Tumor vessel normalization via PFKFB3 inhibition alleviates hypoxia and increases tumor necrosis in rectal cancer upon radiotherapy.

Treatment of patients with locally advanced rectal cancer (RC) is based on neoadjuvant chemoradiotherapy followed by surgery. In order to reduce the development of therapy resistance, it is necessary to further improve previous treatment approaches. Recent in vivo experimental studies suggested that the reduction of tumor hypoxia by tumor vessel normalization (TVN), through the inhibition of the glycolytic activator PFKFB3 could significantly improve tumor response to therapy. We have evaluated in vitro and in vivo the effects of the PFKFB3 inhibitor 2E-3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) on cell survival, clonogenicity, migration, invasion and metabolism using colorectal cancer cells, patient-derived tumor organoids (PDO) and xenografts (PDX). 3PO treatment of colorectal cancer cells increased radiation-induced cell death and reduced cancer cell invasion. Moreover, Gene Set Enrichment Analysis shows that 3PO is able to alter the metabolic status of PDOs towards oxidative phosphorylation. Additionally, in vivo neoadjuvant treatment with 3PO induced TVN, alleviated tumor hypoxia and increased tumor necrosis. Our results support PFKFB3 inhibition as a possible future neoadjuvant addition for rectal cancer patients.

International differences in the selection and outcome of minimally invasive and open distal pancreatectomy: A transatlantic analysis.

BACKGROUND: The efficacy and safety of minimally invasive distal pancreatectomy have been confirmed by randomized trials, but current patient selection and outcome of minimally invasive distal pancreatectomy in large international cohorts is unknown. This study aimed to compare the use and outcome of minimally invasive distal pancreatectomy in North America, the Netherlands, Germany, and Sweden. METHODS: All patients in the 4 Global Audits on Pancreatic Surgery Group (GAPASURG) registries who underwent minimally invasive distal pancreatectomy or open distal pancreatectomy during 2014-2020 were included. RESULTS: Overall, 20,158 distal pancreatectomies were included, of which 7,316 (36%) were minimally invasive distal pancreatectomies. Use of minimally invasive distal pancreatectomy varied from 29% to 54% among registries, of which 13% to 35% were performed robotically. Both the use of minimally invasive distal pancreatectomy and robotic surgery were the highest in the Netherlands. Patients undergoing minimally invasive distal pancreatectomy tended to have a younger age (Germany and Sweden), female sex (North America, Germany), higher body mass index (North America, the Netherlands, Germany), lower comorbidity classification (North America, Germany, Sweden), lower performance status (Germany), and lower rate of pancreatic adenocarcinoma (all). The minimally invasive distal pancreatectomy group had fewer vascular resections (all) and lower rates of severe complications and mortality (North America, Germany). In the multivariable regression analysis, country was associated with severe complications but not with 30-day mortality. Minimally invasive distal pancreatectomy was associated with a lower risk of 30-day mortality compared with open distal pancreatectomy (odds ratio 1.633, 95% CI 1.159-2.300, P = .005). CONCLUSIONS: Considerable disparities were seen in the use of minimally invasive distal pancreatectomy among 4 transatlantic registries of pancreatic surgery. Overall, minimally invasive distal pancreatectomy was associated with decreased mortality as compared with open distal pancreatectomy. Differences in patient selection among countries could imply that countries are in different stages of the learning curve.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction.

Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.

Gallic acid supplementation partially ameliorates reproductive aging in rooster breeders by improving semen quality, sperm kinetics, hormones, and antioxidant status.

Aging leads to decreased fertility in roosters, which is likely due to increased oxidative stress. This study evaluated the antioxidant effects of gallic acid (GA) supplementation on sperm quality and fertility of aged roosters. This study evaluated whether GA supplementation can mitigate age-related fertility decline. Roosters were randomly assigned to: control, 100 mg/kg GA, or 200 mg/kg GA. Semen parameters, sperm kinetics, hormone levels, fertility rate, and hatchability were assessed. GA increased semen concentration, membrane integrity and viability while decreasing defects versus control (P < 0.01). Testosterone was higher in GA groups (P<0.01) without affecting gonadotropins. Furthermore, 200 mg/kg GA optimized motility, velocity, linearity, and beat cross frequency versus control and 100 mg/kg GA (P < 0.01). Fertility and hatchability were higher in both GA groups. In conclusion, GA supplementation in aged roosters improves sperm quality, antioxidant status, testosterone, and fertility outcomes, likely by mitigating oxidative stress. The 200 mg/kg dose elicited optimal effects on motion parameters.

ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

Safety and performance of a synthetic sealant patch aimed to prevent postoperative pancreatic fistula after distal pancreatectomy (SHIELDS) - Prospective international multicenter phase II study.

OBJECTIVE: The incidence for clinically relevant postoperative pancreatic fistulas (CR-POPF) in distal pancreatectomy (DP) ranges up to 25%. None of the available sealants significantly reduce CR-POPF. A new biodegradable sealant patch was able to reduce POPF and to achieve bleeding control in a preclinical porcine DP model. The aim of this first-in-human study was to assess the safety and performance of the sealant patch. METHODS: In this multicenter, single-arm study, 40 patients undergoing distal pancreatectomy were prospectively enrolled from 8 centers. Following surgical resection, the transection plane was closed according to the standard of care and manually covered with the sealant patch. As primary endpoint the incidence of CR-POPF up to 30-days postoperatively was evaluated. The secondary endpoints included the assessment of complications and device usability. RESULTS: Among 40 patients after distal pancreatectomy, CR-POPF occurred in 7 (17.5%) up to postoperative day 30. No type C POPF was observed. There was no intraoperative bleeding observed after patch application. CONCLUSION: The results of this international phase II study demonstrate promising results of a new sealant patch regarding the rate of CR-POPF. Randomized studies are now needed to confirm the superiority of the current patch as compared to the best current practice.

[Management of Injuries to the Parenchymal Abdominal Organs]. / Management von Verletzungen parenchymatöser Abdominalorgane.

The most common organs affected by abdominal trauma are the spleen and the liver, often in combination. Pancreatic injuries are rare. In the case of blunt abdominal trauma, which is much more common, a clinical and laboratory examination as well as sonography should be performed. In the initial assessment, the circulatory situation must be screened. If there is haemodynamic instability and presentation of free fluid, an emergency laparotomy is indicated. If the situation is stable or stabilised and a pathological sonography is present, it is essential to perform triphasic contrast enhanced computed tomography, which is also mandatory in polytraumatised patients. If a renal injury is suspected, a late venous phase should be attached. In addition to the classification of the injury, attention should be paid to possible vascular injury or active bleeding. In this case, angiography with the possibility of intervention should be performed. Endoscopic treatment is possible for injuries of the pancreatic duct. If the imaging does not reveal any intervention target and a circulation is stable, a conservative approach is possible with continuous monitoring using clinical, laboratory and sonographic controls. Most injuries can be successfully treated by non-operative management (NOM).There are various surgical options for treating the injury, such as local and resecting procedures. There is also the option of "damage control surgery" with acute bleeding control and second look. Complex surgical procedures should be performed at centres. Postoperative complications arise out of elective surgery.In the less common case of penetrating abdominal trauma, the actual extent of the injury cannot be estimated from the visible wound. Here again, the circulatory situation determines the next steps. An emergency laparotomy should be carried out in case of instability. If the condition is stable, further diagnostics should be performed using contrast enhanced computed tomography. If penetration through the peritoneum cannot be clearly excluded, diagnostic laparoscopy should be performed.

[State of the Art Rectal Surgery]. / State of the Art Rektumchirurgie.

The multimodal treatment of rectal cancer has differentiated considerably over the last decade depending on the characteristics of the tumor and the patient's circumstances. Surgery continues to be an important pillar of therapy, the quality of which is of prognostic relevance for affected patients. This review provides an up-to-date overview of the indications for the various surgical procedures, current developments in perioperative management and the timing of surgery.

LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism.

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

Perioperative LiMAx Test Analysis: Impact of Portal Vein Embolisation, Chemotherapy and Major Liver Resection.

