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Purpose The purpose of this study was to reveal the clinicopathological characteristics and prognostic implications associated with fibroblast growth factor receptor 1 (FGFR1) amplification in colorectal cancers (CRCs). Materials and Methods We measured the copy number of FGFR1 by droplet digital polymerase chain reaction (ddPCR), and analyzed the FGFR1 expression by immunohistochemistry, in 764 surgically resected CRCs (SNUH2007 dataset, 384 CRCs; SNUH Folfox dataset, 380 CRCs). Results CRCs with ! 3.3 copies of the FGFR1 gene were classified as FGFR1 amplified. FGFR1 amplification was found in 10 of the 384 CRCs (2.6%) in the SNUH2007 dataset, and in 28 of the 380 CRCs (7.4%) in the SNUH Folfox dataset. In the SNUH2007 dataset, there was no association between the FGFR1 copy number status and sex, gross appearance, stage, or differentiation. High FGFR1 expression was associated with female sex and KRASmutation. At the molecular level, FGFR1 amplification was mutually exclusive with BRAF mutation, microsatellite instability, and MLH1 methylation, in both SNUH2007 and SNUH Folfox datasets. Survival analysis revealed that FGFR1 amplification was associated with significantly worse clinical outcome compared with no FGFR1 amplification, in both SNUH2007 and SNUH Folfox datasets. Within the SNUH2007 dataset, CRC patients with high FGFR1 expression had an inferior progression-free survival compared with those with low FGFR1 expression. The FGFR inhibitor, PD173074, repressed the proliferation of a CRC cell line overexpressing FGFR1, but not of cells with FGFR1 amplification. Conclusion FGFR1 amplification measured by ddPCR can be a prognostic indicator of poor clinical outcome in patients with CRCs.
Recent advances in immuno-oncology have increased understanding of the tumor immune microenvironment (TIME), and clinical trials for immune checkpoint inhibitor treatment have shown remission and/or durable response in certain proportions of patients stratified by predictive biomarkers. The TIME in colorectal cancer (CRC) was initially evaluated several decades ago. The prognostic value of the immune response to tumors, including tumor-infiltrating lymphocytes, peritumoral lymphoid reaction, and Crohn’s-like lymphoid reaction, has been well demonstrated. In this review, we describe the chronology of TIME research and review the up-to-date high-dimensional TIME landscape of CRC. We also summarize the clinical relevance of several biomarkers associated with immunotherapy in CRC, such as microsatellite instability, tumor mutational burden, POLE/POLD mutation, consensus molecular subtype, and programmed death-ligand 1 expression.
PurposeThe treatment outcomes and genomic profiles of diffuse midline glioma (DMG) in adult patients are rarely characterized. We performed a retrospective study to evaluate the clinicogenomic profiles of adult patients with brain DMG.Materials and MethodsPatients aged ≥ 18 years diagnosed with brain DMG at Seoul National University Hospital were included. The clinicopathological parameters, treatment outcomes, survival, and genomic profiles using 82-gene targeted next-generation sequencing (NGS) were analyzed. The 6-month progression-free survival (PFS6) after radiotherapy and overall survival (OS) were evaluated.ResultsThirty-three patients with H3-mutant brain DMG were identified. The median OS from diagnosis was 21.8 months (95% confidence interval [CI], 13.2 to not available [NA]) and involvement of the ponto-medullary area tended to have poor OS (median OS, 20.4 months [95% CI, 9.3 to NA] vs. 43.6 months [95% CI, 18.2 to NA]; p=0.07). Twenty-four patients (72.7%) received radiotherapy with or without temozolomide. The PFS6 rate was 83.3% (n=20). Patients without progression at 6 months showed significantly prolonged OS compared with those with progression at 6 months (median OS, 24.9 months [95% CI, 20.4 to NA] vs. 10.8 months [95% CI, 4.0 to NA]; p=0.02, respectively). Targeted NGS was performed in 13 patients with DMG, among whom nine (69.2%) harbored concurrent TP53 mutation. Two patients (DMG14 and DMG23) with PIK3CAR38S+E545K and KRASG12A mutations received matched therapies. Patient DMG14 received sirolimus with a PFS of 8.4 months.ConclusionPFS6 after radiotherapy was associated with prolonged survival in adult patients with DMG. Genome-based matched therapy may be an encouraging approach for progressive adult patients with DMG.
