The effect of neoadjuvant chemotherapy has been associated with increased expression of immune checkpoint molecules, such as PD-1, and tumor infiltrating lymphocytes profiles representing high ...CD8/FOXP3 ratio but has not been associated with genomic alterations in new generation sequence (NGS). ...rectal cancer may be expected to be susceptible to combined immunotherapy with chemotherapy. ...preoperative chemotherapy could be utilized even as an excellent research tool to clarify the treatment response of clinical cancer cells. ...Nakagawa et al. have reported effects of neoadjuvant chemotherapy for patients with highly conditional colon cancer (obstructive cases) in multicenter propensity score-matched analysis (YCOG2101).
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a ...critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.
Promoter DNA methylation, which occurs on cytosine nucleotides across CpG islands, results in gene silencing and represents a major epigenetic alteration in human cancer. Methylation‐specific PCR can ...amplify these modifications as markers in cancer cells. In the present work, we rigorously review the published literatures describing DNA methylation in the promoters of critical tumor suppressor genes; detection of promoter DNA methylation in various body fluids permits early detection of cancer cells during perioperative courses of clinical treatment. The latest whole‐genome comprehensive explorations identified excellent epigenetic biomarkers that could be detected at high frequency with high specificity; these biomarkers, which are designated highly relevant methylation genes (HRMG), permit the discrimination of tumor tissues from the corresponding normal tissues; these markers are also associated with unique cancer phenotypes, including dismal prognosis. In humans, HRMG include the CDO1, GSHR, RASSF1 and SFRP1 genes, with these markers permitting discrimination depending on the organs tested. The combination of several HRMG increased the early detection of cancer and exhibited reliable surveillance potential in human body fluids. Cancer clinics using such epigenetic biomarkers are entering a new era of enhanced decision‐making with the potential for improved cancer prognosis.
This is a review paper describing molecular diagnostics of cancer using DNA methylation. DNA methylation has been recently focused on in relation to liquid biopsy in various cancers. It is a promising candidate to improve cancer treatment and patient prognosis.
Serum carcinoembryonic antigen (CEA) and CA19‐9, a carbohydrate antigen recognized by the monoclonal antibody NS19‐9, are commonly used as classical tumor markers in colorectal cancer (CRC) clinics. ...The roles of tumor markers include: (1) diagnostic screening (diagnostic markers); (2) prediction of prognosis after treatment (prognostic markers); and (3) judgment tools for treatment effect (surveillance markers). Tumor markers can be evaluated in serum, stools, or even in tissues depending on the clinical purpose. The American Society for Clinical Oncology recommends that CEA is the only marker of choice for monitoring the response of metastatic disease to systemic therapy at present. In the present paper, we are the first to review the clinical significance of the classical tumor markers CEA and CA19‐9 in serum, allowing for our original data, and present our view on the newly emerging biomarkers in CRC. Novel promising biomarkers for diagnostic, prognostic, and surveillance purposes are reviewed and considered, some of which are anticipated for further validation. For diagnostic markers, urine or serum might replace fecal samples in the near future. On the other hand, prognostic or predictive markers for treatment sensitivity may be identified from the molecular profiles of primary cancer tissues. Selection of patients who are sensitive to chemotherapy will reduce the number of patients who undergo harmful chemotherapy with no effectiveness. The optimal tumor markers would be generalized, easy to assess, and accurate, and such markers are eagerly anticipated to enable personalized tailored therapy for CRC patients. (Cancer Sci 2009; 100: 195–199)
Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first‐line chemotherapy consists of multidrug regimens including oral 5‐FU agents such as S1/Xeloda ...and platinum preparations, as well as Trastuzumab, which is effective in HER2‐positive cases. Second‐ and third‐line chemotherapy regimens include taxanes, Ramucirumab (R‐mab), and Nivolumab (N‐mab), which have different mechanisms of action from first‐line chemotherapy. R‐mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5‐FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.
History and emerging chemotherapy regimens in first‐line chemotherapy for unresectable and/or recurrent gastric cancer. Japan‐directed evidence recommends SOX as well as CS regimens the best. Extra‐Japan‐directed evidence recommends Xelox as well as XP or EOX.
A growing body of evidences shows that systemic inflammatory responses are involved in patient prognosis in multiple cancers. Combinations of peripheral leukocyte fractions have been shown to be ...useful markers for the inflammatory responses. However, significance of such systemic inflammatory responses is still unknown in thyroid cancer. Accordingly, we aimed to clarify clinical impact of peripheral leukocyte fractions in papillary thyroid cancer (PTC).
Clinicopathological analyses were performed including preoperative leukocyte fractions in 570 patients with curatively resected PTC. Receiver operating characteristic curves were used to determine cutoffs of leukocyte fraction or inflammation indexes such as lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio. A Kaplan–Meier analysis and a Cox's proportional hazard model were used to conduct prognostic analysis. A multivariable logistic regression analysis was performed for correlation assay.
