Randomized double-blind, placebo-controlled multicenter phase III study of prevention of irinotecan-induced diarrhea by a probiotic mixture containing Bifidobacterium BB-12®Lactobacillus rhamnosus LGG® in colorectal cancer patients.

Background: The incidence of irinotecan-induced diarrhea varies between 60-90%, by which the incidence of severe diarrhea is 20-40%. The objective of this phase III trial was to determine the effectiveness of the probiotic mixture containing Bifidobacterium, BB-12® and Lactobacillus rhamnosus, LGG® in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer patients due to a reduction in the activity of intestinal beta-D-glucuronidase. Methods: From March 2016 to May 2022, a total of 242 patients with colorectal cancer starting a new line of irinotecan-based therapy were registered to the study in 11 cancer centers in Slovakia. Patients were randomized in a ratio 1:1 to probiotic formula vs. placebo that was administered for 6 weeks. Each capsule of Probio-Tec® BG-Vcap-6.5 contained 2.7x109 colony-forming units (CFU) of 2 lyophilized probiotic strains Bifidobacterium, BB-12® (50%) and Lactobacillus rhamnosus GG, LGG® (50%). Results: Administration of probiotics compared to placebo was not associated with a significant reduction of grade 3/4 diarrhea (placebo arm 11.8% vs. probiotic arm 7.9%, p=0.38). Neither the overall incidence of diarrhea (46.2% vs. 41.2%, p=0.51) nor the incidence of enterocolitis (3.4% vs. 0.9%, p=0.37) was different in the placebo vs. probiotic arm. Subgroup analysis revealed that patients with colostomy had higher incidence of any diarrhea and grade 3/4 diarrhea in the placebo arm compared to the probiotic arm (48.5% vs. 22.2%, p=0.06 and 15.2% vs. 0%, p=0.06, respectively). Moreover, patients on probiotic arm had significantly better diarrhea-free survival (HR = 0.41, 95%CI 0.18 - 0.95, p=0.05) and needed less loperamide (p=0.01) compared to patients on placebo arm. We did not observe any infection caused by probiotic strains used in this study. Conclusion: This study failed to achieve its primary endpoint, and results suggest a lack of benefit of administered probiotic formula for the prevention of irinotecan-induced diarrhea. However, subgroup analysis suggests a possible benefit in patients with colostomy.

New trends in criteria indicative of neoadjuvant oncological therapy of lower and middle rectal cancers.

The indication for primary surgical resection or neoadjuvant therapy in lower and middle rectal cancers is often disputable. The aim of the study was to evaluate the occurrence of local recurrence of rectal cancer as for a period of at least 4 years after radical resection. The second aim was to evaluate and compare the results of preoperative magnetic resonance (MR) staging with definitive histology.From September 2013 to December 2017, we, at the 3rd Surgical Department Comenius University, Bratislava, prospectively evaluated patients with lower and middle rectal cancers with the distal tumor border being in a 12-cm distance from the anal verge. All patients underwent MR examination at the same MRI department and were operated on at the 3rd Surgical Department, Comenius University, Bratislava. Inclusion criteria included parameters based on MRI examination, i.e., T-staging of T1-T3b, negative extramural vascular infiltration (EMVI), negative circumferential margin (CRM), no mesorectal fascia infiltration with a distance of more than 2 mm. We did not take lymph node staging into account in the indication for primary surgical resection. We performed a radical primary resection procedure (R0 resection) in all patients. The group consisted of 87 patients, of whom 49 were men and 38 were women. The mean age of the patients was 66 years (min. 36 - max. 86 years). Our study also shows significant differences in preoperative T and N staging as compared to definitive histology. The incidence of local recurrence during a period of at least 4 years after surgery was 6.76 %. Study also shows that the indication for preoperative radiotherapy for lower and middle rectal cancers based on N status is inaccurate and leads to unnecessary indications for preoperative radiotherapy which may decrease the patients´ quality of life and increase the post­operative complications. We have also shown that leaving out the N-based radiotherapy from indications does not lead to an increase in the number of local recurrences in lower and middle rectal cancers (Tab. 1, Fig. 5, Ref. 22). Text in PDF www.elis.sk Keywords: rectal cancer, neoadjuvant therapy, local recurrence.

DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines.

Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O2) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.

Squamous cell rectal cancer in a young woman.

BACKGROUND: Rectal squamous cell carcinoma (RSCC) belongs to rare gastrointestinal malignancies. There are no consensus recommendations for the treatment of non-metastatic RSCC, which can cause problems when considering optimal therapy. PURPOSE: The objective of this report is to point out that RSCC is a rare disease which needs to be distinguished from anal squamous cell cancer (ASCC) and the treatment of which differs from that of rectal adenocarcinoma. CASE REPORT: We discuss the dia-gnosis and therapy of a patient with non-metastatic RSCC. A forty-two-year-old woman with a history of diarrhea and rectal bleeding was dia-gnosed for RSCC with locoregional lymphadenopathy, stage T3N1MO. Protective sigmostomy was performed for stenotizing tumor; then the patient underwent chemoradiotherapy with the effect of complete response in MR scans. Subsequently, the patient underwent rectal resection according to Dixon with histological confirmation of complete tumor regression and without detection of residual tumor in the rectum. CONCLUSION: It can be sometimes difficult to distinguish primary RSCC from ASCC. Nowadays, there is no standardized staging system for RSCC, and it causes problems in comparative studies as well as in the determination of treatment protocols. The backbone of RSCC treatment is chemoradiotherapy.

The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.