The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence.

Head and neck squamous cell carcinoma (HNSCC) exhibits considerable variability in patient outcome. It has been reported that SOX2 plays a role in proliferation, tumor growth, drug resistance, and metastasis in a variety of cancer types. Additionally, SOX9 has been implicated in immune tolerance and treatment failures. SOX2 and SOX9 induce treatment failure by a molecular mechanism that has not yet been elucidated. This study explores the inverse association of SOX2/SOX9 and their distinct expression in tumors, influencing the tumor microenvironment and radiotherapy responses. Through public RNA sequencing data, human biopsy samples, and knockdown cellular models, we explored the effects of inverted SOX2 and SOX9 expression. We found that patients expressing SOX2LowSOX9High showed decreased survival compared to SOX2HighSOX9Low. A survival analysis of patients stratified by radiotherapy and human papillomavirus brings additional clinical relevance. We identified a gene set signature comprising newly discovered candidate genes resulting from inverted SOX2/SOX9 expression. Moreover, the TGF-ß pathway emerges as a significant predicted contributor to the overexpression of these candidate genes. In vitro findings reveal that silencing SOX2 enhances tumor radioresistance, while SOX9 silencing enhances radiosensitivity. These discoveries lay the groundwork for further studies on the therapeutic potential of transcription factors in optimizing HNSCC treatment.

Achyrocline satureioides as an adjuvant therapy for the management of mild viral respiratory infections in the context of COVID-19: Preliminary results of a randomized, placebo-controlled, and open-label clinical trial.

We evaluated the impact of an Achyrocline satureioides inflorescence infusion on the clinical outcomes of viral respiratory infections, including those caused by SARS-CoV-2, in a monocentric, randomized, open-label, placebo-controlled clinical trial. Patients with symptoms of viral respiratory infection, including suspected cases of COVID-19, were included and assigned to receive either A. satureioides (n = 57) or Malus domestica (n = 67) infusions twice a day for 14 days. All participants were included before the RT-PCR results, performed using a nasopharyngeal swab. The patients were further divided into subgroups according to real-time polymerase chain reaction results: SARS-CoV-2-positive and SARS-CoV-2-negative subgroups for statistical analyses. We assessed clinical outcomes, such as the latency to resolution of cough, dyspnea, fever, sore throat, chest pain, smell and taste dysfunctions, diarrhea, nausea, abdominal pain, and loss of appetite; hospitalization; and mortality with questionnaires and medical records. The subjects that received early A. satureioides infusion showed a significant reduction in the average number of days with respiratory and neurological symptoms compared with the control group (M. domestica infusion). We conclude that A. satureioides is a safe agent and, in combination with standard care, improves viral respiratory infection symptoms, especially those related to COVID-19.

MiRNAs that target amyloid precursor protein processing machinery in extracellular vesicles and particles derived from oral squamous cells carcinoma.

BACKGROUND: Considering that microRNAs (miRNAs), extracellular vesicles and particles (EVPs) and the amyloid precursor protein (APP) processing have been shown to be altered in oral squamous cells carcinoma (OSCC), it is possible that miRNAs that target APP processing pathways in EVPs are impacted in tumor cells. Our aim was to evaluate miRNAs that target APP itself or disintegrin and metalloproteinase domain 10 (ADAM10), which generate a trophic compound, sAPPα, in EVPs derived from OSCC cell lines, an aggressive and non-invasive, compared to normal keratinocytes. METHODS: We used two OSCC cell lines, an aggressive human oral squamous cell carcinoma cell line (SCC09) and a less aggressive cell line (CAL27) compared with a keratinocyte lineage (HaCaT). Cells were maintained in cell media, from which we isolated EVPs. EVPs were evaluated regarding their size and concentration using Nanotracking Analysis. We measured the levels of miRNAs which had as potential downstream target APP or ADAM10, specifically miR-20a-5p, miR-103a-3p, miR-424-5p, miR-92b-3p, miR-31-5p, and miR-93-5. RESULTS: There were no differences on size distributions and concentration of isolated EVPs. OSCC cell lines-derived EVPs miR-20a-5p, miR-92b-3p, and miR-93-5p were upregulated in comparison to HaCaT-derived EVPs; while miR-31-5p was reduced in EVPs obtained from CAL27 cells. CONCLUSION: Our results indicate changes in miRNAs that target APP machinery processing in EVPs derived from OSCC cell lines of different aggressiveness, which may be involved with abnormal miRNA expression in OSCC tissue and/or releasing tumor suppressor miRNA.

