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Simple Summary: Colorectal cancer (CRC) stands as the third most common cancer globally and the second leading cause of cancer-related deaths, imposing a substantial health burden. Recent studies highlight a concerning rise in CRC rates among individuals below 50 years old, prompting the American Cancer Society (ACS) to recommend screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat's Keynote Conference stresses the urgent need for updated screening strategies to tackle suboptimal adherence rates and effectively manage the increasing burden of CRC. Lowering the adenoma detection screening age could aid in early identification of adenomas in asymptomatic younger patients, potentially reshaping disease epidemiology. Current screening options encompass stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. Moreover, blood-based tests are emerging as promising tools for early CRC detection, utilizing innovative techniques and AI algorithms. Medicare mandates specific criteria for national coverage of blood-based tests. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. Despite breakthroughs, accessibility and affordability challenges persist. Adapting healthcare systems to accommodate changing CRC epidemiology is imperative. Lowering the screening age and integrating blood-based tests hold the potential to alleviate the CRC-related burden amidst evolving epidemiology. Colorectal cancer (CRC) currently ranks as the third most common cancer and the second leading cause of cancer-related deaths worldwide, posing a significant global health burden to the population. Recent studies have reported the emergence of a new clinical picture of the disease, with a notable increase in CRC rates in younger populations of <50 years of age. The American Cancer Society (ACS) now recommends CRC screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat's Keynote Conference highlights the critical need for updated screening strategies, with an emphasis on addressing the suboptimal adherence rates and the effective management of the growing burden of CRC. Lowering the adenoma detection screening age can facilitate early identification of adenomas in younger asymptomatic patients, altering the epidemiologic landscape. However, its implications may not be as profound unless a drastic shift in the age distribution of CRC is observed. Currently, various screening options are available in practice, including stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. In addition to existing screening methods, blood-based tests are now emerging as promising tools for early CRC detection. These tests leverage innovative techniques along with AI and machine learning algorithms, aiding in tumor detection at a significantly earlier stage, which was not possible before. Medicare mandates specific criteria for national coverage of blood-based tests, including sensitivity ≥ 74%, specificity ≥ 90%, FDA approval, and inclusion in professional society guidelines. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. The development of multicancer early detection tests like GRAIL demonstrates a tremendous potential for detecting various solid tumors and hematologic malignancies. Despite these breakthroughs, the question of accessibility and affordability still stands. The ever-evolving landscape of CRC screening reflects the strength of the scientific field in light of an altered disease epidemiology. Lowering screening age along with the integration of blood-based tests with existing screening methods holds great potential in reducing the CRC-related burden. At the same time, it is increasingly important to address the challenges of adaptation of the healthcare system to this change in the epidemiologic paradigm. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastomas are the most aggressive brain tumors, and affected patients still only have an extremely poor prognosis with today's therapeutic options. Further developments are still necessary, particularly in therapeutic approaches. Orlistat can act as an antitumor agent as it inhibits fatty acid synthase, decreases tumor cell proliferation, and stimulates tumor cell apoptosis. Investigations conducted on breast, pancreatic, hepatic, and colorectal tumors showed that FASN—fatty acid synthase, a protein that catalyzes the de novo synthesis of long-chain fatty acids—is strongly upregulated. Using an animal model, we tested whether the drug's effects could be demonstrated visually, quantitatively, and by texture analysis based on MR studies. Histology and immunochemistry were used as references. The key results of the present study are as follows: Firstly, a significant difference was found between orlistat-treated and untreated tumors in MRI studies based on morphology and texture analyses. Secondly, the expression of FASN was reduced in the orlistat group, which, however, did not result in a higher apoptosis rate in the treatment group. Our findings suggest that some effects of orlistat on tumor cell proliferation must have taken place during therapy. Further studies should investigate the effects of FASN inhibition when combined with targeted therapies. Background: This study aimed to investigate the effects of tetrahydrolipstatin (orlistat) on heterotopic glioblastoma in mice by applying MRI and correlating the results with histopathology and immunochemistry. Methods: Human glioblastoma cells were injected subcutaneously into the groins of immunodeficient mice. After tumor growth of >150 mm3, the animals were assigned into a treatment group (n = 6), which received daily intraperitoneal injections of orlistat, and a control group (n = 7). MRI was performed at the time of randomization and before euthanizing the animals. Tumor volumes were calculated, and signal intensities were analyzed. The internal tumor structure was evaluated visually and with texture analysis. Western blotting and protein expression analysis were performed. Results: At histology, all tumors showed high mitotic and proliferative activity (Ki67 ≥ 10%). Reduced fatty acid synthetase expression was measured in the orlistat group (p < 0.05). Based on the results of morphologic MRI-based analysis, tumor growth remained concentric in the control group and changed to eccentric in the treatment group (p < 0.05). The largest area under the receiver operating curve of the predictors derived from the texture analysis of T2w images was for wavelet transform parameters WavEnHL_s3 and WavEnLH_s4 at 0.96 and 1.00, respectively. Conclusions: Orlistat showed effects on heterotopically implanted glioblastoma multiforme in MRI studies of mice based on morphologic and texture analysis. [ABSTRACT FROM AUTHOR]

Simple Summary: Penile cancer is a rare but aggressive cancer. After it metastasizes, the median survival time is less than 12 months. The overall response rate to common first-line combination chemotherapy treatments is approximately 50%. There is an urgent need in advanced-penile-cancer treatment to find novel therapies that would generate better response rates than standard chemotherapy thus far and have less toxicity. Partially due to its rarity, there are few animal models and cell lines of penile cancer. We report on the generation of seven penile cancer animal models that were created by directly implanting human tumor tissue into immunocompromised mice. Metastatic penile squamous cell carcinoma (PSCC) has only a 50% response rate to first-line combination chemotherapies and there are currently no targeted-therapy approaches. Therefore, we have an urgent need in advanced-PSCC treatment to find novel therapies. Approximately half of all PSCC cases are positive for high-risk human papillomavirus (HR-HPV). Our objective was to generate HPV-positive (HPV+) and HPV-negative (HPV−) patient-derived xenograft (PDX) models and to determine the biological differences between HPV+ and HPV− disease. We generated four HPV+ and three HPV− PSCC PDX animal models by directly implanting resected patient tumor tissue into immunocompromised mice. PDX tumor tissue was found to be similar to patient tumor tissue (donor tissue) by histology and short tandem repeat fingerprinting. DNA mutations were mostly preserved in PDX tissues and similar APOBEC (apolipoprotein B mRNA editing catalytic polypeptide) mutational fractions in donor tissue and PDX tissues were noted. A higher APOBEC mutational fraction was found in HPV+ versus HPV− PDX tissues (p = 0.044), and significant transcriptomic and proteomic expression differences based on HPV status included p16 (CDKN2A), RRM2, and CDC25C. These models will allow for the direct testing of targeted therapies in PSCC and determine their response in correlation to HPV status. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) has a poor prognosis, as it has often grown into an advanced stage when diagnosed. Genetic testing is crucial for establishing a treatment plan. In this study, next-generation sequencing (NGS) was performed to discover that LRP1B mutation was associated with a poor prognosis in GC. Through layer-by-layer research, it was found that LRP1B expression in GC was accompanied by a higher-level infiltration of CD4+ T, CD8+ T cells, and CD86/CD163. It is concluded that LRP1B expression can stimulate tumor immune cell infiltration, thus bringing clinical benefits to GC patients. Background: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. Methods: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II–III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. Results: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28–5.14, p = 0.008). The Kaplan–Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10–0.93, p = 0.042). Conclusions: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: Many cancers, especially those most common in adolescents and young adults, are initiated by a single change in the DNA sequence of a gene. The particular change creates a new gene through the fusing of the beginning of one gene to the end of a second gene. This new fusion gene will be expressed as a fusion protein that combines the functions of the two parent genes, but in new ways. Because many of the cancers that are driven by these fusion genes are rare, study of the precise function of the fusion proteins can be difficult. This article reports on the study of a particular fusion protein that drives the rare, but deadly, pediatric cancer clear cell sarcoma. The fusion protein was expressed in mice, leading to the formation of similar tumors to those it causes in humans. This permitted the study of fusion protein function in these tumors. Clear cell sarcoma (CCS) is a rare, aggressive malignancy that most frequently arises in the soft tissues of the extremities. It is defined and driven by expression of one member of a family of related translocation-generated fusion oncogenes, the most common of which is EWSR1::ATF1. The EWSR1::ATF1 fusion oncoprotein reprograms transcription. However, the binding distribution of EWSR1::ATF1 across the genome and its target genes remain unclear. Here, we interrogated the genomic distribution of V5-tagged EWSR1::ATF1 in tumors it had induced upon expression in mice that also recapitulated the transcriptome of human CCS. ChIP-sequencing of V5-EWSR1::ATF1 identified previously unreported motifs including the AP1 motif and motif comprised of TGA repeats that resemble GGAA-repeating microsatellites bound by EWSR1::FLI1 in Ewing sarcoma. ChIP-sequencing of H3K27ac identified super enhancers in the mouse model and human contexts of CCS, which showed a shared super enhancer structure that associates with activated genes. [ABSTRACT FROM AUTHOR]

Simple Summary: Fast-track pathways to detect colorectal cancer have been implemented in several European countries, using different entry criteria. We analyzed 2539 fast-track colonoscopies including referrals in detail, in order to calculate the predictive values and odds ratios of different red flags with respect to the risk for colorectal cancer. Interestingly, we observed that a number of red flags were not at all associated with an increased risk for colorectal cancer. On the other hand, the variable with the highest predictive value: a positive fecal occult blood test (FOBT), is not always part of colorectal cancer fast tracks. These findings are important when selecting patients for fast-track colonoscopy. We propose that the entry criteria should be limited to the following signs/symptoms: patients > 40 years with one or more of the following signs/symptoms: positive FOBT, abnormal radiology, abnormal rectal examination, visible blood in stool, in the absence of hemorrhoids and unexplained iron-deficiency anemia. Background: Fast-track pathways for diagnosing colorectal cancer (CRC) have been implemented in several European countries. In Sweden, a substantial number of CRC are diagnosed via the Swedish Standardized Course of Care for colorectal cancer (SCC-CRC). We evaluated the SCC-CRC in terms of CRC yield, and predictive values and odds ratios (OR) for the entry criteria. Methods: We retrospectively analyzed all 2539 patients referred for SCC-CRC colonoscopy between September 2016 and December 2020. Entry criteria and colonoscopy outcomes were analyzed. Results: CRC yield was 16.4%. Highest positive predictive values (PPVs) were seen for abnormal radiology (PPV 30.5%, OR 4.7 (95% CI 3.4–6.4) p < 0.001), abnormal rectal examination (PPV 28%, OR 3.6 (95% CI 2.7–4.8) p < 0.001), and anemia (PPV 24.8%, OR 2.2 (95% CI 1.5–3.1) p < 0.001). Some entry criteria showed no significant risk increase, i.e., visible blood in stool/rectal bleeding, change in bowel habits, and the combination of changed bowel habits plus anemia. A positive fecal immunochemical test (FIT), although not part of the SCC-CRC, showed the highest OR: 9.9 (95% CI 4.5–21.7) p < 0.001) and PPV of 18.8%. Conclusions: CRC yield from the SCC-CRC is slightly higher compared to other European fast tracks. A number of entry criteria showed no benefit towards assessing CRC risk. FIT testing should be included in CRC fast tracks to increase diagnostic efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian tumors mobilize a heterogenous population of myeloid cells. While these cells initially contribute to anti-tumor immunity, as cancer progresses, they switch from immunostimulatory to immunosuppressive. Ovarian cancer is most frequently restricted to the peritoneal cavity, negating the need for systemic delivery of therapeutics. With a goal of targeting and activating myeloid cells in the tumor microenvironment, this study sought to determine which nanoparticle characteristics enhance uptake by myeloid cells in vitro and in vivo using an animal model of ovarian cancer. Lipids coating a mesoporous silica core were optimized for surface charge, formulation, and inclusion of immunogenic monophosphoryl lipid A. Benefits of a mesoporous core include opportunities for loading with additional therapeutics, such as antigens to direct immune responses or other therapeutic payloads that facilitate anti-cancer immune responses. Immunogenic lipid-coated mesoporous silica nanoparticles (ILM) present pathogen-associated molecular patterns (PAMPs) on the nanoparticle surface to engage pathogen-associated receptors on immune cells. The mesoporous core is capable of loading additional immunogens, antigens or drugs. In this study, the impact of lipid composition, surface potential and intercalation of lipophilic monophosphoryl lipid A (MPL-A) in the lipid coat on nanoparticle properties and cellular interactions is presented. Loading and retention of the model antigen ovalbumin into the mesoporous silica core were found to be similar for all nanoparticle formulations, with presentation of ova peptide (SIINFEKL) by major histocompatibility complex (MHC) evaluated to facilitate the selection of an anionic nanoparticle composition. ILM were able to induce lysosomal tubulation and streaming of lysosomes towards the cell surface in dendritic cells, leading to an enhanced surface presentation of MHC. Myeloid cells robustly internalized all ILM formulations; however, non-myeloid cells selectively internalized cationic ILM in vitro in the presence of 20% serum. Interestingly, ILM administration to the peritoneal cavity of mice with disseminated ovarian cancer resulted in selective accumulation of ILM in tumor-associated tissues (>80%), regardless of nanoparticle surface charge or the presence of MPL-A. Immunofluorescence analysis of the omental tumor showed that ILMs, regardless of surface charge, were localized within clusters of CD11b+ myeloid cells 24 h post administration. Selective uptake of ILMs by myeloid cells in vivo indicates that these cells outcompete other cell populations in the ovarian tumor microenvironment, making them a strong target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: This study found that high levels of STMN1 expression in neuroblastoma indicate malignant potential, proliferation potency, and poor prognosis. STMN1 knockdown inhibited neuroblastoma cell growth regardless of MYCN overexpression. The study suggests that assessing STMN1 expression could be a powerful indicator of prognosis and a promising therapeutic candidate against refractory neuroblastoma. Background. Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. Methods. Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. Result. High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. Conclusion. Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondrial dysfunction and respiratory function changes have been associated with the initiation and progression of cancer. However, no study has comprehensively investigated the relationship between these mitochondrial-related factors and prognosis in a large number of patients with oral squamous cell carcinoma (OSCC). Here, we retrospectively investigated the expression of mitochondrial tumor-suppressor and DNA-repair proteins (PGC-1α, TFAM, OGG1, MTUS1, and SIRT3) in patients with OSCC and evaluated the relationship between their expression and prognosis. The expression levels of the five proteins were associated with patient outcomes. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Particularly, based on the results of multivariate analysis, negative expression of PGC-1α is related to a poor prognosis of OSCC. Low PGC-1α expression and vascular invasion may be clinically effective predictors of oral cancer prognosis. Mitochondrial dysfunction and respiratory function changes have been consistently associated with the initiation and progression of cancer. The purpose of this study was to retrospectively investigate the expression of mitochondrial tumor-suppressor and DNA-repair proteins in patients with oral squamous cell carcinoma (OSCC) and to evaluate the relationship between their expression and prognosis. We enrolled 197 patients with OSCC who underwent surgical resection between August 2013 and October 2018. Clinical, pathological, and epidemiological data were retrospectively collected from hospital records. The expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A, mitochondrial tumor suppressor gene 1, silent information regulator 3, and 8-hydroxyguanine DNA glycosylase was investigated using immunochemistry. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Multivariate analysis revealed that the expression of PGC-1α (hazard ratio, 4.684) and vascular invasion (hazard ratio, 5.690) can predict the DSS rate (p < 0.001). Low PGC-1α expression and vascular invasion are potential clinically effective predictors of the prognosis of OSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, the cases of colorectal cancers has been rising in younger age (<50) individuals. Although current guidelines recommend colorectal cancer screening should be initiated at age 45 instead of 50, the optimal approach of colorectal cancer screening is not clear. This article investigates the efficacy of fecal immunochemical test (FIT), which detects occult blood in stool, in predicting advanced colorectal polyps and tumors among people aged 40–49. The findings suggest FIT is useful to identify such people with high risk to have advanced colorectal lesions. Hence, FIT may be considered as the first-line screening tool for these people, and further comparative study between FIT and colonoscopy will be of great value. Background: The incidence of early-onset colorectal cancer (CRC) is increasing. Many guidelines recommend initiating screening at 45 years. This study investigated the detection rate of advanced colorectal neoplasm (ACRN) by using fecal immunochemical tests (FITs) in individuals aged 40–49 years. Methods: PubMed, Embase, and Cochrane Library databases were searched from inception to May 2022. The primary outcomes were the detection rates and positive predictive values of FITs for ACRN and CRC in people aged 40–49 (younger age group) and ≥50 years (average risk group). Results: Ten studies with 664,159 FITs were included. The FIT positivity rate was 4.9% and 7.3% for the younger age and average risk groups, respectively. Younger individuals with positive FIT results had significantly higher risks of ACRN (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.79–3.73) or CRC (OR 2.86, 95% CI 1.59–5.13) than did individuals in the average-risk group, regardless of FIT results. Individuals aged 45–49 years with positive FIT results had a similar risk of ACRN (OR 0.80, 95% CI 0.49–1.29) to that of people aged 50–59 years with positive FIT results, although significant heterogeneity was observed. The positive predictive values of the FIT were 10–28.1% for ACRN and 2.7–6.8% for CRC in the younger age group. Conclusion: The detection rate of ACRN and CRC based on FITs in individuals aged 40–49 years is acceptable, and the yield of ACRN might be similar between individuals aged 45–49 and 50–59 years. Further prospective cohort and cost-effective analysis are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Considering thermal liquid biopsy (TLB) as a potential secondary test after fecal immunochemical test positivity (FIT+), the aim of this work was to study possible interferences of colonoscopy bowel preparation on TLB outcome on a retrospective study. TLB parameters together with fluorescence spectra and other serum indicators (albumin and C-reactive protein) confirmed the statistically significant differences between normal colonoscopy patients with and without bowel preparation, revealing the distorting effect of bowel preparation on serum composition and discrimination of disease status. The diagnostic capability of other liquid-biopsy-based methods might also be compromised. Blood extraction after bowel preparation for colonoscopy should be avoided. (1) Background: About 50% of prescribed colonoscopies report no pathological findings. A secondary screening test after fecal immunochemical test positivity (FIT+) would be required. Considering thermal liquid biopsy (TLB) as a potential secondary test, the aim of this work was to study possible interferences of colonoscopy bowel preparation on TLB outcome on a retrospective study; (2) Methods: Three groups were studied: 1/514 FIT(+) patients enrolled in a colorectal screening program (CN and CP with normal and pathological colonoscopy, respectively), with blood samples obtained just before colonoscopy and after bowel preparation; 2/55 patients from the CN group with blood sample redrawn after only standard 8–10 h fasting and no bowel preparation (CNR); and 3/55 blood donors from the biobank considered as a healthy control group; (3) Results: The results showed that from the 514 patients undergoing colonoscopy, 247 had CN and 267 had CP. TLB parameters in these two groups were similar but different from those of the blood donors. The resampled patients (with normal colonoscopy and no bowel preparation) had similar TLB parameters to those of the blood donors. TLB parameters together with fluorescence spectra and other serum indicators (albumin and C-reactive protein) confirmed the statistically significant differences between normal colonoscopy patients with and without bowel preparation; (4) Conclusions: Bowel preparation seemed to alter serum protein levels and altered TLB parameters (different from a healthy subject). The diagnostic capability of other liquid-biopsy-based methods might also be compromised. Blood extraction after bowel preparation for colonoscopy should be avoided. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) screening is one of the most effective measures to prevent CRC resulting in a decrease in CRC mortality. Mortality reduction (MR) from CRC screening was estimated based on large-scale randomized control trials (RCTs) as well as in model studies, as there is a wide range on CRC-specific MR and a lack of estimates of all-cause MR. We found that biennial FIT, gFOBT, single/5-yearly FS, and 10-yearly colonoscopy screenings reduced CRC-specific mortality significantly, and 10-yearly colonoscopy is the most effective with a mortality reduction of 73%. The effectiveness of screening increases at younger screening initiation ages and higher adherences. Our findings also suggest that adherence is an important factor in CRC-specific mortality and is an explanation for discrepancy in thus far published pooled estimates. (1) Background: The aim of this study was to pool and compare all-cause and colorectal cancer (CRC) specific mortality reduction of CRC screening in randomized control trials (RCTs) and simulation models, and to determine factors that influence screening effectiveness. (2) Methods: PubMed, Embase, Web of Science and Cochrane library were searched for eligible studies. Multi-use simulation models or RCTs that compared the mortality of CRC screening with no screening in general population were included. CRC-specific and all-cause mortality rate ratios and 95% confidence intervals were calculated by a bivariate random model. (3) Results: 10 RCTs and 47 model studies were retrieved. The pooled CRC-specific mortality rate ratios in RCTs were 0.88 (0.80, 0.96) and 0.76 (0.68, 0.84) for guaiac-based fecal occult blood tests (gFOBT) and single flexible sigmoidoscopy (FS) screening, respectively. For the model studies, the rate ratios were 0.45 (0.39, 0.51) for biennial fecal immunochemical tests (FIT), 0.31 (0.28, 0.34) for biennial gFOBT, 0.61 (0.53, 0.72) for single FS, 0.27 (0.21, 0.35) for 10-yearly colonoscopy, and 0.35 (0.29, 0.42) for 5-yearly FS. The CRC-specific mortality reduction of gFOBT increased with higher adherence in both studies (RCT: 0.78 (0.68, 0.89) vs. 0.92 (0.87, 0.98), model: 0.30 (0.28, 0.33) vs. 0.92 (0.51, 1.63)). Model studies showed a 0.62–1.1% all-cause mortality reduction with single FS screening. (4) Conclusions: Based on RCTs and model studies, biennial FIT/gFOBT, single and 5-yearly FS, and 10-yearly colonoscopy screening significantly reduces CRC-specific mortality. The model estimates are much higher than in RCTs, because the simulated biennial gFOBT assumes higher adherence. The effectiveness of screening increases at younger screening initiation ages and higher adherences. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to correlate primary staging prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) parameters with either prostate final histopathology (pT) or PSMA-immunochemistry (IHC) features in a cohort of high-risk prostate cancer (PCa) patients. Our study demonstrated a correlation between higher SUVmax and IHC-PSMA expression. Moreover, we found correlations between higher total lesion PSMA (PSMA-TL) values and the risk of lymphovascular invasion (LVI), and between PSMA tumor volume (PSMA-TV) and the presence of a cribriform pattern. Our results, if validated by further studies, may help to better identify unfavorable features showed by PSMA-PET/CT in primary staging, thus improving patients' management. PSMA-PET/CT is a suitable replacement for conventional imaging in the primary staging of PCa. The aim of this retrospective study was to assess the correlation between parameters discovered by PSMA PET/CT in primary staging and either prostate histopathology (pT) findings or PSMA-IHC expression in a cohort of biopsy-proven high-risk PCa candidates for surgery. Clinical information (age, iPSA-value, and grading group) and PSMA-PET/CT parameters (SUVmax, PSMA tumor volume [PSMA-TV], and total lesion [PSMA-TL]) were compared with pT (including histologic pattern, Gleason grade, and lymphovascular invasion [LVI]) and PSMA-IHC features, including visual quantification (VS) with a four-tiered score (0 = negative, 1+ = weak, 2+ = moderate, 3+ = strong), growth pattern (infiltrative vs expansive), and visual pattern (cytoplasmic vs membranous). In total, 44 patients were enrolled, with a median age of 67 (IQR 57-77); the median iPSA was 9.4 ng/dL (IQR 12.5-6.0). One patient (3%) was grading group (GG) 3, 27/44 (61%) were GG4, and 16/44 (36%) were GG5. PSMA-PET/CT detection rate for the presence of primary prostate cancer was 100%. Fused/poorly formed Gleason grade 4 features were predominant (22/44–50%); a cribriform pattern was present in 18/44 (41%) and acinar in 4/44 (9%). We found that lower PSMA-TVs were mostly related to acinar, while higher PSMA-TVs correlated with a higher probability to have a cribriform pattern (p-value 0.04). LVI was present in 21/44(48%) patients. We found that higher PSMA-TV and PSMA-TL are predictive of LVI p-value 0.002 and p-value 0.01, respectively. There was no correlation between PET-parameters and perineural invasion (PNI), probably because this was present in almost all the patients. Moreover, patients with high PSMA-TL values displayed the highest PSMA-IHC expression (VS3+) with a membranous pattern. In conclusion, PSMA-TV and PSMA-TL are predictors of a cribriform pattern and LVI. These conditions are mostly related to higher aggressiveness and worse outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancers with p53 mutations tend to recur and develop metastases more frequently. From this point of view, the detection of new potential therapeutic targets such as HER2 is particularly interesting. In this study, we demonstrated that overexpression of HER2 (++ or +++) was present in 31.4% of p53-mutated endometrial carcinomas and that among these, 36.3% showed amplification of the HER2 gene by CISH (Chromogenic In Situ Hybridization). These results suggest that various anti-HER2 agents could constitute interesting future treatments in this type of cancer. p53-mutated endometrial carcinomas tend to recur and develop distant metastases. Therefore, the detection of new potential therapeutic targets such as HER2 is particularly interesting. In this retrospective study, which considered over 118 endometrial carcinomas, the p53 mutation was detected in 29.6% of cases. In these cases, the HER2 protein profile was studied via immunohistochemistry, and an overexpression of HER2 protein (++ or +++) was noted in 31.4%. The CISH technique was used in these cases to determine if gene amplification was present. In 18% of cases, the technique was not conclusive. Amplification of the HER2 gene was observed in 36.3% of cases and 36.3% of cases showed a polysomal-like aneusomy for centromere 17. Amplification was found in serous carcinomas, clear cell carcinomas and carcinosarcomas, highlighting the future potentiality of HER2-targeted therapies in these variants of aggressive carcinomas. [ABSTRACT FROM AUTHOR]

Simple Summary: The current methods for assessing tumor microenvironments (TMEs) using cellular markers and cell density-based assays do not identify the primitive phenotypes of single cells with multilineage selectivity or functional or cellular spatial information in tissues. Here, we combined the strategy of multiplex IHC imaging and cytometry-based cell quantification to assess multiple lineage-selective and functional phenotypic biomarkers and deeply dissect the state of immune complexity in the TME in association with clinical outcomes. Our findings showed that the percentage of CD8+ T cells expressing the T cell exhaustion marker PD-1 and/or the high expression of the checkpoint PD-L1 among CD68+ cells was associated with poor prognosis. The prognostic value of this combined approach is greater than that of lymphocyte and myeloid cell density analyses. Furthermore, a spatial analysis revealed that the abundance of PD-L1+CD68+ tumor-associated macrophages correlated with PD-1+CD8+ T cell infiltration levels. Our findings further strengthen the evidence for applying IHC imaging and cytometry-based cell analyses in precision medicine. Immune complexity status in the TME has been linked to clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. TME assessments with current cell marker and cell density-based analyses do not identify the original phenotypes of single cells with multilineage selectivity, the functional status of the cells, or cellular spatial information in the tissues. Here, we describe a method that circumvents these problems. The combined strategy of multiplexed IHC with computational image cytometry and multiparameter cytometric quantification allows us to assess multiple lineage-selective and functional phenotypic biomarkers in the TME. Our study revealed that the percentage of CD8+ T lymphoid cells expressing the T cell exhaustion marker PD-1 and the high expression of the checkpoint PD-L1 in CD68+ cells are associated with a poor prognosis. The prognostic value of this combined approach is more significant than that of lymphoid and myeloid cell density analyses. In addition, a spatial analysis revealed a correlation between the abundance of PD-L1+CD68+ tumor-associated macrophages and PD-1+CD8+T cell infiltration, indicating pro-tumor immunity associated with a poor prognosis. These data highlight the implications of practical monitoring for understanding the complexity of immune cells in situ. Digital imaging and multiparameter cytometric processing of cell phenotypes in the TME and tissue architecture can reveal biomarkers and assessment parameters for patient stratification. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a scarcity of economic analysis on the use of non-invasive biomarkers to inform policy-making with respect to their application in population-based colorectal cancer (CRC) screening programs. The objective of this study is to conduct a comparative cost-effectiveness analysis on using M3CRC (m3 + Fn + Ch + Bc + FIT) as a primary test for population-based screening, when compared with FIT and colonoscopy. The study can provide economic analysis regarding the use of non-invasive biomarkers in population-based CRC screening programs. This study aimed to examine the cost-effectiveness of fecal biomarker M3 panel compared to fecal immunochemical test (FIT) and colonoscopy in an Asian population. In a hypothetical population of 100,000 persons aged 50 years who received FIT yearly, M3 biomarker yearly, or colonoscopy every 10 years until the age of 75 years. Participants with positive FOBT or a result of "high risk" identified using the M3 biomarker are offered colonoscopy. We assumed surveillance colonoscopy is repeated every 3 years, and examined the treatment cost. A comparison of various outcome measures was conducted using Markov modelling. The incremental cost-effectiveness ratio (ICER) of FIT, M3 biomarker, and colonoscopy was USD108,176, USD133,485 and USD159,596, respectively. Comparing with FIT, the use of M3 biomarker could lead to significantly smaller total loss of cancer-related life-years (2783 vs. 5279); a higher number of CRC cases prevented (1622 vs. 146), a higher proportion of CRC cases prevented (50.2% vs. 4.5%), more life-years saved (2852 vs. 339), and cheaper total costs per life-year saved (USD212,553 vs. 773,894). The total costs per life-year saved is more affordable than that achieved by colonoscopy as a primary screening tool (USD212,553 vs. USD236,909). The findings show that M3 biomarkers may be more cost-effective than colonoscopy. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is a global healthcare challenge that involves both genetic and environmental factors. Several pieces of evidence suggest that alterations of the gut microbiome can influence CRC development. In the present study we analyzed 16S rRNA sequencing data from fecal immunochemical test (FIT) samples from a large cohort, observing a predictive potential of the microbiome, revealing changes along the path from healthy tissue to carcinoma. Our work has implications in the understanding of the roles of microbes on the adenoma to carcinoma progression and opens the door to an improvement of the current CRC screening programmes. Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Early diagnosis of CRC, which saves lives and enables better outcomes, is generally implemented through a two-step population screening approach based on the use of Fecal Immunochemical Test (FIT) followed by colonoscopy if the test is positive. However, the FIT step has a high false positive rate, and there is a need for new predictive biomarkers to better prioritize cases for colonoscopy. Here we used 16S rRNA metabarcoding from FIT positive samples to uncover microbial taxa, taxon co-occurrence and metabolic features significantly associated with different colonoscopy outcomes, underscoring a predictive potential and revealing changes along the path from healthy tissue to carcinoma. Finally, we used machine learning to develop a two-phase classifier which reduces the current false positive rate while maximizing the inclusion of CRC and clinically relevant samples. [ABSTRACT FROM AUTHOR]

Simple Summary: Angiosarcomas (AS) are rare and aggressive soft tissue sarcomas that can be subdivided in de novo primary AS and secondary AS. They have a very poor prognosis and only limited treatment options are available. Immunotherapy is not registered as treatment for AS. Characterization of the immunological landscape of AS and combining this with genetic data enables possible identification of subgroups that are likely to benefit from immunotherapy based treatment strategies. We observed profound clinically relevant differences in a large group of primary and secondary AS. The T-cell infiltrated tumor microenvironment and frequent DNA Damage Response gene mutations, especially in secondary AS, warrant trials with immunotherapy for this subgroup. Angiosarcomas (AS) are extremely rare and aggressive vascular malignancies subdivided in de novo primary AS (pAS) and secondary AS (sAS). We hypothesize that the combination of immunological and genomic profiles significantly differs between primary and secondary AS, with potential impact on treatment strategies and a role for immunotherapy. Tumor-infiltrating lymphocytes were analyzed using multiplex immunohistochemistry from 79 pAS and 178 sAS. Median cell density was significantly higher in sAS for CD3+ T-cells (p < 0.001), CD8+ cytotoxic T-cells (p = 0.033), CD4+ T-helper cells (p < 0.001) and FoxP3+ T-regulatory cells (p < 0.001). CD20+ B-cell density was comparable (p = 0.417). Comprehensive genomic profiling was performed in 25 pAS and 25 sAS. A (likely) pathogenic mutation was detected in 80% of pAS vs. 88% of sAS (p = 0.702). Amplifications were found in 15% of pAS vs. 84% of sAS (p < 0.001). DNA damage response (DDR) pathway mutations (p = 0.021) and MYC amplifications (p < 0.001) were predominantly seen in sAS. In conclusion we observed a clear and clinical relevant distinction in immune infiltration and genomic profiles between pAS and sAS. The T-cell infiltrated tumor microenvironment and frequent DDR gene mutations, especially in sAS, warrant clinical trials with immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: A total of 15% of the annual colonoscopies are undertaken for polyp surveillance, and this causes strain on already stretched endoscopy services in the U.K. Hence, there is an urgent need to triage and prioritise patients with high-risk findings. The performance of the faecal immunochemical test is not adequate to be used within polyp surveillance. In light of this, we investigated the usefulness of urinary volatile organic compounds for the detection of high-risk findings. We confirmed that urinary volatile organic compounds can be used to triage patients with high-risk findings. It can be used alone or in combination with faecal immunochemical tests. (1) Background: The service capacity for colonoscopy remains constrained, and while efforts are being made to recover elective services, polyp surveillance remains a challenge. (2) Methods: This is a multi-centre study recruiting patients already on polyp surveillance. Stool and urine samples were collected for the faecal immunochemical test (FIT) and volatile organic compounds (VOC) analysis, and all participants then underwent surveillance colonoscopy. (3) Results: The sensitivity and specificity of VOC for the detection of a high-risk finding ((≥2 premalignant polyps including ≥1 advanced polyp or ≥5 premalignant polyps) were 0.94 (95% CI, 0.88 to 0.98) and 0.69 (95% CI, 0.64 to 0.75) respectively. For FIT, the sensitivity was (≥10 µg of haemoglobin (Hb) / g faeces) 0.54 (95% CI, 0.43 to 0.65) and the specificity was 0.79 (95% CI, 0.73 to 0.84). The probability reduction for having a high-risk finding following both negative VOC and FIT will be 24% if both tests are applied sequentially. (4) Conclusion: The diagnostic performance of VOC is superior to FIT for the detection of a high-risk finding. The performance further improves when VOC is applied together with FIT sequentially (VOC first and then FIT). VOC alone or the combination of VOC and FIT can be used as a triage tool for patients awaiting colonoscopy within a polyp surveillance population, especially in resource-constrained healthcare systems. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 20 years ago, genomic profiling of breast carcinomas identified tumor subtypes with clinical implications and opened the door for a better understanding of breast cancer biology. The commercialization of multigene tests had a significant impact on clinical practice, and yet, controversy exists as to which methodology is best to inform the choice of therapy and existing recommendations are inconsistent and often driven by cost-effectiveness. Here we report data from a cohort of breast cancer patients in which pathological and molecular subtyping are directly compared in a clinical setting. The findings show that some patients with genomic low-risk tumors could receive unnecessary systemic therapy if only following the classical clinical parameters, while others could remain under-treated. This study suggests that to design precise treatment regimens for patients with early breast cancer, the conventional clinicopathological classification should be complemented with the robust prognostic information provided by molecular subtyping. Precise prognosis is crucial for selection of adjuvant therapy in breast cancer. Molecular subtyping is increasingly used to complement immunohistochemical and pathological classification and to predict recurrence. This study compares both outcomes in a clinical setting. Molecular subtyping (MammaPrint®, TargetPrint®, and BluePrint®) and pathological classification data were compared in a cohort of 143 breast cancer patients. High risk clinical factors were defined by a value of the proliferation factor Ki67 equal or higher than 14% and/or high histological grade. The results from molecular classification were considered as reference. Core needle biopsies were found to be comparable to surgery samples for molecular classification. Discrepancies were found between molecular and pathological subtyping of the samples, including misclassification of HER2-positive tumors and the identification of a significant percentage of genomic high risk T1N0 tumors. In addition, 20% of clinical low-risk tumors showed genomic high risk, while clinical high-risk samples included 42% of cases with genomic low risk. According to pathological subtyping, a considerable number of breast cancer patients would not receive the appropriate systemic therapy. Our findings support the need to determine the molecular subtype of invasive breast tumors to improve breast cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: CDC20 has been shown to function as an oncogene in multiple human malignancies and is recognized as a promising target for developing novel therapeutic strategies. Previous studies showed the role of CDC20 in cancer development and linked its function to drug resistance. Drug resistance can be acquired by multiple mechanisms, including chromatin organization and dynamic changes. It was previously reported that cancer cells with enlarged nuclei and diffuse chromatin showed higher resistance to anti-cancer therapy. We showed that CDC20 interacts with hnRNPU in the chromatin fraction and regulates its ubiquitination in breast cancer cells. CDC20-mediated hnRNPU ubiquitination modulates chromatin condensation by regulating the formation of the CTCF–cohesin complex. Dysregulation of the CDC20–hnRNPU axis results in diffuse chromatin and leads to drug resistance in breast cancer cells. Our findings shared new insights into the implication of the CDC20–hnRNPU axis in regulating chromatin organization and drug resistance, suggesting that the CDC20–hnRNPU axis could be a good target for cancer therapy. Cell division cycle 20 (CDC20) functions as a critical cell cycle regulator. It plays an important role in cancer development and drug resistance. However, the molecular mechanisms by which CDC20 regulates cellular drug response remain poorly understood. Chromatin-associated CDC20 interactome in breast cancer cells was analyzed by using affinity purification coupled with mass spectrometry. hnRNPU as a CDC20 binding partner was validated by co-immunoprecipitation and immunostaining. The molecular domain, comprising amino acid residues 461–653, on hnRNPU required for its interaction with CDC20 was identified by mapping of interactions. Co-immunoprecipitation showed that CDC20-mediated hnRNPU ubiquitination promotes its interaction with the CTCF and cohesin complex. The effects of CDC20–hnRNPU on nuclear size and chromatin condensation were investigated by analyzing DAPI and H2B-mCherry staining, respectively. The role of CDC20–hnRNPU in tumor progression and drug resistance was examined by CCK-8 cell survival and clonogenic assays. Our study indicates that CDC20-mediated ubiquitination of hnRNPU modulates chromatin condensation by regulating the interaction between hnRNPU and the CTCF–cohesin complex. Dysregulation of the CDC20–hnRNPU axis contributes to tumor progression and drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Up to 30% of breast cancer patients are carriers of pathogenic mutations in breast cancer susceptibility genes. Except for BRCA1/2 genes that account only for 22–30% of hereditary breast cancer, less is known about the remaining genes that are prone to breast cancer. Our aim was to retrospectively evaluate the relationship between the pathogenic mutations (BRCA and non-BRCA), US features, and histopathologic findings of breast cancer patients with and without mutations. We concluded that carrier patients (BRCA, TP53, PALB, CHEK, ATM, RAD) seem to exhibit benign imaging findings on US compared to mutation-negative patients. Furthermore, carrier patients had the majority of tumors with higher histologic grade and a higher proliferation index. BRCA1, TP53, and RAD carriers accounted for up to one third of the ER-negative tumors from the mutation group. Axillary US performed worse in depicting axillary metastatic lymph nodes in carrier patients, compared to negative patients. The purpose of this study is to evaluate the relationship between the pathogenic/likely pathogenic mutations, US features, and histopathologic findings of breast cancer in mutation carriers compared to non-carrier patients. Methods: In this retrospective study, we identified 264 patients with breast cancer and multigene panel testing admitted to our clinic from January 2018 to December 2020. Patient data US findings, US assessment of the axilla, multigene panel tests, histopathology, and immunochemistry reports were reviewed according to the BI-RADS lexicon. Results: The study population was comprised of 40% pathogenic mutation carriers (BRCA1, BRCA2, CHEK2, ATM, PALB, TP 53, NBN, MSH, BRIP 1 genes) and 60% mutation-negative patients. The mean patient age was 43.5 years in the carrier group and 44 years in the negative group. Carrier patients developed breast cancer with benign morphology (acoustic enhancement, soft elastography appearance) compared to non-carriers (p < 0.05). A tendency towards specific US features was observed for each mutation. BRCA1 carriers were associated with BC with microlobulated margins, hyperechoic rim, and soft elastography appearance (p < 0.05). Estrogen receptor (ER)-negative tumors were associated with BRCA1, TP53, and RAD mutations, while BRCA2 and CHEK2 were associated with ER-positive tumors. Conclusions: Patients with pathogenic mutations may exhibit BC with benign US features compared to negative, non-carrier patients. BRCA1, TP53, and RAD carriers account for up to one third of the ER tumors from the carrier group. Axillary US performed worse in depicting involved lymph nodes in carrier patients, compared to negative patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Monocarboxylate