Background: Previous studies on synchronous colorectal carcinoma (SCRC) have reported inconsistent results about its clinicopathologic and molecular features and prognostic significance. Methods: Forty-six patients with multiple advanced tumors (T2 or higher category) who did not receive neoadjuvant chemotherapy and/or radiotherapy and who are not associated with familial adenomatous polyposis were selected and 99 tumors from them were subjected to clinicopathologic and molecular analysis. Ninety-two cases of solitary colorectal carcinoma (CRC) were selected as a control considering the distributions of types of surgeries performed on patients with SCRC and T categories of individual tumors from SCRC. Results: SCRC with multiple advanced tumors was significantly associated with more frequent nodal metastasis (p = .003) and distant metastasis (p = .001) than solitary CRC. KRAS mutation, microsatellite instability, and CpG island methylator phenotype statuses were not different between SCRC and solitary CRC groups. In univariate survival analysis, overall and recurrence-free survival were significantly lower in patients with SCRC than in patients with solitary CRC, even after adjusting for the extensiveness of surgical procedure, adjuvant chemotherapy, or staging. Multivariate Cox regression analysis revealed that tumor multiplicity was an independent prognostic factor for overall survival (hazard ratio, 4.618; 95% confidence interval, 2.126 to 10.030; p < .001), but not for recurrence-free survival (p = .151). Conclusions: Findings suggested that multiplicity of advanced T category–tumors might be associated with an increased risk of nodal metastasis and a risk factor for poor survival, which raises a concern about the guideline of American Joint Committee on Cancer’s tumor-node-metastasis staging that T staging of an index tumor determines T staging of SCRC.
Background: This study aimed to investigate the prognostic impact of intratumoral Fusobacterium nucleatum in colorectal cancer (CRC) treated with adjuvant chemotherapy. Methods: F. nucleatum DNA was quantitatively measured in a total of 593 CRC tissues retrospectively collected from surgically resected specimens of stage III or high-risk stage II CRC patients who had received curative surgery and subsequent oxaliplatin-based adjuvant chemotherapy (either FOLFOX or CAPOX). Each case was classified into one of the three categories: F. nucleatum–high, –low, or –negative. Results: No significant differences in survival were observed between the F. nucleatum–high and –low/negative groups in the 593 CRCs (p = .671). Subgroup analyses according to tumor location demonstrated that disease-free survival was significantly better in F. nucleatum–high than in –low/negative patients with non-sigmoid colon cancer (including cecal, ascending, transverse, and descending colon cancers; n = 219; log-rank p = .026). In multivariate analysis, F. nucleatum was determined to be an independent prognostic factor in non-sigmoid colon cancers (hazard ratio, 0.42; 95% confidence interval, 0.18 to 0.97; p = .043). Furthermore, the favorable prognostic effect of F. nucleatum–high was observed only in a non-microsatellite instability- high (non-MSI-high) subset of non-sigmoid colon cancers (log-rank p = 0.014), but not in a MSI-high subset (log-rank p = 0.844), suggesting that the combined status of tumor location and MSI may be a critical factor for different prognostic impacts of F. nucleatum in CRCs treated with adjuvant chemotherapy. Conclusions: Intratumoral F. nucleatum load is a potential prognostic factor in a non-MSI-high/non-sigmoid/non-rectal cancer subset of stage II/III CRCs treated with oxaliplatin-based adjuvant chemotherapy.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder caused by mutations in the tyrosine kinase domain of the CSF1R gene. ALSP is often misdiagnosed as other diseases due to its rarity and various clinical presentations such as Parkinsonism, pyramidal signs, cognitive impairment and/or psychiatric symptoms. We describe an autopsy case of ALSP with a CSF1R mutation. A 61-year-old woman presented insidious-onset gait difficulty for 12 years since her age of 49, and premature ovarian failure since her age of 35. At initial hospital visit, brain magnetic resonance imaging revealed hydrocephalus. Initially, Parkinson’s syndrome was diagnosed, and she was prescribed L-dopa/carbidopa because of spasticity and rigidity of extremities, which had worsened. Subsequently, severe neuropsychiatric symptoms and cognitive impairment developed and radiologically, features of leukoencephalopathy or leukodystrophy were detected. She showed a down-hill course and died, 12 years after initial diagnosis. At autopsy, the brain showed severe symmetric atrophy of bilateral white matter, paper-thin corpus callosum, thin internal capsule, and marked hydrocephalus. Microscopically, diffuse loss of white matter, relatively preserved subcortical U-fibers, and many eosinophilic bulbous neuroaxonal spheroids were noted, but there was no calcification. Pigmented glia with brown cytoplasmic pigmentation were readily found in the white matter, which were positive for Periodic acid-Schiff, p62, and CD163 stains, but almost negative for CD68. Whole-exome and Sanger sequencing revealed a CSF1R mutation (c.2539G>A, p.Glu847Lys) which was reported in prior one ALSP case. This example demonstrates that ALSP could be associated with premature ovarian failure.
