Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum for metastatic, recurrent, or unresectable gastric cancer.

BACKGROUND: We examined the impact of mismatch repair (MMR) status on efficacy of first-line fluoropyrimidine plus platinum (FP) chemotherapy in patients with HER2-negative metastatic, recurrent, or unresectable gastric cancer (mGC). METHODS: Patients with mGC receiving first-line FP between 2015 and 2018 at Asan Medical Center, Korea, were reviewed. We evaluated the clinical characteristics and the efficacy of chemotherapy according to MMR status in patients with available immunohistochemistry results. RESULTS: Of 895 patients, we analyzed 543 with available MMR protein expression results, and deficient MMR (dMMR) was detected in 4.4% (n = 24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p = 0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR. Objective response rate was 27.3% in dMMR and 34.3% in pMMR (p = 0.556). No difference in progression-free survival was noted between patients with dMMR and pMMR (median, 5.6 vs. 5.8 months, p = 0.266). Patients with dMMR tended to have better overall survival than those with pMMR although this difference was not statistically significant (median, 17.9 vs. 12.2 months, p = 0.183). CONCLUSIONS: Efficacy of first-line FP was not different by MMR status in mGC patients.

Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

BACKGROUND: The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. METHODS: The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. RESULTS: A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55 months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. CONCLUSION: Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

Epithelial-Mesenchymal Transition Phenotype and Peritumoral Immune Cell Infiltration in Advanced Biliary Tract Cancer.

BACKGROUND/AIM: This study evaluated the clinical implications of epithelial-mesenchymal transition (EMT) markers and peritumoral immune cell infiltration in patients with biliary tract cancer (BTC) treated with gemcitabine plus cisplatin (GemCis). MATERIALS AND METHODS: Forty-five patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell infiltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with overall survival (OS) less than 10 months (short-term survivor group, SS) and 21 with OS of 20 months or longer (long-term survivor group, LS). RESULTS: The density of tumor cells expressing epithelial marker E-cadherin (E-cadherin+ CK+) at the invasive tumor margin tended to be higher in the LS group than that in the SS group (p=0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin+ CK+) was significantly higher in the SS group than that in the LS group (p=0.021). The density of E-cadherin- vimentin+ tumor cells (E-cadherin- vimentin+ CK+) was also significantly higher in the SS group (p=0.020). The density of OX40 expressing cells was significantly higher in the SS group compared to that in the LS group (p=0.006). The density of vimentin-expressing tumor cells was positively correlated with FoxP3+ CD4+ regulatory T-cells (r=0.29, p=0.047) and OX40+ cells (r=0.48, p<0.001). CONCLUSION: EMT-related features were enriched in BTC patients with poor survival outcomes and associated with regulatory T-cell infiltration.

Phase II study of durvalumab monotherapy in patients with previously treated microsatellite instability-high/mismatch repair-deficient or POLE-mutated metastatic or unresectable colorectal cancer.

The aim of our study is to evaluate the clinical efficacy of durvalumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) or polymerase epsilon (POLE)-mutated metastatic or unresectable colorectal cancer (mCRC) who had disease progression after standard chemotherapy. This prospective, open-label, multicenter, phase II study enrolled patients with mCRC harboring MSI-H/dMMR or POLE mutations treated with at least one prior line of therapy. The participants received durvalumab (1500 mg) every 4 weeks intravenously. The primary endpoint was the objective response rate (ORR). Of the 33 patients, 30 had MSI-H/dMMR and 3 had POLE-mutated microsatellite stable (MSS) CRC. With a median follow-up duration of 11.2 months (95% confidence interval [CI]: 7.3-15.0), the ORR was 42.4% (95% CI: 25.5-60.8). Among three patients with POLE-mutated CRC, one patient who had an exonuclease domain mutation (EDM) achieved an objective response, but the others with mutations in the non-exonuclease domain had progressive disease. Overall, the median duration of response was not reached and 85.7% of the responses were ongoing at data cutoff. The progression-free survival rate of 12 months was 58.2% (95% CI: 39.0-73.1) and the 12-month overall survival rate was 68.3% (95% CI: 48.8-81.7). Grade 3 treatment-related adverse events occurred in 36.4% of the patients and were manageable. In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI-H/dMMR or POLE EDM. In patients with POLE-mutated mCRC, clinical response to durvalumab may be restricted to those with EDM.

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion.

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

Real-World Outcomes of Pazopanib Treatment in Korean Patients with Advanced Soft Tissue Sarcoma: A Multicenter Retrospective Cohort Study.

