Esophageal cancer is one of the most aggressive gastrointestinal cancers. This review focuses on eight topics within the multidisciplinary approach for esophageal cancer. As esophagectomy is highly ...invasive and likely to impair quality of life, the development of less invasive strategies is expected. Endoscopic resection (ER) of early esophageal cancer is a less invasive treatment for early esophageal cancer. A recent phase II trial revealed that combined ER and chemoradiotherapy (CRT) is efficacious as an esophagus-preserving treatment for cT1bN0 squamous cell carcinoma (SCC). Esophagectomy and definitive CRT are equally effective for patients with clinical stage I SCC in terms of long-term outcome. For locally advanced resectable cancers, multidisciplinary treatment strategies have been established through several clinical trials of neoadjuvant or perioperative treatment. Minimally invasive esophagectomy may improve the outcomes of patients and CRT is a curative-intent alternative to esophagectomy. CRT with 50.4 Gy radiotherapy combined with salvage surgery is a promising option to preserve the esophagus. Induction chemotherapy followed by esophagectomy may improve the outcomes of patients with locally advanced unresectable tumors. Immune checkpoint inhibitors are effective for esophageal cancer, and their introduction to clinical practice is awaited.
Colonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain.
We ...examined the association of the use of lower endoscopy (updated biennially from 1988 through 2008) with colorectal-cancer incidence (through June 2010) and colorectal-cancer mortality (through June 2012) among participants in the Nurses' Health Study and the Health Professionals Follow-up Study.
Among 88,902 participants followed over a period of 22 years, we documented 1815 incident colorectal cancers and 474 deaths from colorectal cancer. With endoscopy as compared with no endoscopy, multivariate hazard ratios for colorectal cancer were 0.57 (95% confidence interval CI, 0.45 to 0.72) after polypectomy, 0.60 (95% CI, 0.53 to 0.68) after negative sigmoidoscopy, and 0.44 (95% CI, 0.38 to 0.52) after negative colonoscopy. Negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate hazard ratio, 0.73; 95% CI, 0.57 to 0.92). Multivariate hazard ratios for death from colorectal cancer were 0.59 (95% CI, 0.45 to 0.76) after screening sigmoidoscopy and 0.32 (95% CI, 0.24 to 0.45) after screening colonoscopy. Reduced mortality from proximal colon cancer was observed after screening colonoscopy (multivariate hazard ratio, 0.47; 95% CI, 0.29 to 0.76) but not after sigmoidoscopy. As compared with colorectal cancers diagnosed in patients more than 5 years after colonoscopy or without any prior endoscopy, those diagnosed in patients within 5 years after colonoscopy were more likely to be characterized by the CpG island methylator phenotype (CIMP) (multivariate odds ratio, 2.19; 95% CI, 1.14 to 4.21) and microsatellite instability (multivariate odds ratio, 2.10; 95% CI, 1.10 to 4.02).
Colonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy was also associated with a modest reduction in the incidence of proximal colon cancer. Screening colonoscopy and sigmoidoscopy were associated with reduced colorectal-cancer mortality; only colonoscopy was associated with reduced mortality from proximal colon cancer. Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have CIMP and microsatellite instability. (Funded by the National Institutes of Health and others.).
BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. ...MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval CI =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.
Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel ...contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.
Utilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.
The frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36-40%), followed by falls in the caecum (12-22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27-35% in other sites; p<0.0001).
The frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.
Background
The recurrence patterns and therapeutic outcomes of patients with recurrent esophageal cancer after curative esophagectomy are not fully understood.
Methods
Data on recurrence patterns and ...sites of recurrence in patients with recurrent esophageal cancer after curative esophagectomy from 2005 to 2015 were retrospectively analyzed. Time to recurrence after curative esophagectomy and survival after recurrence were compared among groups stratified by recurrence pattern and site. Multivariate analysis was performed to identify clinicopathological parameters influencing survival after recurrence.
Results
Of the 290 patients identified, a single pattern of recurrence occurred in 224 patients (77.2%) and a multiple pattern of recurrence occurred in 66 patients (22.8%). The most frequent recurrence pattern was lymph node in 173 patients (59.7%), followed by distant organ in 133 patients (45.9%). Median time to recurrence and median survival after recurrence of all patients were 228 and 327 days, respectively. Among patients with lymph node or lung recurrence, there were 5-year survivors after recurrence who underwent multimodal therapy. Multivariate analysis revealed that longer disease-free interval hazard ratio (HR) 0.70, 95% confidence interval (95% CI) 0.52–0.93, single pattern of recurrence (HR 0.54, 95% CI 0.39–0.74), and curative treatment for recurrence (HR 0.17, 95% CI 0.10–0.28) were significantly associated with favorable prognosis.