Asymmetric mitosis contributes to different migratory performance in sister cells.

In cancer, cell migration contributes to the spread of tumor cells resulting in metastasis. Heterogeneity in the migration capacity can produce individual cells with heightened capacity leading to invasion and metastasis. Our hypothesis is that cell migration characteristics can divide asymmetrically in mitosis, allowing a subset of cells to have a larger contribution to invasion and metastasis. Therefore, our aim is to elucidate whether sister cells have different migratory capacity and analyze if this difference is defined by mitosis. Through time-lapse videos, we analyzed migration speed, directionality, maximum displacement of each trajectory, and velocity as well as cell area and polarity and then compared the values between mother-daughter cells and between sister cells of three tumor cell lines (A172, MCF7, SCC25) and two normal cell lines (MRC5 and CHO·K1 cells). We observed that daughter cells had a different migratory phenotype compared to their mothers, and one single mitosis is enough for the sisters behave like nonrelated cells. However, mitosis did not influence cell area and polarity dynamics. These findings indicates that migration performance is not heritable, and that asymmetric cell division might have an important impact on cancer invasion and metastasis, by producing cells with different migratory capacity.

Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression.

Introduction: The tumor microenvironment (TME) of glioblastoma (GB) is characterized by an increased infiltration of immunosuppressive cells that attenuate the antitumor immune response. The participation of neutrophils in tumor progression is still controversial and a dual role in the TME has been proposed. In this study, we show that neutrophils are reprogrammed by the tumor to ultimately promote GB progression. Methods: Using in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME. Results and discussion: Neutrophils have shown to play an important role in tumor malignancy especially in advanced 3D tumor model and Balb/c nude mice experiments, implying a time- and neutrophil concentration-dependent modulation. Studying the tumor energetic metabolism indicated a mitochondria mismatch shaping the TME secretome. The given data suggests a cytokine milieu in patients with GB that favors the recruitment of neutrophils, sustaining an anti-inflammatory profile which is associated with poor prognosis. Besides, glioma-neutrophil crosstalk has sustained a tumor prolonged activation via NETs formation, indicating the role of NFκB signaling in tumor progression. Moreover, clinical samples have indicated that neutrophil-lymphocyte ratio (NLR), IL-1ß, and IL-10 are associated with poor outcomes in patients with GB. Conclusion: These results are relevant for understanding how tumor progression occurs and how immune cells can help in this process.

Cell contractility drives mechanical memory of oral squamous cell carcinoma.

Matrix stiffening is ubiquitous in solid tumors and can direct epithelial-mesenchymal transition (EMT) and cancer cell migration. Stiffened niche can even cause poorly invasive oral squamous cell carcinoma (OSCC) cell lines to acquire a less adherent, more migratory phenotype, but mechanisms and durability of this acquired "mechanical memory" are unclear. Here, we observed that contractility and its downstream signals could underlie memory acquisition; invasive SSC25 cells overexpress myosin II (vs. noninvasive Cal27 cells) consistent with OSCC. However, prolonged exposure of Cal27 cells to a stiff niche or contractile agonists up-regulated myosin and EMT markers and enabled them to migrate as fast as SCC25 cells, which persisted even when the niche softened and indicated "memory" of their prior niche. Stiffness-mediated mesenchymal phenotype acquisition required AKT signaling and was also observed in patient samples, whereas phenotype recall on soft substrates required focal adhesion kinase (FAK) activity. Phenotype durability was further observed in transcriptomic differences between preconditioned Cal27 cells cultured without or with FAK or AKT antagonists, and such transcriptional differences corresponded to discrepant patient outcomes. These data suggest that mechanical memory, mediated by contractility via distinct kinase signaling, may be necessary for OSCC to disseminate.

Applicability of autofluorescence and fluorescent probes in the trans-surgical of oral carcinomas: A systematic review.