Background: Although there are controversies regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy in patients with microsatellite instability–high (MSI-H) colorectal cancer (CRC), the pathologic features affecting postchemotherapeutic prognosis in these patients have not been fully identified yet. Methods: A total of 26 histopathologic and immunohistochemical factors were comprehensively evaluated in 125 stage II or III MSI-H CRC patients who underwent curative resection followed by fluoropyrimidine-based adjuvant chemotherapy. We statistically analyzed the associations of these factors with disease-free survival (DFS). Results: Using a Kaplan-Meier analysis with log-rank test, we determined that ulceroinfiltrative gross type (p=.003), pT4 (p<.001), pN2 (p=.002), perineural invasion (p=.001), absence of peritumoral lymphoid reaction (p=.041), signet ring cell component (p=.006), and cribriform comedo component (p=.004) were significantly associated with worse DFS in patients receiving oxaliplatin-based adjuvant chemotherapy (n=45). By contrast, pT4 (p<.001) and tumor budding-positivity (p=.032) were significant predictors of poor survival in patients receiving non-oxaliplatin–based adjuvant chemotherapy (n=80). In Cox proportional hazards regression model-based univariate and multivariate analyses, pT category (pT1-3 vs pT4) was the only significant prognostic factor in patients receiving non-oxaliplatin–based adjuvant chemotherapy, whereas pT category, signet ring cell histology and cribriform comedo histology remained independent prognostic factors in patients receiving oxaliplatin-based adjuvant chemotherapy. Conclusions: pT4 status is the most significant pathologic determinant of poor outcome after fluoropyrimidine-based adjuvant chemotherapy in patients with stage II/III MSI-H CRC.
Background: Recent studies have revealed that a small subset of Lynch syndrome-associated colorectal carcinomas (CRCs) is caused by a germline EPCAM deletion-induced MSH2 epimutation. Based on the finding of this genetic alteration, we investigated the implications of EPCAM expression changes in microsatellite instability-high (MSI-H) CRCs. Methods: Expression of EPCAM and DNA mismatch repair proteins was assessed by immunohistochemistry in 168 MSI-H CRCs. Using DNA samples of these tumors, MLH1 promoter methylation status was also determined by methylation-specific real-time polymerase chain reaction method (MethyLight). Results: Among 168 MSI-H CRCs, complete loss (CL) and focal loss (FL) of EPCAM expression was observed in two (1.2%) and 22 (13.1%) cases, respectively. Both of the EPCAM-CL cases were found in MSH2-negative tumors without MLH1 promoter methylation. However, only nine of the 22 EPCAM-FL tumors had MSH2 deficiency. Of the 22 EPCAM-FL tumors, 13 showed MLH1 loss, and among them, nine cases were determined to have MLH1 methylation. EPCAM-FL was significantly associated with advanced stage (p=.043), distant metastasis (p=.003), poor differentiation (p=.001), and signet ring cell component (p=.004). Conclusions: Loss of EPCAM expression is differentially associated with clinicopathological and molecular features, depending on the completeness of the loss, in MSI-H CRCs.
Background: Tumor microenvironment has recently drawn attention in that it is related with tumor prognosis. Cancer-associated fibroblast also plays a critical role in cancer invasiveness and progression in colorectal cancers. Periostin (POSTN), originally identified to be expressed in osteoblasts and osteoblast-derived cells, is expressed in cancer-associated fibroblasts in several tissue types of cancer. Recent studies suggest an association between stromal overexpression of POSTN and poor prognosis of cancer patients. Methods: We analyzed colorectal cancer cases for their expression status of POSTN in tumor stroma using immunohistochemistry and correlated the expression status with clinicopathological and molecular features. Results: High level of POSTN expression in tumor stroma was closely associated with tumor location in proximal colon, infiltrative growth pattern, undifferentiated histology, tumor budding, luminal necrosis, and higher TNM stage. High expression status of POSTN in tumor stroma was found to be an independent prognostic parameter implicating poor 5-year cancer-specific survival and 5-year progression-free survival. Conclusions: Our findings suggest that POSTN overexpression in tumor stroma of colorectal cancers could be a possible candidate marker for predicting poor prognosis in patients with colorectal cancers.
Objective: Proper management of lymph nodes (LNs) with ultrasonographic (US) indeterminate features in thyroid cancer patients remains elusive. We aimed to evaluate the malignancy risk and US findings predictive of malignancy for US indeterminate LNs in preoperative thyroid cancer patients through node-by-node correlation. Materials and Methods: A total of 348 LNs in 284 thyroid cancer patients, who underwent fine-needle aspiration or coreneedle biopsy between December 2006 and June 2015, were included. We determined the malignancy risks for US probably benign, indeterminate, and suspicious categories. For US indeterminate LNs, which had neither echogenic hilum nor hilar vascularity in the absence of any suspicious finding, US findings were compared between benign and metastatic LNs using Mann-Whitney U test and Fisher’s exact test. Results: US imaging diagnoses were probably benign in 20.7% (n = 72) cases, indeterminate in 23.6% (n = 82), and suspicious in 55.7% (n = 194). Malignancy risk of US indeterminate LNs (19.5% [16/82]) differed from those of the US probably benign (2.8% [2/72]) (p = 0.002) and US suspicious LNs (78.4% [152/194]) (p < 0.001). Among US indeterminate LNs, there were no significant differences in short, long, and long-to-short diameter (L/S) ratios between benign and metastatic LNs (3.9 vs. 3.8 mm, p = 0.619; 7.3 vs. 7.3 mm, p = 0.590; 1.9 vs. 1.9, p = 0.652). Conclusion: US indeterminate LNs were frequently encountered during preoperative evaluation and had intermediate malignancy risk. Given the lack of discriminative power of size criteria and L/S ratio, clinical factors such as surgical strategy and node size should be considered for proper triage of US indeterminate LNs in thyroid cancer.