Laparoscopic surgery for rectal cancer, specimen extraction: transanal or transabdominal?

BACKGROUND: Comparison of natural orifice specimen extraction (NOSE) and transabdominal specimen extraction (TASE) in colorectal surgery remains controversial. Herein, we aimed to perform a retrospective analysis on surgical outcomes of NOSE and TASE at three hospitals in east of Iran. METHOD: Consecutive locally advanced rectal adenocarcinoma patients who underwent laparoscopic surgery using either NOSE or TASE from 2011 to 2017 were recruited. These patients were followed-up till 2020. Data, including postoperative complications, long-term overall and recurrence-free survival were analyzed retrospectively. RESULTS: 239 eligible patients were included in this study. 169 (70.71%) patients underwent NOSE, and 70 (29.29%) patients underwent TASE. Although this study has achieved similar outcomes in terms of overall and recurrence-free survival, metastasis, circumferential margin involvement as well as complications of intra-operative bleeding, obstruction, anastomosis-fail, rectovaginal-fistula in women and pelvic collection/abscess in both groups, we observed higher rates of locoregional recurrence, incontinency, stenosis and the close distal margins involvement in NOSE group and also obstructed defecation syndrome in TASE cases. CONCLUSION: According to our findings, NOSE laparoscopic surgery showed significantly higher incontinency, impotency, stenosis and involvement of the close distal margins rates. Nevertheless, considering the similarity of long-term overall and recurrence-free survival, metastasis, circumferential margin involvement, NOSE procedure is still could be considered as a second choice for lower rectal adenocarcinoma patients.

Design, synthesis and evaluation of PD-L1 peptide antagonists as new anticancer agents for immunotherapy.

Blocking the interaction of programmed cell death protein 1 (PD-1) and its ligand PD-L1 is known as a promising immunotherapy for treatment of a variety of tumors expressing PD-L1 on their cell surface. In the last decade, several antibodies against the PD-1/PD-L1 interaction have been approved, while there are few reports of small-molecule inhibitors against PD-1/PD-L1 axis. Due to many advantages of cancer treatment with small molecules over antibodies, we developed several peptidic PD-L1 antagonists using computational peptide design methods, and evaluated them both in vitro and in vivo. Importantly, among six peptides with best affinity to PD-L1, four peptides exhibited significant potency to block PD-1/PD-L1 axis at molecular level. Moreover, the PD-L1 expression in nine human colorectal cancer cell lines stimulated with interferon-γ was compared and LoVo cells with the highest expression were selected for further experiments. The peptides could also restore the function of activated Jurkat T cells, which had been suppressed by stimulated LoVo cells. A blockade assay in tumor-bearing mice experiments indicated that peptides HS5 and HS6 consisting of a d-amino acid in their structures, could also effectively reduce tumor growth in vivo, without induction of any observable liver or renal toxicity, tissue damages and loss of body weight. As new designed peptides showed no toxicity against murine colon cancer cells in vitro, the observed anti-tumor results in mice are most probably due to disrupting the PD-1/PD-L1 interaction. Thus, peptides described in this study can be considered as proper low molecular weight candidates for immunotherapy of cancer.

An overview of lipoxygenase inhibitors with approach of in vivo studies.

Lipoxygenases (LOXs) are enzymes which found in organisms that catalyze the peroxidation of polyunsaturated fatty acids (Arachidonic acid, Linoleic acid). The key role of the mentioned enzymes and their metabolites in formation of sensitivities, inflammations, many of cancers (prostate, breast, etc), obesity, diabetes and atherosclerosis had been demonstrated. This review aimed to focus on research findings introducing proved LOXs (5/12/15-LOX) inhibitors, which have been involved in in vivo studies, and discuss on their sources, chemical structures and medicinal applications. By this subject selection, we would introduce the possible LOXs inhibitors (5/12/15-LOX) with special physiological and metabolic levels and open a vision in molecular target selection for the readers.

The importance of 15-lipoxygenase inhibitors in cancer treatment.

Cancer-targeted therapy is an expanding and successful approach in treatment of many types of cancers. One of the main categories of targeted therapy is use of small molecule inhibitors. 15-Lipoxygenase (15-LOX) is an enzyme which reacts with polyunsaturated fatty acids and produces metabolites that are implicated in many important human diseases, such as cancer. Considering the role of 15-LOX (mainly 15-LOX-1) in the progression of some cancers, the discovery of 15-LOX inhibitors could potentially lead to development of novel cancer therapeutics and it can be claimed that 15-LOX inhibitors might be suitable as chemotherapy agents in the near future. This article reviews relevant publications on 15-LOX inhibitors with focus on their anticancer activities in vitro and in vivo. Many 15-LOX inhibitors have been reported for which separate studies have shown their anticancer activities. This review paves the way to further explore the mechanism of their antiproliferative effects via 15-LOX inhibition.

Post recurrence survival in early versus late period and its prognostic factors in rectal cancer patients.

To identify factors associated with post-recurrence survival (PRS), we examined our institutional recurrence patterns following definitive resection for rectal cancer. We reviewed all patients with rectal cancer diagnosed at three hospitals in the east of Iran from 2011 to 2020. The optimal cut-off value was determined by receiver operating characteristic (ROC) analysis to determine early recurrence. The effect of recurrence time was evaluated on PRS. 326 eligible patients with a mean ± SD age of 56 ± 12.8 years were included in this study. In a median (IQR: Inter-quartile range) follow-up time of 76 (62.2) months, 106 (32.5%) patients experienced at least any recurrence (locoregional or distant metastasis) following primary resection. The median (IQR) time from initial surgery to recurrence was 29.5 (31.2) months. Based on ROC analysis, early recurrence was specified at ≤ 29 months. However, for the patients who experienced only locoregional recurrence, 33 months was the cut-off to define early recurrence. Recurrence time and recurrence management were both significant variables on PRS. Moreover, TNM staging was significantly associated with early recurrence (P = 0.003). In this research, recurrence time, recurrence management and TNM staging were found to be correlated with PRS.