Oral cancer represents an important health problem, as it is the sixth most common type of cancer in the world and is associated with high rates of morbidity and mortality. The treatment considered the gold standard for this type of tumor is surgical resection with negative margins, with a distance of at least 5 mm from the tumor. This procedure is strongly associated with local control and disease-specific survival, however, in many cases, large amounts of healthy tissue are removed, resulting in surgical defects, compromising various functions and directly affecting the individual's quality of life. From this perspective, this systematic review aimed to evaluate the use of autofluorescence and fluorescent probes as potential adjuvant techniques to facilitate the delineation of surgical margins for oral cancers. A comprehensive search was performed in Pubmed, Scopus, Web of Science, LIVIVO, Embase, ProQuest Open Access Dissertations & Theses, Open Access Theses and Dissertations, and DART Europe databases, where 1948 articles were found. After the different stages of critical evaluation, 15 articles were selected, eligible for the inclusion criteria. Of these, 7 articles used autofluorescence, 7 used fluorescent probes and 1 article used both methods. As for autofluorescence, the most used device was the VELScope, and indocyanine green was the most used probe. Compared to histopathology, autofluorescence did not obtain significant and/or superiors results. In contrast to fluorescent probes that, most articles showed a good performance of margins during surgical resection, making them a promising alternative. However, it is still necessary to carry out the analysis of more articles, with more significant samples and sensitivity and specificity data to qualify the results.

Effects of different protocols of defocused high-power laser on the viability and migration of myoblasts-a comparative in vitro study.

The aim of the present study was to analyze for the first time the effect of photobiomodulation therapy (PBMT) using defocused high-power laser (DHPL) in myoblast cell line C2C12 viability and migration and compare them with low-power laser therapy. Cells were divided into 9 groups: Sham irradiation 10% fetal bovine serum (FBS); Sham irradiation 5%FBS; low-power laser 0.1 W; DHPL 810 1 W; DHPL 810 2 W; DHPL 980 1 W; DHPL 980 2 W; DHPL dual 1 W; DHPL dual 2 W. To simulate stress conditions, all groups exposed to irradiation were maintained in DMEM 5% FBS. The impact of therapies on cell viability was assessed through sulforhodamine B assay and on cells migration through scratch assays and time-lapse. Myoblast viability was not modified by PBMT protocols. All PBMT protocols were able to accelerate the scratch closure after 6 and 18 h of the first irradiation (p < 0.001). Also, an increase in migration speed, with a more pronounced effect of DHPL laser using dual-wavelength protocol with 2 W was observed (p < 0.001). In conclusion, the diverse PBMT protocols used in this study accelerated the C2C12 myoblasts migration, with 2-W dual-wavelength outstanding as the most effective protocol tested. Benefits from treating muscle injuries with PBMT appear to be related to its capacity to induce cell migration without notable impact on cell viability.

SARS-CoV-2 RNA in dental biofilms: Supragingival and subgingival findings from inpatients in a COVID-19 intensive care unit.

BACKGROUND: Saliva, salivary glands, gingival crevicular fluid, and supragingival biofilms may harbor SARS-CoV-2 RNA. This observational study aimed to investigate the presence and load of SARS-CoV-2 RNA in supragingival, and subgingival biofilms obtained from intensive care unit (ICU) patients. METHODS: A convenience sample, composed of 52 COVID-19+ participants (48.6 ± 14.8 years, 26.9% females), were evaluated for pre-existing comorbidities, number of teeth, and periodontal data [visible plaque (VPI), bleeding on probing (BOP), periodontal probing depth (PPD), and attachment loss (AL)]. Supragingival and subgingival samples (SubDeep: four sites with the deepest PPD; SubRemain: remaining shallower sites) were analyzed by RT-qPCR with corresponding cycle quantification (Cq). Statistical analyses considered the individual (P = 5%). RESULTS: Twenty-six participants tested positive for dental biofilms (Biofilm+) with 96.2% of them being positive for subgingival samples. Pre-existing comorbidities, number of teeth examined, VPI, PPD, AL, and BOP were similar between Biofilm+ and Biofilm-. SubDeep PPD (3.72 ± 0.86), AL (4.34 ± 1.33), and % of BOP (66.0 ± 31.1) values were significantly greater compared to SubRemain values (2.84 ± 0.48, 3.37 ± 0.34, and 20.4 ± 24.1, respectively). Biofilm+ Cqs showed no association with the periodontal condition. Cqs from Nasopharynx/Oropharynx (Naso/Oro; n = 36) were similar between Biofilm+ and Biofilm- participants. Length of time since ICU intake, last Naso/Oro RT-qPCR readings, onset of COVID-19 symptoms, and biofilm samplings were greater for Biofilm-. CONCLUSIONS: ICU patients harbored SARS-CoV-2 RNA in supragingival and subgingival biofilms, irrespective of the periodontal condition, and systemic viral load. The high number of positive patients highlights the need to better understand this habit to provide adequate oral care.