BACKGROUND: Postoperative liver failure (PLF) is a severe complication after major liver resection (MLR). To increase the safety of patients, clinical bedside tests are of great importance. However, limitations of their applicability and validity impair their value. METHODS: Preoperative measurements of the liver maximum capacity (LiMAx) were performed in n = 40 patients, who underwent MLR (≥3 segments). Matched postoperative LiMAx was measured in n = 21 patients. Liver function was compared between pretreated patients (n = 11 with portal vein embolisation (PVE) and n = 19 patients with preoperative chemotherapy) and therapy naïve patients. The LiMAx values were compared with liver-specific blood parameters and volumetric analysis. RESULTS: In total, n = 40 patients were enrolled in this study. The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (>315 µg/kg/h), while only seven patients (17.5%) had medium values (140-315 µg/kg/h), and none of the patients had low values (<140 µg/kg/h). A comparison of pretreated patients (with PVE and/or chemotherapy) and therapy naïve patients showed no significant difference in the preoperative LiMAx values (p > 0.05). The preoperative LiMAx values were significantly higher than the matched postoperative values on postoperative day 1 (p < 0.0001). A comparison between the expected and measured postoperative LiMAx showed a difference (≥10%) in 7 out of 13 patients (53.8%). After an initial postoperative decrease in the LiMAx, the patients without complications (n = 12) showed a continuous increase until 14 days after surgery. In the patients with postoperative complications, a decrease in the LiMAx was associated with a prolonged recovery. CONCLUSIONS: For patients undergoing MLR within the 0.5% rule, which is the clinical gold standard, the LiMAx values do not offer any additional information. Additionally, the LiMAx may have reflected liver function, but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule.

Short- and Long-Term Outcomes of Patients with Postoperative Arrhythmia after Liver Surgery.

BACKGROUND: New-onset postoperative arrhythmia (PA) has previously been described as a pivotal risk factor for postoperative morbidity and mortality after visceral surgery. However, there is a lack of data concerning liver surgery. The incidence and impact of new-onset postoperative arrhythmia after liver surgery was, therefore, analyzed in a monocentric study. METHODS: In total, n = 460 patients (221 female, 239 male) who underwent liver surgery between January 2012 and April 2020 without any prior arrhythmia in their medical history were included in this retrospective analysis. Clinical monitoring started with the induction of anesthesia and was terminated with discharge from the intensive care unit (ICU) or intermediate care unit (IMC). Follow-up included documentation of complications during the hospital stay, as well as long-term survival analysis. RESULTS: Postoperative arrhythmia after liver surgery was observed in 25 patients, corresponding to an incidence of 5.4%. The occurrence of arrhythmia was significantly associated with intraoperative complications (p < 0.05), liver fibrosis/cirrhosis (p < 0.05), bile fistula/bile leakage/bilioma (p < 0.05), and organ failure (p < 0.01). Survival analysis showed a significantly poorer overall survival of patients who developed postoperative arrhythmia after liver surgery (p < 0.001). CONCLUSIONS: New-onset postoperative arrhythmia after liver surgery has an incidence of only 5.4% but is significantly associated with higher postoperative morbidity and poorer overall survival.

Effects of dietary Moringa oleifera leaf extract on semen characteristics, fertility, and hatchability in aged broiler breeder roosters.

Declining semen quality will have a negative impact on the fertility of aged roosters. Various factors influence this decrease in quality. This study was conducted to investigate the effects of different levels of Moringa plant extract on semen characteristics, fertility, and hatchability in aged broiler breeder roosters. A total of 24 roosters were fed 1 of 4 dietary supplements for 10 wk: Control, 100 µL/kg (Moringa oleifera leaf extract [MOLE]-100), 200 µL/kg (MOLE-200), or 400 µL/kg body weight (MOLE-400) of Moringa oleifera extract. Results showed supplementation with MOLE-200 significantly improved (P < 0.05) semen concentration, total motility, progressive motility, sperm membrane integrity compared to other treatments. However, semen volume and body weight were unaffected (P > 0.05). Sperm lipid peroxidation, as indicated by malondialdehyde concentration, was lowest in MOLE-200. There was a significant difference observed among the treatments in terms of total antioxidant capacity (TAC) results. The testosterone concentration in the MOLE-200 treatment was significantly higher than the other treatments (P < 0.05). However, no significant differences were observed in the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) hormones among the experimental treatments. Fertility and hatchability rates were measured at the end of the trial. Fertility, defined as the number of fertilized eggs, was greatest in the MOLE-200 treatment compared to the other treatments. Similarly, hatchability (hatched chicks/fertilized eggs %) was highest at 88.02% for MOLE-200. In conclusion, dietary supplementation with M. oleifera extract improved semen quality, fertility, and hatchability in aged broiler breeder roosters.

Visualization of deglutition and gastroesophageal reflux using real-time MRI: a standardized approach to image acquisition and assessment.

