Antibiotics in early life and childhood pre-B-ALL. Reasons to analyze a possible new piece in the puzzle

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with precursor B-cell ALL (pB-ALL) accounting for ~ 85% of the cases. Childhood pB-ALL development is influenced by genetic susceptibility and host immune responses. The role of the intestinal microbiome in leukemogenesis is gaining increasing attention since Vicente-Dueñas’ seminal work demonstrated that the gut microbiome is distinct in mice genetically predisposed to ALL and that the alteration of this microbiome by antibiotics is able to trigger pB-ALL in Pax5 heterozygous mice in the absence of infectious stimuli. In this review we provide an overview on novel insights on the role of the microbiome in normal and preleukemic hematopoiesis, inflammation, the effect of dysbiosis on hematopoietic stem cells and the emerging importance of the innate immune responses in the conversion from preleukemic to leukemic state in childhood ALL. Since antibiotics, which represent one of the most widely used medical interventions, alter the gut microbial composition and can cause a state of dysbiosis, this raises exciting epidemiological questions regarding the implications for antibiotic use in early life, especially in infants with a a preleukemic “first hit”. Sheading light through a rigorous study on this piece of the puzzle may have broad implications for clinical practice.

Factors associated with positive predictive value of preliminary screening in a two-step screening strategy for colorectal neoplasms in China

Background The positive predictive value (PPV) of high risk factor questionnaire (HRFQ) plus fecal immunochemical test (FIT) as preliminary screening strategy for colorectal-related neoplasia is relatively low. We aim to explore independent factors associated with PPVs of HRFQ combined FIT for selecting high risk individuals for colonoscopy. Methods A total of 6971 residents were enrolled in a community-based screening program. Participants who had positive results of HRFQ and/or FIT and subsequently received colonoscopy were involved. The associations of socio-demographic factors, lifestyle behaviors, and high risk factors of colorectal cancer with PPVs of HRFQ, FIT, and their combination were evaluated by multivariable logistic regression models. Results Among 572 involved cases, 249 (43.5%) colorectal neoplasms were detected by colonoscopy, including 71 advanced adenoma (12.4%) and 9 colorectal cancer (CRC) (1.6%). The PPVs of preliminary screening were 43.5% for total colorectal neoplasms, 14.0% for advanced neoplasm, and 1.6% for CRC. Adding positive HRFQ to FIT could improve the PPV from 3.5 to 8.0% for detecting CRC. Preliminarily screened positive individuals who were males [adjusted odds ratio (AOR): 1.95, 95% CI 1.31, 2.90; p < 0.001], elders (> 60 years) (AOR: 1.70, 95% CI 1.17, 2.46; p = 0.005), or ex-/current smokers (AOR: 3.04, 95% CI 1.31, 7.09; p = 0.10) had higher odds of PPVs of detecting colorectal neoplasms. Conclusions Combining HRFQ and FIT could largely improve PPVs for screening advanced neoplasm and CRC. Gender and age-specific FIT cut-off values as well as initiating ages for CRC screening might be recommended to improve the accuracy and effectiveness of current screening algorithm.

DCE-MRI radiomics nomogram can predict response to neoadjuvant chemotherapy in esophageal cancer

Objectives To assess volumetric DCE-MRI radiomics nomogram in predicting response to neoadjuvant chemotherapy (nCT) in EC patients. Methods This retrospective analysis of a prospective study enrolled EC patients with stage cT1N + M0 or cT2-4aN0-3M0 who received DCE-MRI within 7 days before chemotherapy, followed by surgery. Response assessment was graded from 1 to 5 according to the tumor regression grade (TRG). Patients were stratified into responders (TRG1 + 2) and non-responders (TRG3 + 4 + 5). 72 radiomics features and vascular permeability parameters were extracted from DCE-MRI. The discriminating performance was assessed with ROC. Decision curve analysis (DCA) was used for comparing three different models. Results This cohort included 82 patients, and 72 tumor radiomics features and vascular permeability parameters acquired from DCE-MRI. mRMR and LASSO were performed to choose the optimized subset of radiomics features, and 3 features were selected to create the radiomics signature that were significantly associated with response (P < 0.001). AUC of combining radiomics signature and DCE-MRI performance in the training (n = 41) and validation (n = 41) cohort was 0.84 (95% CI 0.57–1) and 0.86 (95% CI 0.74–0.97), respectively. This combined model showed the best discrimination between responders and non-responders, and showed the highest positive and positive predictive value in both training set and test set. Conclusions The radiomics features are useful for nCT response prediction in EC patients.