Applicability of autofluorescence and fluorescent probes in early detection of oral potentially malignant disorders: A systematic review and meta-data analysis.

Oral potentially malignant disorders (OPMD) represent a group of lesions with increased risk for malignant transformation. The management of such injuries is based on surgical treatment or detailed follow-up throughout the patient's lifetime. This systematic review and meta-analysis investigated and critically evaluated the use of autofluorescence and fluorescent probes as potential techniques for the early detection of OPMD. A comprehensive search was performed on Pubmed, Scopus, Web of Science and LIVIVO databases. The gray literature was also consulted and included Google Scholar, Proquest and Open gray databases. 2715 articles were retrieved, and after the different stages of critical evaluation, were reduced to 25 articles that fully met the inclusion criteria. VELscope® was the most used equipment for autofluorescence, while aminolevulinic acid (5-ALA) was the main representative of the probes. The meta-analysis performed included 10 articles that used VELscope® as a method to detect oral disorders. A 95% confidence interval (CI) with a p value significance <0.05 was considered as a criterion for the statistical analysis. The combined sensitivity was 74% (CI95 60-76%, p = 0.0001) and the specificity was 57% (CI95 52-60%, p = 0.0000). The inclusion of these adjunct methods in clinical practice is very promising, since they are able to help both the clinician and the specialist in the early detection of potentially malignant oral disorders, favoring a better prognosis. However, it is still necessary to carry out further studies, with the aim of establishing a protocol for use and qualification of results.

The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma.

AIMS: To investigate the role of tumor acidification in cell behavior, migration, and treatment resistance of oral squamous cell carcinoma (OSCC). MAIN METHODS: The SCC4 and SCC25 cell lines were exposed to acidified (pH 6.8) cell culture medium for 7 days. Alternatively, a long-term acidosis was induced for 21 days. In addition, to mimic dynamic pH fluctuation of the tumor microenvironment, cells were reconditioned to neutral pH after experimental acidosis. This study assessed cell proliferation and viability by sulforhodamine B and flow cytometry. Individual and collective cell migration was analyzed by wound healing, time lapse, and transwell assays. Modifications of cell phenotype, EMT induction and stemness potential were investigated by qRT-PCR, western blot, and immunofluorescence. Finally, resistance to chemo- and radiotherapy of OSCC when exposed to acidified environmental conditions (pH 6.8) was determined. KEY FINDINGS: The exposure to an acidic microenvironment caused an initial reduction of OSCC cells viability, followed by an adaptation process. Acidic adapted cells acquired a mesenchymal-like phenotype along with increased migration and motility indexes. Moreover, tumoral extracellular acidity was capable to induce cellular stemness and to increase chemo- and radioresistance of oral cancer cells. SIGNIFICANCE: In summary, the results showed that the acidic microenvironment leads to a more aggressive and treatment resistant OSCC cell population.

Salivary biomarkers and neuropsychological outcomes: A non-invasive approach to investigate pollutants-associated neurotoxicity and its effects on cognition in vulnerable populations.

The occurrence of neurotoxicity caused by xenobiotics such as pesticides (dichlorodiphenyltrichloroethane, organophosphates, pyrethroids, etc.) or metals (mercury, lead, aluminum, arsenic, etc.) is a growing concern around the world, particularly in vulnerable populations with difficulties on both detection and symptoms treatment, due to low economic status, remote access, poor infrastructure, and low educational level, among others features. Despite the numerous molecular markers and questionnaires/clinical evaluations, studying neurotoxicity and its effects on cognition in these populations faces problems with samples collection and processing, and information accuracy. Assessing cognitive changes caused by neurotoxicity, especially those that are subtle in the initial stages, is fundamentally challenging. Finding accurate, non-invasive, and low-cost strategies to detect the first signals of brain injury has the potential to support an accelerated development of the research with these populations. Saliva emerges as an ideal pool of biomarkers (with interleukins and neural damage-related proteins, among others) and potential alternative diagnostic fluid to molecularly investigate neurotoxicity. As a source of numerous neurological biomarkers, saliva has several advantages compared to blood, such as easier storage, requires less manipulation, and the procedure is cheaper, safer and well accepted by patients compared with drawing blood. Regarding cognitive dysfunction, neuropsychological batteries represent, with their friendly interface, a feasible and accurate method to evaluate the eventual cognitive deficits associated with neurotoxicity in people from diverse cultural and educational backgrounds. The association of these two tools, saliva and neuropsychological batteries, to cover the molecular and cognitive aspects of neurotoxicity in vulnerable populations, could potentially increase the prevalence of early intervention and successful treatment.