transporters (MCT) are cell membrane proteins transporting lactate, pyruvate, and ketone bodies. For most non-neoplastic cells, the aforementioned energy metabolites are waste products and must be exported via MCTs. However, it seems tumor cells have developed means to shuttle these metabolites through MCTs and utilize them for energy production. MCTs contribute to the acidification of the tumor microenvironment and are associated with drug resistance making them potential therapeutic targets. MCT expression has been shown to correlate with prognosis in a range of human solid tumors. In small bowel neuroendocrine tumors, the expression of MCTs 1 and 4 is reported for the first time. High MCT4 expression is associated with improved prognosis. Monocarboxylate transporters (MCTs) are cell membrane proteins transporting lactate, pyruvate, and ketone bodies across the plasma membrane. The prognostic role of MCTs in neuroendocrine tumors is unknown. We aimed to analyze MCT1 and MCT4 expression in small bowel neuroendocrine tumors (SB-NETs). The cohort included 109 SB-NETs and 61 SB-NET lymph node metastases from two Finnish hospitals. Tumor samples were immunohistochemically stained with MCT1 and MCT4 monoclonal antibodies. The staining intensity, percentage of positive cells, and stromal staining were assessed. MCT1 and MCT4 scores (0, 1 or 2) were composed based on the staining intensity and the percentage of positive cells. Survival analyses were performed with the Kaplan–Meier method and Cox regression, adjusted for confounders. The primary outcome was disease-specific survival (DSS). A high MCT4 intensity in SB-NETs was associated with better DSS when compared to low intensity (85.7 vs. 56.6%, p = 0.020). A high MCT4 percentage of positive cells resulted in better DSS when compared to a low percentage (77.4 vs. 49.1%, p = 0.059). MCT4 scores 0, 1, and 2 showed DSS of 52.8 vs. 58.8 vs. 100% (p = 0.025), respectively. After adjusting for confounders, the mortality hazard was lowest in the patients with a high MCT4 score. MCT1 showed no association with survival. According to our study, a high MCT4 expression is associated with an improved prognosis in SB-NETs. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial ovarian cancer is one of the greatest challenges for a gynecologist and oncologist both in terms of diagnosis and treatment. Modern imaging techniques such as DWI or DCE MRI allow for better planning of the treatment strategy. This is related not only to a more precise localization of lesions, but also to the relationship between the values of DWI and DCE parameters and specific histological types of ovarian cancer. In our study, we demonstrated the previously suggested relationships between the values of DWI parameters and the types of ovarian cancer. We described the relationship with the results of immunohistochemical tests. We also showed a correlation between DWI and DCE values with time to relapse. We have made an attempt to describe such correlations in the group of patients treated with bevacizumab. Background. The aim of our study was to describe the selected parameters of diffusion-weighted imaging (DWI) and perfusion dynamic contrast enhancement (DCE) MRI in primary tumors in patients with serous epithelial ovarian cancer (EOC), as well as in disease course prognosis and treatment response, including bevacizumab maintenance therapy. Materials and Methods. In total, 55 patients with primary serous EOC were enrolled in the study. All patients underwent MR imaging using a 1.5 T clinical whole-body MR system in preoperative DWI and DCE MRI selected parameters: apparent diffusion coefficients (ADC), time to peek (TTP) and perfusion maximum enhancement (Perf. Max. En.) were measured. The data were compared with histopathological and immunochemistry results (with Ki67 and VEGF expression) and clinical outcomes. Results. Higher mean ADC values were found in low-grade EOC compared to high-grade EOC: 1151.27 vs. 894,918 (p < 0.0001). A negative correlation was found between ADC and Ki67 expression (p = 0.027), and between ADC and VEGF expression (p = 0.042). There was a negative correlation between TTP and PFS (p = 0.0019) and Perf. Max. En. and PSF (p = 0.003). In the Kaplan–Meier analysis (log rank), a longer PFS was found in patients with ADC values greater than the median; p = 0.046. The Kaplan–Meier analysis showed a longer PFS (p = 0.0126) in a group with TTP below the mean value for this parameter in patients who received maintenance treatment with bevacizumab. Conclusions. The described relationships between PFS and DCE and DWI allow us to hope to include these parameters in the group of EOC prognostic factors. This aspect seems to be of particular interest in the case of the association of PFS with DCE values in the group of patients treated with bevacizumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Hemoglobin degradation can be affected by ambient temperature and humidity. How this modifies the advanced neoplasia detection rate and interval cancer rate remains understudied. We conducted a retrospective study and analyzed the impact of ambient temperature and humidity on the fecal immunochemical test (FIT) positivity rate, detection rate for advanced neoplasia, and interval colorectal cancer (CRC). The results of our study indicated that at >24 °C, the positivity rate was lower, whereas the detection rate of the FIT for advanced neoplasia and the interval cancer detection rate were not affected, probably because we have adopted measures to minimize the impact of ambient temperature on FIT sensitivity. Humidity did not affect FIT sensitivity. The results emphasize the importance of organizational efforts on the procedures along the screening process (such as the cold chain) to minimize the effect of seasonal variations in temperature on the positivity rate. Exposure of the fecal immunochemical test (FIT) to different ambient temperatures and humidity is unavoidable in population-based screening programs in Southern European countries, and it could lead to a decrease in target colorectal lesions. The objective was to evaluate the effect of ambient temperature and humidity on the FIT sensitivity in a population-based screening program for colorectal cancer (CRC) using an ecological design. The retrospective cohort included individuals aged 50–69 years who participated in CRC screening (Barcelona) from 2010–2015, and were followed until 2017 to identify interval CRCs. The positivity rate, and detection rates for advanced polyps and CRC were compared according to ambient temperature, humidity, and quarters of the year. A positive FIT was defined as the detection of ≥20 μg Hb/g in feces. The monthly ambient temperature and humidity were recorded on the day that the FIT was performed. In total, 92,273 FIT results from 53,860 participants were analyzed. The FIT positivity rate was lower at >24 °C than at ≤24 °C (p = 0.005) but was not affected by humidity. The temperature's impact on positivity did not lead to a decrease in the FIT detection rate for advanced neoplasia or the interval cancer detection rate in a program where the samples were refrigerated until the analysis and screening invitations were discontinued in July and August. [ABSTRACT FROM AUTHOR]