BACKGROUND: Pazopanib is the only tyrosine kinase inhibitor approved for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy, but there have been limited real-world data on pazopanib for the treatment of advanced STS. OBJECTIVE: We aimed to evaluate clinical outcomes of pazopanib in patients with multiple histologic STS types in real-world settings. PATIENTS AND METHODS: We retrospectively analyzed clinical data of Korean patients with advanced STS treated with pazopanib between 2008 and 2019. Outcomes of interest included treatment response, survival according to histologic subtypes, and adverse events. RESULTS: The analysis included 347 STS patients. The disease control rate for all pazopanib-treated patients was 54.8% (95% confidence interval (CI) 49.5-60.0); 54 patients (15.6%) achieved a partial response and 136 (39.2%) had stable disease. Patients with alveolar soft-part sarcoma (ASPS; 90%), solitary fibrous tumor (SFT; 88.2%), synovial sarcoma (66.7%), leiomyosarcoma (61.1%), and undifferentiated pleomorphic sarcoma (59.6%) showed higher disease control rates than those with other STS subtypes. Overall, median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% CI 4.5-6.0) and 12 months (95% CI 10-14), respectively. Noticeable survival outcomes occurred in patients with ASPS and SFT, with a median PFS of 24.5 (95% CI 2.5-30.0) and 13.0 (95% CI 3.0-21.3) months, respectively. The median OS of patients with ASPS and SFT was 48 (95% CI 17-52) and 32 (95% CI 19-66) months, respectively. Adverse drug reactions occurred in 170 patients (49.0%) but were not life-threatening. CONCLUSIONS: This real-world data analysis showed acceptable efficacy and tolerability of pazopanib in patients pretreated with cytotoxic chemotherapy for advanced STS, with favorable treatment outcomes for ASPS and SFT.

Genome-wide copy number alteration and VEGFA amplification of circulating cell-free DNA as a biomarker in advanced hepatocellular carcinoma patients treated with Sorafenib.

BACKGROUND: Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. METHODS: This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients. RESULTS: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/µL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/µL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes. CONCLUSION: Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.

Prognostic Value of the Microsatellite Instability Status in Patients With Stage II/III Rectal Cancer Following Upfront Surgery.

BACKGROUND: We investigated whether the microsatellite instability (MSI) status affects the survival outcomes in patients with stage II/III rectal cancer who have undergone an upfront curative resection. PATIENTS AND METHODS: A total of 1103 patients with curatively resected stage II/III rectal cancer who had available polymerase chain reaction-based MSI results were included in the final analysis. RESULTS: Twenty-four (2.2%) patients in the total cohort were found to be MSI-high (MSI-H). In univariate analysis, neither disease-free survival (DFS) nor overall survival (OS) demonstrated significant differences between patients with MSI-H tumors and those with MSI-low (MSI-L) or microsatellite stable (MSS) tumors. The 5-year DFS rate was 78.0% in MSI-H patients and 69.9% in MSI-L/MSS patients (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.35-2.02; P = .689). The 5-year OS rates for MSI-H and MSI-L/MSS patients were 84.0% and 83.1%, respectively (HR, 0.86; 95% CI, 0.27-2.69; P = .790). By multivariate analysis, the MSI status did not affect either the DFS (HR, 1.00; 95% CI, 0.40-2.47; P = .994) or OS (HR, 0.85; 95% CI, 0.26-2.73; P = .778). CONCLUSIONS: MSI-H tumors are rarely observed in rectal adenocarcinoma, and the MSI status may not affect the survival outcome in patients with a resected rectal cancer.

Gastrocolocutaneous Fistula: An Unusual Case of Gastrostomy Tube Malfunction with Diarrhea.

A gastrocolocutaneous fistula is a rare complication of percutaneous endoscopic gastrostomy (PEG). We report a case of a gastrocolocutaneous fistula presenting with intractable diarrhea and gastrostomy tube malfunction. A 62-year-old woman with a history of multiple system atrophy was referred to us because of PEG tube malfunction. Twenty days prior to presentation, the patient started developing sudden diarrhea within minutes after starting PEG feeding. Fluoroscopy revealed that the balloon of the PEG tube was located in the lumen of the transverse colon with the contrast material filling the colon. Subsequently, the PEG tube was removed and the opening of the gastric site was endoscopically closed using hemoclips. Clinicians should be aware of gastrocolocutaneous fistula as one of the complications of PEG insertion. Sudden onset of diarrhea, immediately after PEG feedings, might suggest this complication, which can be effectively treated with endoscopic closure.