Mannose enhances the radio-sensitivity of esophageal squamous cell carcinoma with low MPI expression by suppressing glycolysis

Background To investigate the effect of mannose on radio-sensitivity of human esophageal squamous cell carcinoma (ESCC) cell line and its possible mechanism. Methods The expression of mannose phosphate isomerase (MPI) in human esophageal cancer cell lines were detected by Western blot. The inhibitory effect of mannose on human esophageal cancer cell lines were observed by MTT assay. Plate clone formation assay was performed to investigate the efficacy of mannose on radio-sensitivity of human esophageal cancer cells. The apoptosis rates of tumor cells treated with mannose and/or radiation therapy was calculated by flow cytometry. Furthermore, we analyzed intracellular metabolites using liquid chromatography mass spectrometry to identify selective sugar metabolites. Results MPI expression was various in human esophageal cancer cells. KYSE70 cells was associated with the highest MPI expression whereas KYSE450 cells had the lowest MPI expression level. When administrated with 11.1 mM/L mannose, the same inhibitory effect was observed in both KYSE70 and KYSE450 cell lines. Moreover, the inhibitory effect was significant on KYSE450 cell lines with an increased mannose concentration. The application of 11.1 mM/L mannose could significantly enhance the radio-sensitivity of KYSE450 cell line; and tumor cell apoptosis rate was also increased. However, there was limited efficacy of mannose on the radio-sensitivity and apoptosis rate of KYSE70 cell line. Additionally, intracellular metabolites analyzation revealed that glycolysis could be disturbed by mannose when combined with radiation therapy in esophageal cancer cells. Conclusion In esophageal cancer cell lines with low MPI expression, the administration of mannose was associated with enhanced radio-sensitivity.

Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study

Background/Aims Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases. Methods The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed. Results The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week < 8 (p = 0.0285), radiological response, stable disease or progression disease (p = 0.0212), and pathological stage > IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion. Conclusions This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.

Mitophagy in carcinogenesis and cancer treatment

In order to maintain a functional mitochondrial network, cells have developed a quality control mechanism, namely mitophagy. This process can be induced through different pathways. The most studied is the so-called PINK1/Parkin pathway, which is associated with ubiquitylation of several mitochondrial proteins that were initially found to be related to Parkinson’s disease. Another type of mitophagy is known as receptor-mediated mitophagy, which includes proteins, such as BNIP3 and BNIP3L, also known as Nix. Through these two mechanisms, mitophagy fulfills its functions and maintains cellular homeostasis. Here, we summarize the current knowledge about the mechanisms of mitophagy regulation and their interplay with cancer progression as well as anticancer treatment.

Radiation boost for synchronous solitary inguinal lymph node metastasis during neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Background Some patients with locally advanced rectal cancer (LARC) present with inguinal lymph node metastases without evidence of other systemic disease, known as solitary inguinal lymph node metastasis (SILNM). These patients may represent a distinct subset who have a more favorable prognosis and should be treated with curative intent. The optimal treatment strategy for these patients has not been determined. Methods We retrospectively reviewed 16 consecutive LARC patients diagnosed between January 2017 and December 2019, who had SILNM, were treated with an inguinal lymph nodes (ILN) radiation boost with curative intent during neoadjuvant chemoradiotherapy (nCRT) and underwent total mesorectal excision (TME). We used Kaplan–Meier survival curves to calculate survival rates, and recorded radiation-related toxicity. Results None of these 16 patients developed pelvic or inguinal recurrences, and 3 of the patients developed distant metastases. The 3-year overall survival rate and locoregional relapse-free survival rate were both 100%. The 3-year disease-free rate and distant metastasis-free survival rate were both 81.3%. Of 5 patients who had ILN dissection for suspicious ILNs after neoadjuvant treatment, 2 had residual nodal tumor confirmed. Grade 3 toxicity was found in 5 patients, and no patients had lymphedema or other grade 4 or 5 toxicities. Conclusions In LARC patients with synchronous SILNM, a radiation boost to the ILNs during nCRT achieved excellent local control with acceptable toxicity. Though the optimal treatment strategy remains unclear, nCRT with an ILN radiation boost prior to TME may be a reasonable therapeutic approach to consider for this subset of patients.