Conclusions
Although the prognosis of recurrent esophageal cancer remains unfavorable, if multimodal treatment that includes local therapy was curative, prognosis could improve, especially in patients with lymph node or lung recurrence.
CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level ...of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38
MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21
CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.
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► CD44v contributes to the reduction of intracellular reactive oxygen species ► CD44v promotes GSH synthesis by interacting with glutamate-cystine transporter xCT ► Variant 8–10 region is required for CD44v-xCT interaction leading to GSH synthesis ► xCT inhibitor sulfasalazine suppresses CD44-dependent cancer cell expansion in vivo
The aim of this study was to clarify the correlation between oropharyngeal microflora and postoperative complications as well as long-term survival after esophagectomy.
Although the oral cavity is ...known to be a potential reservoir for pathogens, the influence of abnormal oropharyngeal microflora on the outcomes of patients undergoing esophagectomy remains unknown.
This study included 675 patients who underwent esophagectomy between 2007 and 2014. Saliva samples from the oropharynx were collected 2 days before the operation. There were 442 patients with indigenous flora (Ind group) and 233 with allopatric flora. Among the patients with allopatric flora, 140 had antibiotic-sensitive microbes only (Allo-S group) while 93 had different types of antibiotic-resistant microbes (Allo-R group). We investigated the correlation between the types of oropharyngeal microflora and the incidence of postoperative complications as well as long-term outcomes.
Sixteen microbes could be cultivated from the saliva samples. The incidence of postoperative pneumonia in the Allo-S and Allo-R groups was significantly higher than in the Ind group (P < 0.001). In addition, acute respiratory distress syndrome was more often observed in the Allo-R group than in the other groups (P = 0.002). A significantly higher rate of antibiotic use and longer hospital stays were observed in the Allo-R group compared with the Ind group. Multivariate logistic regression analysis revealed that the presence of allopatric antibiotic-resistant microbes in the oropharynx was an independent risk factor for postoperative pneumonia (odds ratio, 3.93; 95% confidence interval, 2.41-6.42). The overall survival was significantly poorer in the Allo-R group than in the other groups.
Preoperative oropharyngeal culture is a simple and low-cost method that can predict both the occurrence of postoperative pneumonia and poor prognosis after esophagectomy.
Mutations in PIK3CA the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase (PI3K) play an important role in colorectal carcinogenesis. Experimental evidence suggests that ...PIK3CA exon 9 and exon 20 mutations trigger different biologic effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior.
We sequenced PIK3CA by pyrosequencing in 1,170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) PIK3CA mutated tumors. Mortality HR according to PIK3CA status was computed using Cox proportional hazards model, adjusting for clinical and molecular features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and BRAF and KRAS mutations.
Compared with PIK3CA wild-type cases, patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly worse cancer-specific survival log-rank P = 0.031; multivariate HR = 3.51; 95% confidence interval (CI): 1.28-9.62 and overall survival (log-rank P = 0.0008; multivariate HR = 2.68; 95% CI: 1.24-5.77). PIK3CA mutation in either exon 9 or 20 alone was not significantly associated with patient survival. No significant interaction of PIK3CA mutation with BRAF or KRAS mutation was observed in survival analysis.
Coexistence of PIK3CA (the PI3K p110α subunit) exon 9 and 20 mutations, but not PIK3CA mutation in either exon 9 or 20 alone, is associated with poor prognosis of colorectal cancer patients.
Background
A nutritional indicator suitable for predicting complications after esophagectomy has not been confirmed. The nutritional screening tool CONUT is a potential candidate.
Methods
We ...retrospectively analyzed 352 patients who underwent elective esophagectomy with lymphadenectomy for esophageal cancer between April 2005 and December 2014. Patients were divided into three groups according to the malnutrition degree in controlling nutritional status (CONUT): normal, light malnutrition, moderate or severe malnutrition.
Results
The numbers of patients assigned to the normal, light malnutrition, and moderate or severe malnutrition groups were 205, 126, and 21, respectively. One hundred forty-seven (41.8 %) patients were considered malnourished. Patients with moderate or severe malnutrition had a significantly high incidence of any morbidity, severe morbidities, and surgical site infection. Hospital stay in patients with moderate or severe malnutrition was significantly longer. Logistic regression analysis suggested that moderate or severe malnutrition was an independent risk factor for any morbidity hazard ratio (HR) 2.75, 95 % confidence interval (CI) 1.081–7.020;
p
= 0.034 and severe morbidities (HR 3.07, 95 % CI 1.002–9.432;
p
= 0.049).
Conclusions
CONUT was a convenient and useful tool to assess nutritional status before esophagectomy. Patients with moderate or severe malnutrition according to CONUT are at high risk for postoperative complications.
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