This study aims to develop a standardized algorithm for gastroesophageal image acquisition and diagnostic assessment using real-time MRI. Patients with GERD symptoms undergoing real-time MRI of the esophagus and esophagogastric junction between 2015 and 2018 were included. A 10 ml bolus of pineapple juice served as an oral contrast agent. Patients performed Valsalva maneuver to provoke reflux and hiatal hernia. Systematic MRI assessment included visual presence of achalasia, fundoplication failure in patients with previous surgical fundoplication, gastroesophageal reflux, and hiatal hernia. A total of 184 patients (n = 92 female [50%], mean age 52.7 ± 15.8 years) completed MRI studies without adverse events at a mean examination time of 15 min. Gastroesophageal reflux was evident in n = 117 (63.6%), hiatal hernia in n = 95 (52.5%), and achalasia in 4 patients (2.2%). Hiatal hernia was observed more frequently in patients with reflux at rest (n = 67 vs. n = 6, p < 0.01) and during Valsalva maneuver (n = 87 vs. n = 8, p < 0.01). Real-time MRI visualized a morphologic correlate for recurring GERD symptoms in 20/22 patients (90%) after fundoplication procedure. In a large-scale single-center cohort of patients with GERD symptoms undergoing real-time MRI, visual correlates for clinical symptoms were evident in most cases. The proposed assessment algorithm could aid in wider-spread utilization of real-time MRI and provides a comprehensive approach to this novel imaging modality.

SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits distinct molecular subtypes: classical/progenitor and basal-like/squamous. Our study aimed to identify genes contributing to the development of the basal-like/squamous subtype, known for its aggressiveness. Transcriptome analyses revealed consistent upregulation of SERPINB3 in basal-like/squamous PDAC, correlating with reduced patient survival. SERPINB3 transgene expression in PDAC cells enhanced in vitro invasion and promoted lung metastasis in a mouse PDAC xenograft model. Metabolome analyses unveiled a metabolic signature linked to both SERPINB3 and the basal-like/squamous subtype, characterized by heightened carnitine/acylcarnitine and amino acid metabolism, associated with poor prognosis in patients with PDAC and elevated cellular invasiveness. Further analysis uncovered that SERPINB3 inhibited the cysteine protease calpain, a key enzyme in the MYC degradation pathway, and drove basal-like/squamous subtype and associated metabolic reprogramming through MYC activation. Our findings indicate that the SERPINB3-MYC axis induces the basal-like/squamous subtype, proposing SERPINB3 as a potential diagnostic and therapeutic target for this variant.

Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients' Outcome.

Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), the impact of radiotherapy on the TME and specifically the tumor immune microenvironment (TIME) is increasingly recognized. Both promoting as well as suppressing effects on anti-tumor immunity have been reported in response to rectal cancer (chemo-)radiotherapy and various targets for combination therapies are under investigation. A literature review was conducted searching the PubMed database for evidence regarding the pleiotropic effects of (chemo-)radiotherapy on the rectal cancer TIME, including alterations in cytokine levels, immune cell populations and activity as well as changes in immune checkpoint proteins. Radiotherapy can induce immune-stimulating and -suppressive alterations, potentially mediating radioresistance. The response is influenced by treatment modalities, including the dosage administered and the highly individual intrinsic pre-treatment immune status. Directly addressing the main immune cells of the TME, this review aims to highlight therapeutical implications since efficient rectal cancer treatment relies on personalized strategies combining conventional therapies with immune-modulating approaches, such as immune checkpoint inhibitors.

Impact of Portal Vein Resection (PVR) in Patients Who Underwent Curative Intended Pancreatic Head Resection.

The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, and comparison of oncological outcomes in PVR patients. We retrieved n = 90 patients from a prospectively collected data bank who underwent pancreas surgery between 2012 and 2019 at the University Medical Centre Göttingen (Germany) and showed a histologically confirmed pancreatic ductal adenocarcinoma (PDAC). While 50 patients (55.6%) underwent pancreatic resection combined with PVR, 40 patients (44.4%) received standard pancreatic surgery. Patients with distal pancreatectomy or a tumor other than PDAC were excluded. PVR was performed either as local excision or circular resection of the portal vein. Clinical/patient data and follow-ups were retrieved. The median follow-up period was 20.5 months. Regarding the oncological outcome, a statistically poorer CSS (p = 0.04) was observed in PVR patients. There was no difference (p = 0.18) in patients' outcomes between tangential and complete PVR, while n = 21 (42% of PVR patients) showed portal vein infiltration. The correlation between performed PVR and resection status was statistically significant: 48.6% of PVR patients achieved R0 resections compared to 75% in non-PVR patients (p = 0.03). Patients who underwent PDAC surgery with PVR show a significantly poorer outcome regardless of PVR type. Tumor size and R-status remain two important variables significantly associated with outcome. Since there is a lack of standardization for the indication of PVR, it remains unknown if the need for resection of vein structures during pancreatic resection represents the biological aggressiveness of the tumor or is biased by the experience of the surgeon.

