVE: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking. METHODS: A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort. RESULTS: Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001). CONCLUSION: For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Independent Validation and Assay Standardization of Improved Metabolic Biomarker Signature to Differentiate Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature. METHODS: We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography-tandem mass spectrometry platform. A machine learning-aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance. RESULTS: The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-9 >2 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-9 <37 U/mL, 39.7%, 94.1%, and 76.3%, respectively. CONCLUSIONS: The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.

Effect of home-based online training and activity feedback on oxygen uptake in patients after surgical cancer therapy: a randomized controlled trial.

BACKGROUND: Exercise training is beneficial in enhancing physical function and quality of life in cancer patients. Its comprehensive implementation remains challenging, and underlying cardiopulmonary adaptations are poorly investigated. This randomized controlled trial examines the implementation and effects of home-based online training on cardiopulmonary variables and physical activity. METHODS: Of screened post-surgical patients with breast, prostate, or colorectal cancer, 148 were randomly assigned (1:1) to an intervention (2 × 30 min/week of strength-endurance training using video presentations) and a control group. All patients received activity feedback during the 6-month intervention period. Primary endpoint was change in oxygen uptake after 6 months. Secondary endpoints included changes in cardiac output, rate pressure product, quality of life (EORTC QoL-C30), C-reactive protein, and activity behavior. RESULTS: One hundred twenty-two patients (62 intervention and 60 control group) completed the study period. Change in oxygen uptake between intervention and control patients was 1.8 vs. 0.66 ml/kg/min (estimated difference after 6 months: 1.24; 95% CI 0.23 to 2.55; p = 0.017). Rate pressure product was reduced in IG (estimated difference after 6 months: - 1079; 95% CI - 2157 to - 1; p = 0.05). Physical activity per week was not different in IG and CG. There were no significant interaction effects in body composition, cardiac output, C-reactive protein, or quality of life. CONCLUSIONS: Home-based online training among post-surgery cancer patients revealed an increase of oxygen uptake and a decrease of myocardial workload during exercise. The implementation of area-wide home-based training and activity feedback as an integral component in cancer care and studies investigating long-term effects are needed. TRIAL REGISTRATION: DRKS-ID: DRKS00020499 ; Registered 17 March 2020.

The influence of socioeconomic aspects and hospital case volume on survival in colorectal cancer in Saxony, Germany.

BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer in Western civilization and responsible for a high number of yearly deaths. Long-term outcome is influenced by many factors, potentially including socioeconomic aspects like income, education, and employment. Furthermore, annual surgical case volume plays a major role in achieving good oncological results. In our retrospective study, we evaluated the effect of socioeconomic deprivation and hospital volume on overall survival (OS) in the federal state of Saxony, Germany. METHODS: All patients with CRC who underwent surgery in Saxony, Germany between 2010 and 2020 and were living in Saxony at the time of diagnosis were included in our retrospective analysis. Uni- and multivariate analyses were conducted considering age, sex, tumor localization, UICC tumor stage, surgical approach (open/laparoscopic), number of resected lymph nodes, adjuvant chemotherapy, year of surgery, and hospital case volume. In addition, our model was adjusted for social disparity using the German Index of Socioeconomic Deprivation (GISD). RESULTS: A total of 24,085 patients were analyzed (15,883 with colon cancer and 8,202 with rectal cancer). Age, sex, UICC tumor stage and tumor localization were distributed as expected for CRC. Median overall survival time was 87.9 months for colon cancer and 110.0 months for rectal cancer. Univariate analysis revealed laparoscopic surgery (colon and rectum P < 0.001), high case volume (rectum: P = 0.002) and low levels of socioeconomic deprivation (colon and rectum P < 0.001) to be significantly associated with better survival. In multivariate analyses, the associations of laparoscopic surgery (colon: HR = 0.76, P < 0.001; rectum: HR = 0.87, P < 0.01), and mid-low to mid-high socioeconomic deprivation (colon: HR = 1.18-1.22, P < 0.001; rectum: HR = 1.18-1.36, P < 0.001-0.01) remained statistically significant. Higher hospital case volume was associated with better survival only in rectal cancer (HR = 0.89; P < 0.01). CONCLUSION: In Saxony, Germany, better long-term survival after CRC surgery was associated with low socioeconomic deprivation, laparoscopic surgery and partly with high hospital case volume. Thus, there is a need to reduce social differences in access to high-quality treatment and prevention and increase hospital patient volume.

Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment.

Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. We determined if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

3D liver model-based surgical education improves preoperative decision-making and patient satisfaction-a randomized pilot trial.

OBJECTIVE: Hepatobiliary surgery bares obstacles to informed consent for the patients due to its complexity and related risk of postoperative complications. 3D visualization of the liver has been proven to facilitate comprehension of the spatial relationship between anatomical structures and to assist in clinical decision-making. Our objective is to utilize individual 3D-printed liver models to enhance patient satisfaction with surgical education in hepatobiliary surgery. DESIGN, SETTING: We conducted a prospective, randomized pilot study comparing 3D liver model-enhanced (3D-LiMo) surgical education against regular patient education during preoperative consultation at the department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Dresden, Germany. PARTICIPANTS: Of 97 screened patients, undergoing hepatobiliary surgery, 40 patients were enrolled from July 2020 to January 2022. RESULTS: The study population (n = 40) was predominantly of male gender (62.5%) with a median age of 65.2 years and a high prevalence of preexisting diseases. Underlying disease, warranting hepatobiliary surgery, was malignancy in the majority of cases (97.5%). Patients in the 3D-LiMo group were more likely to feel very thoroughly educated and exhibited a higher level of satisfaction following surgical education than the control group (80 vs. 55%, n.s.; 90 vs. 65%, n.s.; respectively). Applying 3D models was also associated with enhanced understanding of the underlying disease with regard to amount (100% vs. 70%, p = 0.020) and location of liver masses (95 vs. 65%, p = 0.044). 3D-LiMo patients also demonstrated enhanced understanding of the surgical procedure (80 vs. 55%, n.s.), leading to better awareness for the occurrence of postoperative complications (88.9, vs. 68.4%, p = 0.052). Adverse event profiles were similar. CONCLUSION: In conclusion, individual 3D-printed liver models increase patient satisfaction with surgical education and facilitate patients' understanding of the surgical procedure as well as awareness of postoperative complications. Therefore, the study protocol is feasible to apply to an adequately powered, multicenter, randomized clinical trial with minor modifications.

Active learning for extracting surgomic features in robot-assisted minimally invasive esophagectomy: a prospective annotation study.

BACKGROUND: With Surgomics, we aim for personalized prediction of the patient's surgical outcome using machine-learning (ML) on multimodal intraoperative data to extract surgomic features as surgical process characteristics. As high-quality annotations by medical experts are crucial, but still a bottleneck, we prospectively investigate active learning (AL) to reduce annotation effort and present automatic recognition of surgomic features. METHODS: To establish a process for development of surgomic features, ten video-based features related to bleeding, as highly relevant intraoperative complication, were chosen. They comprise the amount of blood and smoke in the surgical field, six instruments, and two anatomic structures. Annotation of selected frames from robot-assisted minimally invasive esophagectomies was performed by at least three independent medical experts. To test whether AL reduces annotation effort, we performed a prospective annotation study comparing AL with equidistant sampling (EQS) for frame selection. Multiple Bayesian ResNet18 architectures were trained on a multicentric dataset, consisting of 22 videos from two centers. RESULTS: In total, 14,004 frames were tag annotated. A mean F1-score of 0.75 ± 0.16 was achieved for all features. The highest F1-score was achieved for the instruments (mean 0.80 ± 0.17). This result is also reflected in the inter-rater-agreement (1-rater-kappa > 0.82). Compared to EQS, AL showed better recognition results for the instruments with a significant difference in the McNemar test comparing correctness of predictions. Moreover, in contrast to EQS, AL selected more frames of the four less common instruments (1512 vs. 607 frames) and achieved higher F1-scores for common instruments while requiring less training frames. CONCLUSION: We presented ten surgomic features relevant for bleeding events in esophageal surgery automatically extracted from surgical video using ML. AL showed the potential to reduce annotation effort while keeping ML performance high for selected features. The source code and the trained models are published open source.