Turnbull-Cutait pull-through coloanal anastomosis versus standard coloanal anastomosis plus diverting ileostomy for low anterior resection: a meta-analysis and systematic review.

PURPOSE: Coloanal anastomosis with loop diverting ileostomy (CAA) is an option for low anterior resection of the rectum, and Turnbull-Cutait coloanal anastomosis (TCA) regained popularity in the effort to offer patients a reconstructive option. In this context, we aimed to compare both techniques. METHODS: PubMed, Cochrane, and Scopus were searched for studies published until January 2024. Odds ratios (RRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. Statistical significance was defined as p < 0.05. Heterogeneity was assessed using the Cochran Q test and I2 statistics, with p-values inferior to 0.10 and I2 >25% considered significant. Statistical analysis was conducted in RStudio version 4.1.2 (R Foundation for Statistical Computing). Registered number CRD42024509963. RESULTS: One randomized controlled trial and nine observational studies were included, comprising 1,743 patients, of whom 899 (51.5%) were submitted to TCA and 844 (48.5%) to CAA. Most patients had rectal cancer (52.2%), followed by megacolon secondary to Chagas disease (32.5%). TCA was associated with increased colon ischemia (OR 3.54; 95% CI 1.13 to 11.14; p < 0.031; I2 = 0%). There were no differences in postoperative complications classified as Clavien-Dindo ≥ IIIb, anastomotic leak, pelvic abscess, intestinal obstruction, bleeding, permanent stoma, or anastomotic stricture. In subgroup analysis of patients with cancer, TCA was associated with a reduction in anastomotic leak (OR 0.55; 95% CI 0.31 to 0.97 p = 0.04; I2 = 34%). CONCLUSION: TCA was associated with a decrease in anastomotic leak rate in subgroups analysis of patients with cancer.

Capsaicinoids and Their Effects on Cancer: The "Double-Edged Sword" Postulate from the Molecular Scale.

Capsaicinoids are a unique chemical species resulting from a particular biosynthesis pathway of hot chilies (Capsicum spp.) that gives rise to 22 analogous compounds, all of which are TRPV1 agonists and, therefore, responsible for the pungency of Capsicum fruits. In addition to their human consumption, numerous ethnopharmacological uses of chili have emerged throughout history. Today, more than 25 years of basic research accredit a multifaceted bioactivity mainly to capsaicin, highlighting its antitumor properties mediated by cytotoxicity and immunological adjuvancy against at least 74 varieties of cancer, while non-cancer cells tend to have greater tolerance. However, despite the progress regarding the understanding of its mechanisms of action, the benefit and safety of capsaicinoids' pharmacological use remain subjects of discussion, since CAP also promotes epithelial-mesenchymal transition, in an ambivalence that has been referred to as "the double-edge sword". Here, we update the comparative discussion of relevant reports about capsaicinoids' bioactivity in a plethora of experimental models of cancer in terms of selectivity, efficacy, and safety. Through an integration of the underlying mechanisms, as well as inherent aspects of cancer biology, we propose mechanistic models regarding the dichotomy of their effects. Finally, we discuss a selection of in vivo evidence concerning capsaicinoids' immunomodulatory properties against cancer.

Identifying New Contributors to Brain Metastasis in Lung Adenocarcinoma: A Transcriptomic Meta-Analysis.

Lung tumors frequently metastasize to the brain. Brain metastasis (BM) is common in advanced cases, and a major cause of patient morbidity and mortality. The precise molecular mechanisms governing BM are still unclear, in part attributed to the rarity of BM specimens. In this work, we compile a unique transcriptomic dataset encompassing RNA-seq, microarray, and single-cell analyses from BM samples obtained from patients with lung adenocarcinoma (LUAD). By integrating this comprehensive dataset, we aimed to enhance understanding of the molecular landscape of BM, thereby facilitating the identification of novel and efficient treatment strategies. We identified 102 genes with significantly deregulated expression levels in BM tissues, and discovered transcriptional alterations affecting the key driver 'hub' genes CD69 (a type II C-lectin receptor) and GZMA (Granzyme A), indicating an important role of the immune system in the development of BM from primary LUAD. Our study demonstrated a BM-specific gene expression pattern and revealed the presence of dendritic cells and neutrophils in BM, suggesting an immunosuppressive tumor microenvironment. These findings highlight key drivers of LUAD-BM that may yield therapeutic targets to improve patient outcomes.