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to systemic treatment, including new immunotherapeutic approaches. Biomarkers are urgently needed for early disease detection, patient stratification for treatment, and response prediction. The role of soluble CD40 (sCD40) is unknown in PDAC. In this study, we performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum samples from patients with various stages of PDAC in a discovery study (n = 107) and analyzed sCD40 by ELISA in a validation study (n = 317). Youden's J statistic was used for diagnostic cut-off optimization. A Cox proportional hazards regression model was applied in an empiric approach for prognostic threshold optimization. Kaplan-Meier estimator and multivariable Cox regression analyses were used for survival analysis. sCD40 was significantly increased in the serum of patients with PDAC compared to healthy cohorts and patients with IPMN. In the validation cohort, the area under the receiver operating characteristic (ROC) c-statistic was 0.8, and combining sCD40 with CA19-9 yielded a c-statistic of 0.95. sCD40 levels were independent of the tumor stage. However, patients who received neoadjuvant chemotherapy had significantly lower sCD40 levels than those who underwent upfront surgery. Patients with a sCD40 level above the empirical threshold of 0.83 ng/ml had a significantly reduced overall survival with a hazard ratio of 1.4. This observation was pronounced in patients after neoadjuvant chemotherapy. Collectively, soluble CD40 may be considered as both a diagnostic and prognostic non-invasive biomarker in PDAC.

Overall Survival After Treatment Failure Among Patients With Rectal Cancer.

Importance: Oncologic outcomes among patients with rectal cancer after developing local recurrence and/or distant metastases remain poorly studied. Objective: To analyze the trend of overall survival after treatment failure for patients with rectal cancer within three consecutive phase 2 or 3 trials of the German Rectal Cancer Study Group. Design, Setting, and Participants: This cohort study is a post hoc analysis of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trials, conducted in Germany) that included 1948 patients with locally advanced rectal adenocarcinoma. The CAO/ARO/AIO-94 trial recruited patients between February 1995 and September 2002, the CAO/ARO/AIO-04 trial recruited patients between July 2006 and February 2010, and the CAO/ARO/AIO-12 trial recruited patients between June 2015 and January 2018. Statistical analysis was conducted between September 2022 and March 2023. Exposures: A total of 119 of 391 patients in the CAO/ARO/AIO-94 trial group A, 295 of 1236 patients in the CAO/ARO/AIO-04 trial, and 69 of 306 in the CAO/ARO/AIO-12 trial experienced treatment failure (R2 resection or local recurrence or distant metastases) and were included in further analyses. Main Outcomes and Measures: Characteristics of treatment failure and overall survival were assessed in all 3 trial cohorts. Results: Of the 1948 patients treated in the 3 trials, 15 were excluded because of missing data. Of the remaining 1933 patients (median age, 62.5 years [range, 19-84 years]; 1363 men [71%] and 570 women [29%]) with locally advanced rectal adenocarcinoma (cT3 or 4 or cN+) treated within 3 consecutive clinical trials, 483 experienced treatment failure and were analyzed. After a median follow-up of 36 months (IQR, 24-51 months) for all patients, overall survival after treatment failure was significantly improved in the CAO/ARO/AIO-04 trial (at 3 years, 44% [IQR, 37%-51%]; hazard ratio [HR], 0.61 [95% CI, 0.47-0.79]) and further improved in the CAO/ARO/AIO-12 trial (at 3 years, 73% [IQR, 60%-87%]; HR, 0.32 [95% CI, 0.18-0.54]) compared with the CAO/ARO/AIO-94 trial (at 3 years, 30% [IQR, 22%-39%]) (both P < .001). Distant metastasis was the main reason for treatment failure throughout a 5-year follow-up (range, 67%-87%), and the relative risk for treatment failure was highest in the first 18 months in all 3 trials. ypTNM stage was significantly associated with the risk and time interval to treatment failure. Improvement in overall survival after treatment failure was independent of sex. Conclusions and Relevance: This cohort study suggests that advancements in salvage strategies during the past decades have likely improved overall survival among patients with rectal cancer who experienced treatment failure.