Preoperative low LMR predicted recurrence with high sensitivity (63.3%) and specificity (68.7%) (P = 0.002). The multivariable prognostic analyses revealed that preoperative low LMR (P = 0.025), pathological N1b (P = 0.019), high metastatic lymph node ratio (node density) (P = 0.014), and high thyroglobulin level (P = 0.002) independently predicted worse prognosis. The combination of these independent parameters clearly enriched high-risk patients (P < 0.001). Of note, low LMR was dramatically associated with recurrence especially in patients with advanced PTC.
Preoperative low LMR dramatically predicts high-risk patients for recurrences. The results in this study give rational to focusing on immune cell profiles to tackle advanced PTC.
Epigenetic alterations by promoter DNA hypermethylation and gene silencing in cancer have been reported over the past few decades. DNA hypermethylation has great potential to serve as a screening ...marker, a prognostic marker, and a therapeutic surveillance marker in cancer clinics. Some bodily fluids, such as stool or urine, were obtainable without any invasion to the body. Thus, such bodily fluids were suitable samples for high throughput cancer surveillance. Analyzing the methylation status of bodily fluids around the cancer tissue may, additionally, lead to the early detection of cancer, because several genes in cancer tissues are reported to be cancer-specifically hypermethylated. Recently, several studies that analyzed the methylation status of DNA in bodily fluids were conducted, and some of the results have potential for future development and further clinical use. In fact, a stool DNA test was approved by the U.S. Food and Drug Administration (FDA) for the screening of colorectal cancer. Another promising methylation marker has been identified in various bodily fluids for several cancers. We reviewed studies that analyzed DNA methylation in bodily fluids as a less-invasive cancer screening.
Background
Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers ...of IPMN are required for detection of invasive disease, and
cysteine dioxygenase 1
(
CDO1
) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN.
Patients and Methods
A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied.
CDO1
promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy.
Results
The methylation values (TaqMeth Vs) of
CDO1
increased when noncancerous pancreas tissues were compared with IPMA and HGD (
p
< 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (
p
= 0.0016), which were in turn higher than the corresponding noncancerous tissues (
p
< 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (
p
< 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (
p
= 0.0277).
Conclusions
CDO1
promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma–carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.
In normal tissue, p53 protein has a wide range of functions involving cell homeostasis; its mutation, however, permits a carcinogenic acquisition of function.
gene mutation is a major genomic ...aberration in various human cancers and is a critical event in the multi-step carcinogenesis process.
mutation is clinically relevant for the molecular classification of carcinogenesis, as most recently described rigorously by the Cancer Genome Atlas Research Network.
gene mutation has been considered to work as a tumor suppressor gene through the loss of its transcriptional activity, which is designated as a canonical function. However, in cancer patients with mutant
, mutated p53 protein is frequently overexpressed, suggesting the activation of an oncogenic process through a gain of function (GOF). As part of this GOF, molecular mechanisms explaining the non-canonical function of
gene abnormality have been reported, in which mutant p53 unconventionally binds with various critical molecules suppressing oncogenic properties, such as p63 and p73. Moreover, mutant
gene-targeted therapy has been rigorously developed, and promising clinical trials have been started. In this study, we summarize the novel aspects of mutant p53 and describe its prominent therapeutic potentials in human cancer.
Background
Little is known about the disadvantages of the coronavirus disease 2019 (COVID-19) pandemic in patients with gastric cancer. This study aimed to examine the negative impact of the COVID-19 ...pandemic on patients with gastric cancer in the first era in Japan.
Methods
This retrospective study included 725 patients diagnosed with gastric cancer who visited our hospital between April 2019 and March 2021. The number of patients and their characteristics before and during the COVID-19 pandemic were compared.
Results
The number of patients diagnosed with gastric cancer during the COVID-19 pandemic decreased by 26.2% (from 417 to 308;
p
= 0.013) compared to that before the COVID-19 pandemic. There was a significant decrease in cStage I cancer and an increase in cStage III cancer (
p
= 0.004). Patients were often symptomatic (
p
= 0.029), especially those with stenosis-related symptoms (
p
< 0.001) and longer symptom duration (
p
< 0.001). The number of endoscopic resections was decreased by 34.8% (
p
= 0.005). The number of total gastrectomy was higher than that of partial gastrectomy (
p
= 0.021). The median time to treatment was significantly shorter (
p
< 0.001).
Conclusions
In Japan, delays diagnosing patients with gastric cancer, probably due to refraining from consultation, may have resulted in an increase in the diagnosis of advanced-stage cancer. Moreover, an increasing proportion of patients required more invasive gastrectomy. Therefore, it may be necessary to educate patients not to refrain from consultation, even during the COVID-19 pandemic, as it can have a negative impact on treatment, policy decision, and prognosis of gastric cancer.
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