Advancing Immunotherapies for HPV-Related Cancers: Exploring Novel Vaccine Strategies and the Influence of Tumor Microenvironment.

The understanding of the relationship between immunological responses and cancers, especially those related to HPV, has allowed for the study and development of therapeutic vaccines against these neoplasias. There is a growing number of studies about the composition and influence of the tumor microenvironment (TME) in the progression or establishment of the most varied types of cancer. Hence, it has been possible to structure immunotherapy approaches based on therapeutic vaccines that are even more specific and directed to components of TME and the immune response associated with tumors. Among these components are dendritic cells (DCs), which are the main professional antigen-presenting cells (APCs) already studied in therapy strategies for HPV-related cancers. On the other hand, tumor-associated macrophages are also potential targets since the profile present in tumor infiltrates, M1 or M2, influences the prognosis of some types of cancer. These two cell types can be targets for therapy or immunomodulation. In this context, our review aims to provide an overview of immunotherapy strategies for HPV-positive tumors, such as cervical and head and neck cancers, pointing to TME immune cells as promising targets for these approaches. This review also explores the potential of immunotherapy in cancer treatment, including checkpoint inhibitors, cytokine immunotherapies, immunotherapy vaccines, and cell therapies. Furthermore, it highlights the importance of understanding the TME and its effect on the design and achievement of immunotherapeutic methods.

Tumor Microenvironment Role in Pancreatic Cancer Stem Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a majority of patients presenting with unresectable or metastatic disease, resulting in a poor 5-year survival rate. This, in turn, is due to a highly complex tumor microenvironment and the presence of cancer stem cells, both of which induce therapy resistance and tumor relapse. Therefore, understanding and targeting the tumor microenvironment and cancer stem cells may be key strategies for designing effective PDAC therapies. In the present review, we summarized recent advances in the role of tumor microenvironment in pancreatic neoplastic progression.

The antitumor effect induced by an IL-2 'no-alpha' mutein depends on changes in the CD8+ T lymphocyte/Treg cell balance.

High doses of interleukin-2 (IL-2) have been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy, with a ~15% response rate. Remarkably, 7%-9% of patients achieve complete or long-lasting responses. Many patients treated with IL-2 experienced an expansion of regulatory T cells (Tregs), specifically the expansion of ICOS+ highly suppressive Tregs, which correlate with worse clinical outcomes. This partial efficacy together with the high toxicity associated with the therapy has limited the use of IL-2-based therapy. Taking into account the understanding of IL-2 structure, signaling, and in vivo functions, some efforts to improve the cytokine properties are currently under study. In previous work, we described an IL-2 mutein with higher antitumor activity and less toxicity than wtIL-2. Mutein was in silico designed for losing the binding capacity to CD25 and for preferential stimulation of effector cells CD8+ and NK cells but not Tregs. Mutein induces a higher anti-metastatic effect than wtIL-2, but the extent of the in vivo antitumor activity was still unexplored. In this work, it is shown that mutein induces a strong antitumor effect on four primary tumor models, being effective even in those models where wtIL-2 does not work. Furthermore, mutein can change the in vivo balance between Tregs and T CD8+ memory/activated cells toward immune activation, in both healthy and tumor-bearing mice. This change reaches the tumor microenvironment and seems to be the major explanation for mutein efficacy in vivo.

Cytokine-driven positive feedback loop organizes fibroblast transformation and facilitates gastric cancer progression.

