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Background: Although the incidence and mortality have decreased, gastric cancer (GC) is still a public health issue globally. An international study reported higher survival in Korea and Japan than other countries, including the United States. We examined the determinant factors of the high survival in Japan compared with the United States. Methods: We analysed data on 78,648 cases from the nationwide GC registration project, the Japanese Gastric Cancer Association (JGCA), from 2004–2007 and compared them with 16,722 cases from the Surveillance, Epidemiology, and End Results Program (SEER), a United States population-based cancer registry data from 2004–2010. We estimated 5-year relative survival and applied a multivariate excess hazard model to compare the two countries, considering the effect of number of lymph nodes (LNs) examined. Results: Five-year relative survival in Japan was 81.0%, compared with 45.0% in the United States. After controlling for confounding factors, we still observed significantly higher survival in Japan. Among N2 patients, a higher number of LNs examined showed better survival in both countries. Among N3 patients, the relationship between number of LNs examined and differences in survival between the two countries disappeared. Conclusion: Although the wide differences in GC survival between Japan and United States can be largely explained by differences in the stage at diagnosis, the number of LNs examined may also help to explain the gaps between two countries, which is related to stage migration.

Background In 2016, the National Comprehensive Cancer Network included neoadjuvant chemotherapy as a treatment option for patients with clinical T4b colon cancer. However, there is little published data on the survival impact of neoadjuvant chemotherapy for locally advanced colon cancer. Methods Adult patients with non-metastatic clinically staged T3 or T4 colon cancer who underwent surgical resection were identified from the National Cancer Data Base between 2006 and 2014. Treatment was categorized as neoadjuvant chemotherapy followed by surgery and surgery followed by adjuvant chemotherapy. Overall survival was compared between the two groups using propensity score matching. Results Of 27,575 patients that met inclusion criteria, 26,654 (97%) were treated with surgery followed by adjuvant chemotherapy and 921 (3%) received neoadjuvant chemotherapy followed by surgery. After propensity score matching, patients with T4b colon cancer treated with neoadjuvant chemotherapy had a 23% lower risk of death at 3 years compared to patients that had adjuvant chemotherapy (HR 0.77, 95% CI 0.60–0.98; p  = 0.04). However, neoadjuvant chemotherapy did not demonstrate a similar significant benefit for patients with T3 and T4a disease. Conclusions Patients with clinical T4b colon cancer treated with neoadjuvant chemotherapy may have an improved survival compared to those who receive adjuvant chemotherapy. Further prospective investigation is warranted.

Background Although resection historically played a prominent role in the treatment of metastatic melanoma, recent advances have altered the therapeutic landscape, and potentially the role of surgery. We examined surgical selection and metastasectomy outcomes before and after the onset of the effective drug therapy era. Methods Patients with stage IV melanoma were identified and characterized by treatment era (either 1965–2007 or 2008–2015) and by systemic therapy agents. BRAF and/or MEK inhibitors, as well as checkpoint inhibitors, were included as modern agents. Selection factors for metastasectomy were examined by era. A matched-pair analysis of outcomes of surgical and non-surgical patients receiving modern systemic agents was performed. Results Among 2353 eligible patients, 1065 (45.2%) underwent surgical treatment. Factors associated with selection for metastasectomy in the early era included female sex, no prior stage III disease, single-organ involvement, and M1a (vs. M1c) disease (all p  < 0.007). In the current era, the proportion of surgically treated patients increased modestly (54.5% vs. 44.7%, p  = 0.02) and age was the only independent selection factor ( p  < 0.01). Surgery followed by modern therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival (MSS) versus modern therapy alone (58.8% vs. 38.9%, p  = 0.049). Multivariable regression showed single-organ involvement (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.21–0.90, p  = 0.02) and first-line surgery (HR 0.47, 95% CI 0.23–0.98, p  = 0.04), as well as use of modern agents (HR 0.29, 95% CI 0.21–0.40, p  < 0.001), were independently associated with improved MSS. Conclusions and Relevance While modern systemic agents have improved outcomes in stage IV melanoma, metastasectomy remains associated with favorable survival. Resection remains a viable therapeutic approach, possibly worthy of prospective evaluation.

Background Recent randomized trials suggest improved outcomes in patients with locally advanced colon cancer (LACC) treated with neoadjuvant chemotherapy (NAC). Optimal selection of patients for NAC depends on accurate clinical staging. The purpose of this study was to examine the degree of correlation between clinical and pathologic staging in patients with colon cancer (CC). Methods Adult patients with non-metastatic CC who underwent surgery were identified from the National Cancer Data Base between 2006 and 2014. Data on clinical and pathologic staging was obtained. Kappa index was used to determine the correlation between clinical and pathologic staging. Results One hundred five thousand five hundred sixty-nine patients were identified. The overall correlation rate between clinical and pathologic staging for T stage was 80% (kappa 0.7) and 83% for N stage (kappa 0.6). The correlation rate was 54% for T1, 76% for T2, 95% for T3, and 94% for T4 ( P  < 0.001). This compared with 81% for N0, 82% for N1, and 97% for N2 ( P  < 0.001). The sensitivity and specificity of clinical staging for identifying T3/T4 vs T1/T2 were 80 and 98%, respectively, compared to 60 and 98% for N1/N2 vs N0 ( P  < 0.001). Conclusions Our findings suggest that current modalities used for clinical staging are accurate in predicting pathologic stage for advanced but not early T and N disease. Further optimization of clinical staging is essential for the accurate selection of patients who may benefit from neoadjuvant therapy and to avoid overtreatment of low-risk patients.