Dental biofilm of symptomatic COVID-19 patients harbours SARS-CoV-2.

AIMS: SARS-CoV-2 RNA has been recovered from different sites in the human body, including the mouth. The present study aimed to investigate the presence of SARS-CoV-2 RNA in the dental biofilm of symptomatic patients who tested positive in nasopharyngeal and oropharyngeal (NASO/ORO) samples. MATERIALS & METHODS: An observational clinical study of individuals with flu-like symptoms was conducted between July and September 2020. Dental biofilm (BIO) samples were collected and analysed using real-time quantitative polymerase chain reaction (RT-qPCR) to determine the virus's presence. RESULTS: Seventy participants (40 ± 9.8 years of age, 71.4% female) tested positive for SARS-CoV-2 RNA in NASO/ORO samples and were included in the study. Among them, 13 tested positive in BIO samples (18.6%; 95% CI: [9.5, 27.7]). The median and interquartile range of cycle quantification (Cq) for NASO/ORO and BIO samples were 15.9 [6.9] and 35.9 [4.0] (p = .001), respectively. BIO-positive participants showed a higher virus load in NASO/ORO samples (p = .012) than those testing negative (Cq = 20.4 [6.1]). CONCLUSIONS: Dental biofilms from symptomatic COVID-19 patients harbour SARS-CoV-2 RNA and might be a potential reservoir with an essential role in COVID-19 transmission.

Tumor microenvironment and Oral Squamous Cell Carcinoma: A crosstalk between the inflammatory state and tumor cell migration.

OBJECTIVES: To analyze the inflammatory millieu in oral squamous cell carcinoma (OSCC) tumors and the influence of macrophages related-cytokines on the tumor cell migration. MATERIALS AND METHODS: Inflammatory protein profile and macrophage population (M2/M1 ratio) of human OSCC fragments were analyzed by proteomic analysis and flow cytometry assay respectively. To evaluate the effects of inflammation on OSCC behavior, we analyzed the role of polarized macrophages and cytokines (IL-6, IL-1ß and TNF-α) on OSCC cell lines (SCC25 and Cal27) responsiveness by western blotting (cell signaling) and time-lapse (cell migration). Also, it was addressed the crosstalk of IL-6-STAT3 axis with cell migration signaling using a STAT3 inhibitor (Stattic®) and a pull down assay for the RhoGTPase Rac1 activity. RESULTS: It was observed a ~2 fold predominance of M2 over M1 macrophages and a pro-inflammatory state in OSCC fragments. The M2 conditioned media increased migration speed and directionality of highly invasive OSCC cells (SCC25). OSCC cell lines were responsive to cytokine stimuli (IL6, IL-1ß and TNF-α), but only IL-6 increased migration properties of OSCC cells. This effect was dependent on STAT3-phosphorylation levels, which interfered with Rac1 activation levels. CONCLUSION: Our results suggest that the inflammatory milieu might favor invasion and metastasis of OSCC by the direct effect of macrophage-related cytokines on tumor migration.

The anti-tumor effects of imidazolium salts on oral squamous cell carcinoma.

