Second-line chemoimmunotherapy with nivolumab and paclitaxel in immune-related biomarker-enriched advanced gastric cancer: a multicenter phase Ib/II study.

BACKGROUND: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC). METHODS: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m2 or dose level 2, 80 mg/m2) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis. RESULTS: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival. CONCLUSIONS: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy.

First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors.

Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.

PD-L1 expression and overall survival in Asian and western patients with gastric cancer.

Aim: Data are limited on PD-L1 expression and its association with overall survival (OS) in gastric cancer (GC) patients receiving routine care in different regions. Materials & methods: In a retrospective study, PD-L1 expression was assayed using the 22C3 pharmDx on GC tumor samples collected between 2003 and 2017 at South Korean and US cancer centers. PD-L1 positivity was defined as combined positive score (CPS) ≥1. The relationship between PD-L1 and OS was analyzed. Results: Of 574 GC tumor samples, 67.4% were CPS ≥1 (68.7% in Korean and 65.7% in US patients). PD-L1 expression was not associated with OS (adjusted hazard ratio: 0.94; 95% CI: 0.75-1.17). Conclusion: PD-L1 prevalence and its association with OS was similar between South Korean and US GC patients.

PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. METHODS: Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. RESULTS: Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006). CONCLUSION: We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Phase 2 study of afatinib among patients with recurrent and/or metastatic esophageal squamous cell carcinoma.

BACKGROUND: The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC). METHODS: Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single-nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole-exome sequencing and their associations with clinical outcomes were analyzed. RESULTS: Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow-up of 6.6 months, the median progression-free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment-related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole-exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib. CONCLUSIONS: The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum-resistant R/M-ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M-ESCC who may benefit from afatinib. LAY SUMMARY: Esophageal squamous cell carcinoma (ESCC) is a type of cancer with a dismal prognosis and very limited treatment options. The clinical efficacy of afatinib was evaluated in patients with recurrent and/or metastatic ESCC, with adverse events demonstrating the modest efficacy with manageable toxicity of this irreversible, pan-ErbB kinase inhibitor. Whole-exome sequencing analysis of 41 cases of ESCC further revealed that the patients harboring epidermal growth factor receptor (EGFR) amplifications and disruptive TP53 mutations are more likely to benefit from treatment with afatinib. The results of the current study have highlighted the clinical value of EGFR and TP53 as predictive biomarkers of platinum-resistant recurrent and/or metastatic ESCC for afatinib sensitivity.

Comprehensive Immuno-Molecular Profiles for Liposarcoma: Roles of Programmed Death Ligand 1, Microsatellite Instability, and PIK3CA.

BACKGROUND: Developing personalized strategies for cancer has shown good efficacies. METHODS: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. RESULTS: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL- tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). CONCLUSIONS: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Differences in the Efficacies of Pazopanib and Gemcitabine/Docetaxel as Second-Line Treatments for Metastatic Soft Tissue Sarcoma.

BACKGROUND: We retrospectively investigated the treatment outcomes of second-line treatment with pazopanib or gemcitabine/docetaxel in patients with advanced soft tissue sarcoma (STS). METHODS: Ninety-one patients who were treated with pazopanib or gemcitabine/docetaxel for advanced STS between 1995 and 2015 were analyzed. RESULTS: Forty-six and 45 patients received pazopanib and gemcitabine/docetaxel, respectively. The median progression-free survival for the group treated with pazopanib was 4.5 months compared with 3.0 months for the gemcitabine/docetaxel group (p = 0.593). The median overall survival for the group treated with pazopanib was 12.6 months compared with 14.2 months for the gemcitabine/docetaxel group (p = 0.362). The overall response rates (ORRs) were 6.5 and 26.7% in the pazopanib and gemcitabine/docetaxel groups, respectively. The following parameters had ORRs favoring gemcitabine/docetaxel: age ≥50 years (31.6 vs. 2.9%, p = 0.006), histologic grade 1-2 (40.9 vs. 0%, p = 0.001), and poor first-line treatment response (23.3 vs. 3.0%, p = 0.022). Gemcitabine/docetaxel was associated with better ORRs for the following histologic subtypes: leiomyosarcoma (p = 0.624), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (p = 0.055), and angiosarcoma (p = 0.182). However, the ORR of synovial sarcoma favored pazopanib (p = 0.99). CONCLUSIONS: The efficacies of pazopanib and gemcitabine/docetaxel as second-line treatments after doxorubicin or ifosfamide failure differed among clinical and histologic subgroups and appeared to facilitate a more personalized treatment approach for advanced STS.

Clinical analysis of patients with skeletal metastasis of lung cancer.