BACKGROUND: Gastric cancer (GC) is a malignancy that belongs to one of the most common leading causes of cancer death. Cancer-associated fibroblasts (CAFs) promote the GC cells' malignant behavior. It is still unknown how GC converts normal fibroblasts (NFs) to CAFs. METHODS: GC cells were co-cultured with NFs. Bioinformatics was used to analyze the genes and signaling pathways that were changed in fibroblast. RT-PCR, western blot, and Elisa assays were used to detect the expression of cytokines in fibroblast and condition medium. Western blot and immunofluorescence demonstrated activation of relevant pathways in CAFs-like cells. Transwell, scrape, colony formation, and CCK-8 assays were performed to reveal the feedback effect of CAFs-like cells on GC cells. RESULTS: GC promoted the conversion of NFs to CAFs by secreting Interleukin 17A (IL-17). It included both morphological and molecular marker changes. This process was achieved by activating the nuclear factor-κB (NF-κB) pathway. On the other hand, CAFs cells could secrete C-X-C Motif Chemokine Ligand 8 (IL-8, IL-8), which promoted the malignant phenotype of GC cells. In this way, a feedback loop of mutual influence was constructed in the GC and tumor microenvironment (TME). CONCLUSIONS: Our research proved a novel model of GC-educated NFs. GC-IL-17-fibroblast-IL-8-GC axis might be a potential pathway of the interaction between GC and TME.

Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications.

Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome.

Small extracellular vesicle-mediated bidirectional crosstalk between neutrophils and tumor cells.

Neutrophils are the first line of defense against tissue injury and play an important role in tumor progression. Tumor-associated neutrophils (TANs) mediate pro-tumor immunosuppressive activity and their infiltration into tumors is associated with poor outcome in a variety of malignant diseases. The tumor cell-neutrophil crosstalk is mediated by small extracellular vesicles (sEVs) also referred to as exosomes which represent a major mechanism for intercellular communication. This review will address the role of neutrophil-derived sEVs (NEX) in reprogramming the TME and on mechanisms that regulate the dual potential of NEX to promote tumor progression on one hand and suppress tumor growth on the other. Emerging data suggest that both, NEX and tumor-derived sEVs (TEX) carry complex molecular cargos which upon delivery to recipient cells in the tumor microenvironment (TME) modulate their behavior and reprogram them to mediate pro-inflammatory or immunosuppressive responses. Although it remains unknown how the balance between the often conflicting signaling of TEX and NEX is regulated, this review is an attempt to provide insights into mechanisms that underpin this complex bidirectional crosstalk. A better understanding of the signals NEX process or deliver in the TME might lead to the development of novel approaches to the control of tumor progression in the future.

Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment.

Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet-derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

Exosomes in the tumor microenvironment: from biology to clinical applications

Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome.

Matrix Metalloproteinases' Role in Tumor Microenvironment.

Cancer cells evolve in the tumor microenvironment (TME) by the acquisition of characteristics that allow them to initiate their passage through a series of events that constitute the metastatic cascade. For this purpose, tumor cells maintain a crosstalk with TME non-neoplastic cells transforming them into their allies. "Corrupted" cells such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs) as well as neoplastic cells express and secrete matrix metalloproteinases (MMPs). Moreover, TME metabolic conditions such as hypoxia and acidification induce MMPs' synthesis in both cancer and stromal cells. MMPs' participation in TME consists in promoting events, for example, epithelial-mesenchymal transition (EMT), apoptosis resistance, angiogenesis, and lymphangiogenesis. MMPs also facilitate tumor cell migration through the basement membrane (BM) and extracellular matrix (ECM). The aim of the present chapter is to discuss MMPs' contribution to the evolution of cancer cells, their cellular origin, and their influence in the main processes that take place in the TME.

Poor clinical outcome in metastatic melanoma is associated with a microRNA-modulated immunosuppressive tumor microenvironment.

BACKGROUND: Interaction between malignant cells and immune cells that reside within the tumor microenvironment (TME) modulate different aspects of tumor development and progression. Recent works showed the importance of miRNA-containing extracellular vesicles in this crosstalk. METHODS: Interested in understanding the interplay between melanoma and immune-related TME cells, we characterized the TCGA's metastatic melanoma samples according to their tumor microenvironment profiles, HLA-I neoepitopes, transcriptome profile and classified them into three groups. Moreover, we combined our results with melanoma single-cell gene expression and public miRNA data to better characterize the regulatory network of circulating miRNAs and their targets related to immune evasion and microenvironment response. RESULTS: The group associated with a worse prognosis showed phenotypic characteristics that favor immune evasion, including a strong signature of suppressor cells and less stable neoantigen:HLA-I complexes. Conversely, the group with better prognosis was marked by enrichment in lymphocyte and MHC signatures. By analyzing publicly available melanoma single-cell RNA and microvesicle microRNAs sequencing data we identified circulating microRNAs potentially involved in the crosstalk between tumor and TME cells. Candidate miRNA/target gene pairs with previously reported roles in tumor progression and immune escape mechanisms were further investigated and demonstrated to impact patient's overall survival not only in melanoma but across different tumor types. CONCLUSION: Our results underscore the impact of tumor-microenvironment interactions on disease outcomes and reveal potential non-invasive biomarkers of prognosis and treatment response.