AURKA gene polymorphisms and central nervous system tumor susceptibility in Chinese children

Introduction Central nervous system (CNS) tumors comprise 15–20% of all malignancies occurring in childhood and adolescence. Previous researches have shown that overexpression and amplification of the AURKA gene could induce multiple human malignancies, with which the connection of CNS tumor susceptibility has not been extensively studied. Material and methods In this study, we assessed whether and to what extent AURKA gene single nucleotide polymorphisms (SNPs) (rs1047972 C > T, rs2273535 T > A, rs8173 G > C) were associated with CNS tumor susceptibility, based on a case–control analysis in 191 CNS tumor patients and 248 controls. We determined this correlation using odds ratios (ORs) and 95% confidence intervals (CIs). Results AURKA gene rs8173 G > C exhibited a crucial function to CNS tumor susceptibility fall-off (GC/CC vs. GG: adjusted OR = 0.68, 95% CI = 0.46–0.998, P = 0.049). In addition, the combined effect of lowering the risk of developing CNS tumors was more pronounced in carriers with 3 protective genotypes than others (adjusted OR = 0.55, 95% CI = 0.31–0.98, P = 0.044). Further stratification analysis illustrated that the existence of rs8173 GC/CC and three protective genotypes lowered CNS tumor risk in some subgroups. Conclusions Our research suggested that the AURKA gene rs8173 G > C could significantly reduce CNS tumor susceptibility in Chinese children. More functional experiments are needed to explore the role of the AURKA gene rs8173 G > C.

Association of pigment epithelium derived factor expression with cancer progression and prognosis: a meta-analysis study

Background Pigment epithelium derived factor (PEDF) is a secreted protein that strongly suppresses angiogenesis and directly inhibits cancer cells proliferation. The differential expression of PEDF has been observed in multiple types of human tumors. However, it is unclear as to how PEDF expression is associated with cancer progression and if PEDF could serve as a prognostic marker for cancer patients. Methods We performed a comprehensive search for the studies on PEDF expression in 14 top-ranked types of solid tumor cancer with the highest incidence. A systemic approach was used to screen for qualified studies and to extract data. Meta-analysis was performed to investigate if PEDF expression is associated with the TNM staging, tumor size, lymph node invasion, distal metastasis and pathological grade of tumor in a pan-cancer manner. A Kaplan–Meier curve was plotted with the digitally-reconstituted patient survival data to study the effect of PEDF expression on the prognosis of cancer patients. Results A total of nine studies were selected, reviewed and analyzed. Meta-analysis suggested that decreased PEDF protein expression was associated with higher TNM staging (OR = 2.13, 95% CI: 1.61–2.81), larger tumor size (OR = 1.42, 95% CI: 1.1–1.84), larger possibility of lymph node invasion (OR = 1.68, 95% CI: 1.26–2.22) and higher pathological grade (OR = 1.6, 95% CI: 1.2–2.13). No correlation was found between PEDF expression and tumor distal metastasis, gender or age. In addition, low PEDF protein level in tumor tissue is correlated with shorter overall survival (P < 0.05). Conclusions Low PEDF protein expression in cancer is significantly associated with more advanced cancer progression and significantly poorer survival. The differential clinical outcome among patients with various PEDF expression suggests its prognostic value.

FAM65A as a novel prognostic biomarker in human tumors reveal by a pan-cancer analysis

Background Family with sequence similarity 65 member A (FAM65A), also known as RIPOR1, is differentially expressed between human tumor and non-tumor tissues in kinds of cancers. In addition, it was reported that the product of FAM65A may be a biomarker for cholangiocarcinoma patients. However, there is still no evidence on the relationship between the FAM65A and different types of tumors. Our study is mainly for exploring the prognostic values of FAM65A in pan-cancer and for further discovering a potential therapeutics target. Methods We analyzed FAM65A expression, prognostic values, genetic alteration, protein phosphorylation, immune infiltration and enrichment analysis across different types of human malignant tumors based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Additionally, Real-Time PCR (RT-qPCR) was performed to further confirm the roles of FAM65A in the pathogenesis of colorectal cancer. Results We found that FAM65A expression was associated with the prognosis of multiple human tumors, especially colorectal cancer. Moreover, we also observed that FAM65A was highly expressed in colorectal cancer through RT-qPCR. We observed that decreasing phosphorylation level of the S351 locus in colon adenocarcinoma, uterine corpus endometrial carcinoma and lung adenocarcinoma. And the expression of FAM65A was positively related to cancer-associated fibroblasts (CAFs) infiltration in many tumors, such as colon adenocarcinoma. Therefore, FAM65A may be a potential prognostic biomarker of human tumors.