BACKGROUND: Many factors influence bone metastases of lung cancer, and several studies report about survival of skeletal metastasis. However, few studies have focused on identifying the prognostic factors for skeletal metastasis of lung cancer, especially following orthopedic surgery. We conducted a retrospective analysis of the clinical characteristics of skeletal metastasis from lung cancer and discuss the prognostic factors. METHODS: We performed a medical record review of 202 patients who were diagnosed with skeletal metastasis from lung cancer. Adenocarcinoma was found in 116 patients (57.4%), squamous cell carcinoma in 29 (14.4%), small-cell lung cancer (SCLC) in 37 (18.7%), and large-cell carcinoma and other types of cancer in 20 patients (9.9%). Orthopedic surgery for skeletal metastasis was performed in 41 patients (20.3%). RESULTS: Lung cancer survival was 12.1 months. After diagnosis of lung cancer, skeletal metastasis was found at a mean of 2.5 months, and skeletal metastasis survival was 9.8 months. Lung cancer survival in patients younger than 60 years was 13.8 months, and lung cancer survival in patients 60 years or older was 10.8 months (p = 0.009). Skeletal metastasis survival in patients younger than 60 years was 11.0 months, and skeletal metastasis survival in patients 60 years or older was 8.8 months (p = 0.002). Mean skeletal metastasis survival with surgery was 12.6 months and without surgery was 9.1 months (p < 0.000). In the multivariate analysis of lung cancer survival, age under 60 years [HR (95% CI) 1.549 (1.122-2.139), p = 0.008], non-small cell lung cancer pathology type [HR (95% CI) 1.711 (1.157-2.532), p = 0.008], chemotherapy for skeletal metastasis [HR (95% CI) 8.064 (3.981-16.332), p < 0.000], and radiation therapy for skeletal metastasis [HR (95% CI) 1.791 (1.170-2.742), p = 0.007] were significant, independent, good prognostic factors. In the multivariate analysis of skeletal metastasis survival, age under 60 years [HR (95% CI) 1.549 (1.124-2.134), p = 0.007], non-small cell lung cancer pathology type [HR (95% CI) 2.045 (1.373-3.047), p < 0.000], chemotherapy for skeletal metastasis [HR (95% CI) 7.121 (3.542-14.317), p < 0.000], and orthopedic surgical treatment for skeletal metastasis [HR (95% CI) 1.710 (1.148-2.547), p = 0.008] were significant, independent, good prognostic factors. CONCLUSIONS: Patients who survived longer were less than 60 years old, received chemotherapy as treatment for skeletal metastasis, had NSCLC rather than SCLC, and underwent orthopedic surgery for skeletal metastasis.

Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer.

PURPOSE: Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). EXPERIMENTAL DESIGN: CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. RESULTS: Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. CONCLUSIONS: These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.

Marked Loss of Muscle, Visceral Fat, or Subcutaneous Fat After Gastrectomy Predicts Poor Survival in Advanced Gastric Cancer: Single-Center Study from the CLASSIC Trial.

BACKGROUND: There is increasing interest in the influence of body composition on oncological outcomes. We evaluated the role of skeletal muscle and fat among patients with gastric cancer (GC) who underwent gastrectomy with or without adjuvant chemotherapy, as well as those changes' associations with survival outcomes. METHODS: The present study evaluated 136 patients with GC who were enrolled in the CLASSIC Trial at Yonsei Cancer Center. Baseline body compositions including skeletal muscle area, Hounsfield units (HU), visceral fat area, and subcutaneous fat area were measured by preoperative computed tomography (CT). CT before and after the gastrectomy were used to determine the 6-month relative changes in body composition parameters. Continuous variables were dichotomized according to the best cutoff values by Contal and O'Quigley method. RESULTS: Seventy-three patients (53.7%) underwent surgery alone, and 63 patients (46.3%) underwent surgery followed by adjuvant chemotherapy. The baseline body composition parameters were not associated with disease-free survival (DFS) or overall survival (OS). Except for the HU, the marked loss of muscle, visceral fat, or subcutaneous fat significantly predicted shorter DFS and OS. Patients with a marked loss in at least one significant body composition parameter had significantly shorter DFS (hazard ratio 2.9, 95% confidence interval 1.7-4.8, P < 0.001) and OS (hazard ratio 2.9, 95% confidence interval 1.7-5.0, P < 0.001). CONCLUSIONS: Marked loss in body composition parameters significantly predicted shorter DFS and OS among patients with GC who underwent gastrectomy. Postoperative nutrition and active healthcare interventions could improve the prognosis of these GC patients.

A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer.