The prognostic relevance of lymphatic micrometastases in colorectal carcinoma is unclear. To determine the prognostic significance of micrometastases in colorectal cancer, a meta-analysis was performed on all studies, which reported 3-year disease-free survival (DFS) and overall survival (OS). Published studies selected for meta-analysis contained sufficient data from which to extrapolate estimates of 3-year DFS and/or OS. From 1991-2003, 25 studies re-examined N0 lymph nodes by serial sectioning and immunohistochemical (IHC) staining or reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Eight studies (566 patients) with IHC detected micrometastases and three (173 patients) with RT-PCR micrometastases were used to determine DFS and OS. Weighted estimates of 3-year survival were combined across studies within each group, and the combined survival estimates were compared across groups using a binomial test. Micrometastases were identified in all IHC studies; upstaging, including N1, N1mi and N0(i+), was achieved in 32% (179/566 patients). All RT-PCR studies identified micrometastases; upstaging to N0(mol+) was achieved in 37% (64/173 patients). There was a statistically significant difference in 3-year OS between RT-PCR positive N0(mol+) patients (77.8%) and those for whom micrometastases were not detected (96.6%) (P < .001). The prognostic value of micrometastases detected retrospectively by RT-PCR is significant in AJCC stage II colorectal patients. Studies utilizing RT-PCR performed a more complete nodal analysis when compared to studies using IHC techniques. RT-PCR may also be more specific for the detection of clinically relevant micrometastases compared to IHC detected cytokeratins. Prospective studies are needed to evaluate the potential benefit of systemic chemotherapy in patients with molecular metastases.

Background Expression of CD3+ T cells, CD8+ cytotoxic T cells, CD45RO+ memory T cells, and FOXP3+ regulatory T cells at the invasive margin (IM) and tumor center (TC) has correlated with survival in gastric adenocarcinoma (GA) patients from East Asia, independent of anatomic staging. The reason for improved survival in East Asians compared with Western patients is a subject of debate. This study examined the immune profiles of a cohort of Western patients with GA, and their association with overall survival (OS). Methods Immunohistochemistry (IHC) using antibodies to CD3, CD4, CD8, CD45RO, and FOXP3 was performed on a randomly selected resected GA specimens from 88 Western patients. Cutoffs for high or low expression of each marker were determined with maximally selected rank statistics, and multivariable Cox proportional-hazards models constructed to evaluate the relationship between OS and expression of each marker at the IM and TC. Results Immune cell density was independent of anatomic staging. High expression of CD3, CD4, CD8, and CD45RO at the IM along with CD4 and FOXP3 at the TC were associated with improved OS. A combined marker of CD3, CD8, CD45RO, and FOXP3 associated with OS in East Asian GA was also validated. Discussion This is the first report in US patients to demonstrate that high expression of multiple subsets of T lymphocytes in GA is associated with better OS independent of clinical factors and anatomic stage. Further evaluation of immune-modulating mechanisms may explain survival differences between Western and Eastern patients and provide opportunity for novel treatments.

The incidence of sporadic early-onset colon cancer (EOCC) has increased worldwide. The molecular mechanisms in the tumor and the tumor microenvironment (TME) in EOCC are not fully understood. The aim of this study is to unravel unique spatial transcriptomic and proteomic profiles in tumor epithelial cells and cancer-associated fibroblasts (CAFs). Here, we divide the sporadic colon cancer tissue samples with transcriptomic data into patients diagnosed with EOCC (<50 yrs) and late-onset colon cancer (LOCC, ≥50 yrs) and then, analyze the data using CIBERSORTx deconvolution software. EOCC tumors are more enriched in CAFs with fibroblast associated protein positive expression (FAP(+)) than LOCC tumors. EOCC patients with higher FAP mRNA levels in CAFs have shorter OS (Log-rank test, p  < 0.029). Spatial transcriptomic analysis of 112 areas of interest, using NanoString GeoMx digital spatial profiling, demonstrate that FAP(+) CAFs at the EOCC tumor invasive margin show a significant upregulation of WNT signaling and higher mRNA/protein levels of fibroblast growth factor 20 (FGF20). Tumor epithelial cells at tumor invasive margin of EOCC tumors neighboring FAP(+) CAFs show significantly higher mRNA/protein levels of fibroblast growth factor receptor (FGFR2) and PI3K/Akt signaling activation. NichNET analysis show a potential interaction between FGF20 and FGFFR2. The role of FGF20 in activating FGFR2/pFGFR2 and AKT/pAKT was validated in-vitro. In conclusion, we identify a unique FAP(+) CAF population that showed WNT signaling upregulation and increased FGF20 levels; while neighbor tumor cells show the upregulation/activation of FGFR2-PI3K/Akt signaling at the tumor invasive margin of EOCC tumors.