The association of preoperative hematologic parameters with short-term clinical outcomes in rectal cancer: A feature importance analysis.

BACKGROUND: Various hematologic parameters have been proposed as prognostic factors in rectal cancer management, but data are conflicting and unclear. This study is designed to investigate the prognostic factor capability of preoperative hematologic parameters with postoperative morbidities and mortality in rectal cancer patients undergoing curative resection. METHODS: All 200 consecutive rectal cancer patients diagnosed at Ghaem University Hospital from 2017 to 2022 were retrospectively evaluated. The receiver operating characteristic (ROC) curves and machine learning (ML) algorithms of Random Forest, Recursive Feature Elimination, simulated annealing, Support Vector Machine, Decision Tree, and eXtreme Gradient Boosting were administered to investigate the role of preoperative hematologic parameters accompanied by baseline characteristics on three clinical outcomes including surgical infectious complications, recurrence, and death. RESULTS: The frequency of infectious complications was correlated with the surgical procedure, while tumor recurrence was significantly influenced by T stage and N stage. In terms of mortality, alongside T and N stage, the status of resection margin involvement was significantly correlated. Based on the ROC analysis, the NLR >2.69, MPV ≤9 fL, and PDW ≤10.5 fL were more classified patients to mortality status. Likewise, the PLT >220 109/L, MPV ≤9 fL, PDW ≤10.4 fL, and PLR >13.6 were correlated with recurrence. However, all factors examined in this study were not significant classifiers for the outcome of surgical infectious complications. The results of ML algorithms were also in line with ROC analysis. CONCLUSION: According to the results of both ROC analysis and ML models, preoperative hematologic parameters are considerable prognostic factors of postoperative outcomes in rectal cancer patients, and are recommended to be monitored by clinicians to prevent unfavorable outcomes.

Use of anticancer peptides as an alternative approach for targeted therapy in breast cancer: a review.

Breast cancer is the most common cancer in women worldwide. Traditional therapies are expensive and cause severe side effects. Targeted therapy is a powerful method to circumvent the problems of other therapies. It also allows drugs to localize at predefined targets in a selective manner. Currently, there are several monoclonal antibodies which target breast cancer cell surface markers. However, using antibodies has some limitations. In the last two decades, many investigators have discovered peptides that may be useful to target breast cancer cells. In this article, we provide an overview on anti-breast cancer peptides, their sources and biological activities. We further discuss the pros and cons of using anticancer peptides with further emphasis on how to improve their effectiveness in cancer therapy.

7-Farnesyloxycoumarin Exerts Anti-cancer Effects on a Prostate Cancer Cell Line by 15-LOX-1 Inhibition.

BACKGROUND: Prostate cancer is one of the leading causes of cancer related deaths in males worldwide. Overexpression of 15-lipoxygenase-1 (15-LOX-1) enzyme and high activity of its metabolic pathway is reported to be a driver for prostate cancer malignancy. Farnesyloxycoumarin derivatives (3f, 4f and 7f) inhibit lipoxygenase enzyme. We hypothesized that farnesyloxycoumarins may exert an anti-cancer effect on prostate cancer cells due to their 15-LOX-1 inhibitory potential. METHODS: The enzyme inhibitory activity of 3f, 4f and 7f was initially evaluated on PC-3 and DU145 prostate cancer cell lines. MTT assay was performed on cancer cell lines and HFF3 cell line to assess cytotoxicity of the compounds. The apoptotic morphology of cells after treatments was assessed by DAPI staining and single cell gel electrophoresis. Propidium iodide staining was also performed to detect cell cycle variations after treatment. RESULTS: 7f inhibited 15-LOX-1 at IC50=4.3 µg/mL, while 3f and 4f did not show high inhibitory activity. 7f reduced cell viability in PC-3 cells at IC50=22-31 µg/mL, however, no significant cytotoxicity was revealed on normal cells. DAPI staining and comet assay confirmed apoptosis and DNA damage in PC-3 cells after 7f treatment, while flow cytometry results revealed G1 arrest in PC-3 cells. CONCLUSION: The results are indicative of a distinctive cytotoxic mechanism for 7f compared to other coumarins, possibly due to its 15-LOX-1 inhibitory potential. Thus, this compound is valued for further assessments with the aim of developing a promising targeted therapy for prostate cancer patients.

Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors.

All of the mono isopentenyloxy, -geranyloxy and -farnesyloxy derivatives of coumarin were synthesized and their inhibitory potency against soybean 15-lipoxygenase (SLO) and human 15-lipoxygenase-1 (HLO-1) were determined. Amongst the synthetic analogs, 5-farnesyloxycoumarin showed the most potent inhibitory activity against SLO (IC(50) = 0.8 µM) while 6-farnesyloxycoumarin was the strongest HLO-1 inhibitor (IC(50) = 1.3 µM). The IC(50) variations of the farnesyl derivatives for HLO-1 (1.3 to ∼75 µM) were much higher than that observed for SLO (0.8-5.8 µM). SAR studies showed that hydrogen bonding, CH/π, anion-π and S-OC interactions with Fe(III)-OH, Leu408, Glu357 and Met419 were the distinct intermolecular interactions which can lead to important role of the coumarin substitution site in HLO-1 inhibitory potency, respectively.