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches.

Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as "Warburg effect or aerobic glycolysis." As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

New Strategies in Rectal Cancer.

In recent years, our understanding of rectal cancer has improved, including how locally advanced disease responds to chemotherapy and radiation. This has led to new innovations and advances in the treatment of rectal cancer, which includes organ-preserving strategies for responsive disease, and minimally invasive approaces for the performance of total mesorectal excision/protectomyh for persistently advanced disease. This article discusses new strategies for rectal cancer therapy, including Watch and Wait, local excision, minimally invasive proctectomy, and transanal total mesorectal excision particularly in the setting of preoperative multimodality treatment.

"Down-to-Up" transanal NOTES Total mesorectal excision for rectal cancer: Preliminary series of 9 patients.

BACKGROUND: Applications for natural orifice translumenal endoscopic surgery (NOTES) to access the abdominal cavity have increased in recent years. Despite potential advantages of transanal and transcolonic NOTES for colorectal pathology, it has not been widely applied in the clinical setting. This study describes a series of nine patients for whom we performed transanal retrograde ("Down-to-Up") total mesorectal excision for rectal cancer. MATERIALS AND METHODS: Under IRB approval, informed consent was obtained from each patient with rectal adenocarcinoma. Rectosigmoidectomy with total mesorectal excision was performed using low rectal translumenal access to the mesorectal fascia and subsequent dissection in a retrograde fashion. This was achieved using either a single port device or flexible colonoscope with endoscopic instrumentation and laparoscopic assistance. This was followed by transanal extraction of the specimen and hand-sewn anastomosis. RESULTS: Mean operative time was 311 min. Mean hospital stay was 7.56 days. Complications occurred in two patients, and consisted of one anastomotic leakage with reoperation and one intraoperative conversion to open surgery because of impossibility to dissect the specimen. TME specimen integrity was adequate in six patients. CONCLUSION: This series suggests that a retrograde mesorectal dissection via a NOTES technique is feasible in patients with rectal adenocarcinoma. This technique may act as a complimentary part of operative treatment for rectal cancer alongside other minimally invasive strategies. Long-term follow up will be needed to assess oncological results.

As LER/DORT e os fatores psicossociais / The RSI/WMSD and the psychosocial factors / Las LER/ TME y los factores psicosociales

As Lesões por Esforço Repetitivo/Distúrbios Osteomusculares Relacionados ao Trabalho (LER/DORT) provocam sequelas irreversíveis aos trabalhadores, podendo acarretar invalidez permanente. Além das despesas previdenciárias e do custo organizacional, os trabalhadores enfrentam um intenso sofrimento psíquico, estresse e insatisfação com o trabalho. O objetivo deste artigo, apoiado em uma revisão da literatura, é analisar a complexidade dos fatores psicossociais associados às LER/DORT e discutir a fragmentação das pesquisas na área. As LER/DORT são um fenômeno multifatorial (fatores: biomecânicos, organizacionais e psicossocais) e multidimensional (dimensões: individual, grupal e social). Um desafio para a pesquisa é compreender como os fatores e as dimensões interagem entre si para produzir ou potencializar os sintomas e como impactam na reabilitação e prevenção. As pesquisas indicam que o fator biomecânico, por si só, não é suficiente para a compreensão do fenômeno

The Repetitive Strain Injury/ Work Related Musculoskeletal Disorders (RSI/WMSD) cause irreversible consequences to workers and can result in permanent disability. In addition to the pension costs and organizational costs, workers face an intense psychological distress, stress and job dissatisfaction. The purpose of this article, which is supported by a literature review, is to analyze the complexity of the psychosocial factors associated with RSI/WMSD and to discuss the fragmentation of research in this area. RSI/WMSD is a multifactorial phenomenon (the factors are: biomechanical, organizational and psychosocial) and multidimensional (the dimensions are: individual, group and social). A challenge for research is to understand how these factors and dimensions interact with each other to bring on the symptoms and how they impact upon rehabilitation and prevention. Research indicates that the biomechanical factor by itself is not sufficient for understanding the phenomenon