BACKGROUND: Imidazolium salts (IS), ionic derivatives of neutral imidazoles, have properties that can be adjusted by structural modifications to their cations and anions, which makes this particular class of compounds a promising option for developing biologically active compounds. The anti-tumor effects of the IS 1-n-butyl-3-methylimidazolium chloride (C4 MImCl), 1-n-decyl-3-methylimidazolium chloride (C10 MImCl), 1-n-hexadecyl-3-methylimidazolium chloride (C16 MImCl), 1-n-hexadecyl-2,3-dimethylimidazolium chloride (C16 M2 ImCl), 1-n-octadecyl-3-methylimidazolium chloride (C18 MImCl), 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16 MImMeS), and 1-n-hexadecyl-2,3- dimethylimidazolium methanesulfonate (C16 M2 ImMeS) on oral squamous cell carcinoma (OSCC) have been studied here. METHODS: Oral squamous cell carcinoma cells (CAL27) were incubated with increasing IS doses and then submitted to proliferation (2D), cell death (2D) and spheroid assay (3D). RESULTS: The IS anti-tumor effect was dependent on both its N-alkyl chain length and anion, whereby C16 MImCl proved to be more effective in combination for inhibiting cell proliferation and cell-cell adhesion, outperforming the methylated C16 M2 ImCl derivative and, most importantly, the gold standard-cisplatin. In addition, C16 MImCl had little effect on keratinocytes and more pronounced effects on more aggressive tumor cells. It also exhibited similar effects on inducing cell death when compared to Cisplatin. This compound spread to a greater area of the tumor sphere and produced an enhanced number of apoptotic and necrotic cells in the tumor cell line, demonstrating only a small rise in the healthy cells. CONCLUSION: These data indicate that the effect of C16 MlmCl on OSCC is promising, as it is selective for cancer cells.

Use of autofluorescence and fluorescent probes as a potential diagnostic tool for oral cancer: A systematic review.

INTRODUCTION: The prognosis of patients with Oral squamous cell carcinoma (OSCC) are directly related to the stage of development of the tumor at the time of diagnosis, but it is estimated an average delay in diagnosis of 2-5 months. New non-invasive techniques for the early diagnosis of OSCC are being developed, such as methodologies to detect spectral changes of tumor cells. We conducted a systematic review to analyze the potential use of autofluorescence and/or fluorescent probes for OSCC diagnosis. MATERIAL AND METHODS: Four databases (PubMed, Scopus, Embase and Web of Science) were used as research sources. Protocol was registered with PROSPERO. It was included studies that evaluated tissue autofluorescence and/or used fluorescent probes as a method of diagnosing and/or treatment of oral cancer in humans. RESULTS: Forty-five studies were selected for this systematic review, of which 28 dealt only with autofluorescence, 18 on fluorescent probes and 1 evaluated both methods. The VELscope® was the most used device for autofluorescence, exhibiting sensitivity (33%-100%) and specificity (12%-88.6%). 5-Aminolevulinic acid (5-ALA) was the most used fluorescent probe, exhibiting high sensitivity (90%-100%) and specificity (51.3%-96%). Hypericin, rhodamine 6 G, rhodamine 610, porphyrin and γ-glutamyl hydroxymethyl rhodamine green have also been reported. CONCLUSION: Thus, the autofluorescence and fluorescent probes can provide an accurate diagnosis of oral cancer, assisting the dentist during daily clinical activity, but it is not yet possible to suggest that this method may replace histopathological examination.

Correction to: Periodontal Disease Impairs Muscle Recovery by Modulating the Recruitment of Leukocytes.

The original version of this article contained mistakes, and the authors would like to correct them.

Flavonoids as anticancer therapies: A systematic review of clinical trials.

Flavonoids have been proposed as potential chemotherapeutic agents because they are toxic against cancer cells but not harmful to healthy cells. This systematic review analyzed flavonoid effectiveness in human cancer chemotherapy. Overall, 22 phase II and 1 phase III clinical trials (PubMed, Scopus, and Web of Science) that used flavonoids as a single agent or combined with other therapeutics against hematopoietic/lymphoid or solid cancer published by January 2019 were selected for analysis. Flavopiridol was the most commonly used flavonoid (at a dose of 50-mg/m2 IV) for all tumor types. Aside from the relatively low rate of complete response (CR) or partial response (PR) with any administration protocol, flavonoids showed higher positive outcomes for hematopoietic and lymphoid tissues (140 patients with CR and 88 with PR among 615 patients in 11 trials) than for solid tumors (4 patients with CR and 21 with PR among 525 patients in 12 trials). However, because of the high variety in administration schedule, more studies are needed to further understand how flavonoids can promote positive outcomes for cancer patients.