Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma.

BACKGROUND: Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. METHODS: The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. DISCUSSION: Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. TRIAL REGISTRATION: Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review.

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). METHODS: This study is prospective single-arm, multicenter phase II trial adopting Simon's two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3-4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. RESULTS: 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33-73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. CONCLUSION: In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1 .

Antibacterial activity of Ilex paraguariensis (Yerba Mate) against Gram-positive and Gram-negative bacteria.

INTRODUCTION: Limited research was performed on the antibacterial activity of the aqueous extract of Yerba Mate. The purpose of this study is to evaluate the anti-bacterial activity of Yerba Mate against Gram-positive and Gram-negative bacterial strains and its action against some resistant bacteria with genotypic molecular testing of resistance profiles. METHODOLOGY: Commercial Ilex paraguariensis stems and leaves were purchased and extracts were prepared by adding water at 70oC for 2 hrs. ATCC bacterial strains and clinical strains from Centre Hospitalier Du Nord (CHN) were used for testing. Macro dilution method was used to determine the minimal inhibitory. Minimal bactericidal concentration (MBC) was determined by sub-culturing the tubes with clear broth. For phenotypic and genotypic detection of ß-lactamases, Double Disk Synergy method, E-test, phenylboronic acid disc method and multiplex PCR were performed for the identification of the mechanisms of resistance. RESULTS: Antibacterial activity was observed against all tested strains, with a greater activity against Gram-positive bacteria. This study showed mostly a greater antibacterial activity of aqueous extract of Yerba Mate in comparison to different extraction methods published. In general, the MIC and MBC values ranged between 0.468 mg/mL and 15 mg/mL. No correlation was found between the different molecular resistance profiles and the antibacterial activity. CONCLUSION: More studies are needed to determine the molecule or molecules responsible for this activity. Moreover, testing a wider range of bacterial isolates is important for a better understanding of the potential role of Yerba Mate.

Antibacterial activity of Ilex paraguariensis (Yerba Mate) against Gram-positive and Gram-negative bacteria.

INTRODUCTION: The stems and leaves of Ilex paraguariensis are popularly used for tea infusions in South America and the Middle East. The health benefits have been previously studied, revealing anti-mutagenic, anti-oxidant, hepatoprotective, hypocholesteremic and glycemic improvement. Limited research was performed on the antibacterial activity of the aqueous extract of Yerba Mate on standard and clinical isolates of Gram-positive and Gram-negative bacteria. METHODOLOGY: Commercial Ilex paraguariensis stems and leaves were ground and extracted with sterile deionized water at 70°C. Four ATCC bacterial strains and twenty-five bacterial clinical strains were used for testing. To obtain the minimal inhibitory concentration (MIC), the Yerba Mate aqueous solution was serially diluted according to the microdilution method. For the minimal bactericidal concentration (MBC), the tubes with clear broth were sub-cultured. To identify the types of ESBLs present in the clinical isolates, a multiplex PCR was performed. RESULTS: An antibacterial activity was observed against most of tested strains, with a greater activity against Gram-positive bacteria. MIC and MBC values ranged between 0.468 mg/mL and 15 mg/mL of aqueous extract of Yerba Mate. CONCLUSION: The aqueous extract of the stems and leaves of Ilex paraguariensis extracted at 70°C showed a significant antibacterial activity. There was no correlation found between the different molecular resistance profiles and the antibacterial activity range.