Las Lesiones por Esfuerzos Repetidos/ Trastornos Músculoesqueléticos Vinculados con el Trabajo (LER/TME) provocan secuelas irreversibles a los trabajadores, y pueden provocar discapacidad permanente. Además de los costos de la seguridad social y los costos de organización, los trabajadores enfrentan un sufrimiento psíquico intenso, el estrés y la insatisfacción con el trabajo. El objetivo de este artículo, basado en una revisión de la literatura, es analizar la complejidad de los factores psicosociales asociados a LER/TME y discutir la fragmentación de la investigación en el área. Las LER/TME son un fenómeno multifactorial envuelve factores biomecánicos, organizacionales y psicosocialesy multidimensional - de dimensiones individual, grupal y social. Un reto para la investigación es entender cómo los factores y las dimensiones interactúan entre sí para producir o potenciar los síntomas. La investigación indica que el factor biomecánico por sí solo no es suficiente para la comprensión del fenómeno

As LER/DORT e os fatores psicossociais / The RSI/WMSD and the psychosocial factors / Las LER/ TME y los factores psicosociales

As Lesões por Esforço Repetitivo/Distúrbios Osteomusculares Relacionados ao Trabalho (LER/DORT) provocam sequelas irreversíveis aos trabalhadores, podendo acarretar invalidez permanente. Além das despesas previdenciárias e do custo organizacional, os trabalhadores enfrentam um intenso sofrimento psíquico, estresse e insatisfação com o trabalho. O objetivo deste artigo, apoiado em uma revisão da literatura, é analisar a complexidade dos fatores psicossociais associados às LER/DORT e discutir a fragmentação das pesquisas na área. As LER/DORT são um fenômeno multifatorial (fatores: biomecânicos, organizacionais e psicossocais) e multidimensional (dimensões: individual, grupal e social). Um desafio para a pesquisa é compreender como os fatores e as dimensões interagem entre si para produzir ou potencializar os sintomas e como impactam na reabilitação e prevenção. As pesquisas indicam que o fator biomecânico, por si só, não é suficiente para a compreensão do fenômeno(AU)

The Repetitive Strain Injury/ Work Related Musculoskeletal Disorders (RSI/WMSD) cause irreversible consequences to workers and can result in permanent disability. In addition to the pension costs and organizational costs, workers face an intense psychological distress, stress and job dissatisfaction. The purpose of this article, which is supported by a literature review, is to analyze the complexity of the psychosocial factors associated with RSI/WMSD and to discuss the fragmentation of research in this area. RSI/WMSD is a multifactorial phenomenon (the factors are: biomechanical, organizational and psychosocial) and multidimensional (the dimensions are: individual, group and social). A challenge for research is to understand how these factors and dimensions interact with each other to bring on the symptoms and how they impact upon rehabilitation and prevention. Research indicates that the biomechanical factor by itself is not sufficient for understanding the phenomenon(AU)

Las Lesiones por Esfuerzos Repetidos/ Trastornos Músculoesqueléticos Vinculados con el Trabajo (LER/TME) provocan secuelas irreversibles a los trabajadores, y pueden provocar discapacidad permanente. Además de los costos de la seguridad social y los costos de organización, los trabajadores enfrentan un sufrimiento psíquico intenso, el estrés y la insatisfacción con el trabajo. El objetivo de este artículo, basado en una revisión de la literatura, es analizar la complejidad de los factores psicosociales asociados a LER/TME y discutir la fragmentación de la investigación en el área. Las LER/TME son un fenómeno multifactorial envuelve factores biomecánicos, organizacionales y psicosocialesy multidimensional - de dimensiones individual, grupal y social. Un reto para la investigación es entender cómo los factores y las dimensiones interactúan entre sí para producir o potenciar los síntomas. La investigación indica que el factor biomecánico por sí solo no es suficiente para la comprensión del fenómeno(AU)