Simple Summary: This study is a systematic review and meta-analysis of international literature on the achievements of various performance indicators for colorectal cancer screening programs. We systematically summarized performance indicators of organized colorectal cancer screening that used fecal immunochemical test as a primary screening modality, and colonoscopy as a subsequent confirmatory test, from 93 studies involving nearly 90 million people-times, and reported their pooled achievements based on random-effects models. We also performed meta-regression and subgroup analyses to explore the heterogeneity. Our findings could help to identify the areas that could be improved and finally optimize the organized colorectal cancer screening programs. (1) Background: To summarize the achievements of the performance indicators of colorectal cancer (CRC) screening programs that used the fecal immunochemical test (FIT) as a primary screening modality and colonoscopy as a subsequent confirmatory test. (2) Methods: PubMed, Ovid MEDLINE, Embase, and Cochrane were searched from inception to September 2020. We included original articles published in English, and performed hand searching for relevant national reports. We generated pooled achievement estimates of the performance indicators by "metaprop" (R software 3.6.3). Meta-regression analyses and subgroup analyses were also conducted. (3) Results: We included 93 studies involving nearly 90 million people-times. The participation rate ranged from 6.80% to 95.98%, which was associated with study type, continents, FIT number, age, and round. The pooled FIT invalid rate and positivity rate were 1.08% and 7.28%, respectively. The pooled estimates of FIT detection were 2.26% for adenoma, 1.26% for advanced adenoma, and 0.28% for CRC. In addition, only seven studies reported that their colonoscopy compliance rate reached 90% among 69 studies. The colonoscopy completion rate (21/40 studies > 95%) and the complication rate (18/27 studies < 0.5%) were acceptable. (4) Conclusions: Our findings could help to identify the areas that could be improved and finally optimize the CRC screening programs. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is a significant public health problem, being a major cause of cancer death worldwide. Hence, the identification of biomarkers able to support CRC detection is crucial. This work analyses a panel of six biomarkers, namely interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-2, MMP-9, haemoglobin (Hb) and M2-pyruvate kinase (M2-PK), in stool samples from patients with CRC, advanced adenomas, other lesions and healthy individuals. Our results indicate that the levels of Hb and M2-PK were increased in CRC patients in comparison to the controls. Moreover, the combination of these biomarkers increased the specificity or sensitivity for CRC detection and thus present potential for diagnosis of CRC. Background: Colorectal cancer (CRC) is a major cause of cancer-related death worldwide. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. Current methods for CRC screening commonly consist of a combination of faecal immunochemical test (FIT) for stool occult blood detection and invasive procedures such as colonoscopy. Considering the slow progression of CRC, and that symptoms usually emerge at advanced stages, its early diagnostic can limit cancer's spread and provide a successful treatment. Biomarkers have a high potential for the diagnosis of CRC in either blood or stool samples. Methods: In this study, we analysed the diagnostic value of six different biomarkers in stool samples of patients with CRC, advanced adenomas, other lesions and healthy individuals. We have also assessed the overall performance of the combination of these biomarkers for CRC detection. Results: The results indicate that haemoglobin (Hb) and M2-pyruvate kinase (M2-PK) levels were increased in CRC patients in comparison to the controls. Conversely, the concentrations of matrix metalloproteinase (MMP)-2, MMP-9, and tumour necrosis factor-alpha (TNF-α) were not significantly different between the tested groups. Conclusion: The combination of FIT-Hb with the M2-PK levels increased the specificity or sensitivity for CRC detection and thus present potential as faecal diagnostic biomarkers for CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Autophagy is a process in which the cell recycles components that are not needed at that moment and uses the resulting elements to satisfy more urgent needs. Depending on the specific context, this can be beneficial or detrimental for tumor development. We found that in glioblastoma, the most lethal brain tumor, autophagy is upregulated and contributes to glioblastoma stem cell survival under starvation. Importantly, the antitumor peptide TAT-Cx43266-283 blocks autophagy flux, contributing to the death of glioblastoma stem cells. This peptide induces glioblastoma stem cell death in nutrient-deprived and complete environments, while the effect of other unsuccessful drugs for glioblastoma depends on nutrient context, supporting the potential of TAT-Cx43266-283 as a treatment to improve the lives of glioblastoma patients. Autophagy is a physiological process by which various damaged or non-essential cytosolic components are recycled, contributing to cell survival under stress conditions. In cancer, autophagy can have antitumor or protumor effects depending on the developmental stage. Here, we use Western blotting, immunochemistry, and transmission electron microscopy to demonstrate that the antitumor peptide TAT-Cx43266-283, a c-Src inhibitor, blocks autophagic flux in glioblastoma stem cells (GSCs) under basal and nutrient-deprived conditions. Upon nutrient deprivation, GSCs acquired a dormant-like phenotype that was disrupted by inhibition of autophagy with TAT-Cx43266-283 or chloroquine (a classic autophagy inhibitor), leading to GSC death. Remarkably, dasatinib, a clinically available c-Src inhibitor, could not replicate TAT-Cx43266-283 effect on dormant GSCs, revealing for the first time the possible involvement of pathways other than c-Src in TAT-Cx43266-283 effect. TAT-Cx43266-283 exerts an antitumor effect both in nutrient-complete and nutrient-deprived environments, which constitutes an advantage over chloroquine and dasatinib, whose effects depend on nutrient environment. Finally, our analysis of the levels of autophagy-related proteins in healthy and glioma donors suggests that autophagy is upregulated in glioblastoma, further supporting the interest in inhibiting this process in the most aggressive brain tumor and the potential use of TAT-Cx43266-283 as a therapy for this type of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the performance of nine faecal immunochemical tests among participants of screening colonoscopy. A total of 216 cases of advanced neoplasia (AN, colorectal cancer or advanced adenoma) and 300 randomly selected participants without AN were included. Diagnostic performance for detection of AN was assessed by sex and age (50–64 vs. 65–79 years), for each of the nine faecal immunochemical tests (FITs) individually and for all FITs combined. Major differences in diagnostic performance by sex and age were consistently seen across nine different FIT brands. Sensitivities were consistently lower, and specificities were consistently higher, for females as compared with males. Positive predictive values were similar between both sexes, but negative predictive values were higher for females. A negative FIT is less reliable in ruling out AN among men than among women and among older than among younger participants. Evidence on diagnostic performance of faecal immunochemical tests (FITs) by sex and age is scarce. We aimed to evaluate FIT performance for detection of advanced colorectal neoplasia (AN) by sex and age across nine different FIT brands in a colonoscopy-controlled setting. The faecal samples were obtained from 2042 participants of colonoscopy screening. All eligible cases with AN (n = 216) and 300 randomly selected participants without AN were included. Diagnostic performance for detection of AN was assessed by sex and age (50–64 vs. 65–79 years for each of the nine FITs individually and for all FITs combined. Sensitivity was consistently lower, and specificity was consistently higher for females as compared with males (pooled values at original FIT cutoffs, 25.7% vs. 34.6%, p = 0.12 and 96.2% vs. 90.8%, p < 0.01, respectively). Positive predictive values (PPVs) were similar between both sexes, but negative predictive values (NPVs) were consistently higher for females (pooled values, 91.8% vs. 86.6%, p < 0.01). Sex-specific cutoffs attenuated differences in sensitivities but increased differences in predictive values. According to age, sensitivities and specificities were similar, whereas PPVs were consistently lower and NPVs were consistently higher for the younger participants. A negative FIT is less reliable in ruling out AN among men than among women and among older than among younger participants. Comparisons of measures of diagnostic performance among studies with different sex or age distributions should be interpreted with caution. [ABSTRACT FROM AUTHOR]