BACKGROUND: We conducted a phase I/Ib, open-label, single-arm trial to assess the safety, tolerability and optimal scheduling regimen of OTSGC-A24 cancer vaccine in patients with advanced gastric cancer. METHODS: Patients with advanced gastric cancer with HLA-A*24:02 haplotype were included in this study. OTSGC-A24 was administered at 1 mg in 3-weekly (3w), 2-weekly (2w), and weekly (1w) cohorts to evaluate the safety, immunological response and schedule. Based on the highest specific cytotoxic T lymphocyte (CTL) induction rate at 4 weeks, using the ELISPOT test, cohorts were expanded to define the optimal dosing schedule for OTSGC-A24. RESULTS: In this study, 24 advanced gastric cancer patients with HLA-A*24:02 haplotype were enrolled and treated in 3 cohorts (3w cohort: 3; 2w cohort: 11 and 1w cohort: 10 patients). The most common adverse events were decreased appetite (29%), diarrhea (21%), myalgia (25%). The most common treatment-related adverse event was injection site erythema (25%). No dose-limiting toxicities were observed in any cohort and OTSGC-A24 was well tolerated. Positive CTL responses after vaccination were observed in 15 patients (75%) at 4 weeks: 3w cohort (33%), 2w cohort (88%), 1w cohort (78%). At 12 weeks, 18 patients had responded (90%); 3w cohort (100%), 2w cohort (100%), 1w cohort (78%). The best radiological was stable disease (40%). Median progression free survival was 1.7 months (95% CI: 1.4 to 3.5) and median overall survival was 5.7 months (95% CI 3.8 to 8.6). CONCLUSIONS: OTSGC-A24 combined peptide cancer vaccine was well tolerated. Significant responses in CTL were observed and the recommended phase 2 dose is 1 mg OTSGC-A24 sub-cutaneous, every 2 weeks. Although no radiological response was observed, a respectable overall survival was achieved, consistent with other immunotherapy agents being investigated in gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01227772 , Date registered: 21 Oct 2010.

Multidisciplinary treatment for patients with stage IV gastric cancer: the role of conversion surgery following chemotherapy.

BACKGROUND: With advances in gastric cancer chemotherapy, conversion surgery has drawn attention as a new strategy to improve the outcome of stage IV disease. We investigated the efficacy of conversion surgery following chemotherapy for patients with stage IV gastric cancer. METHODS: We retrospectively reviewed clinico-pathologic variables and oncologic outcomes for 101 patients with stage IV gastric cancer who were treated with systemic chemotherapy followed by gastrectomy with intension of curative resection from January 2005 to December 2012. RESULTS: In terms of the best response from palliative chemotherapy, complete or partial response were observed in 65 patients (64.4%) in overall. Complete response of metastatic site were observed in 72 (71.3%) and 66 (65.3%) patients as best and pre-operative response, respectively. The overall complete macroscopic resection, rate was 56.4%. Eleven patients (10.9%) received combined metastasectomy. There was no postoperative surgery-related mortality for 1 month. The median overall survival time was 26.0 months. Multivariable analysis identified complete macroscopic resection, chemotherapy response (complete response/partial response) of metastatic sites, and change in CEA level as independent prognostic factors contributing to overall survival. CONCLUSIONS: Patients with stage IV gastric cancer who exhibit a good clinical response to chemotherapy might obtain greater survival benefit from gastrectomy following chemotherapy compared with patients who exhibit a poor response to chemotherapy. Prospective, randomized trials are required to determine the best strategy for combining initial chemotherapy with subsequent gastrectomy.

Prognostic implications of polycomb proteins ezh2, suz12, and eed1 and histone modification by H3K27me3 in sarcoma.

BACKGROUND: Polycomb repressive complex 2 (PRC2; formed by EZH2, SUZ12, and EED protein subunits) and PRC1 (BMI1 protein) induce gene silencing through histone modification by H3K27me3. In the present study, we characterized the PRC expression pattern and its clinical implication in sarcoma. METHODS: Using immunohistochemistry, we analyzed PRC expression in 105 sarcoma patients with 5 subtypes: synovial sarcoma (n = 18), rhabdomyosarcoma (n = 28), Ewing sarcoma (n = 15), osteosarcoma (n = 30), and others (n = 14). RESULTS: The median age at diagnosis in the patient cohort was 26.8 years (range: 1-78 years) and the male-to-female ratio was 1:4. Initial disease presentation was locoregional disease in 83% of patients and initial metastatic disease in the remaining 17%. PRC expression was not significantly different according to histologic subtype (P = 0.400). Overall survival (OS) was significantly poor for SUZ12 high (P = 0.001), EED1 high (P = 0.279), and H3K27me3 high (P = 0.009). Ultimately, patients with PRC2high had significantly inferior OS than the no expression group (P = 0.009). In the Cox proportional hazard model adjusted for stage, histologic grade, surgery, margin and initial metastasis, SUZ12 expression (P = 0.020, HR 29.069, 95% CI 1.690-500.007), H3K27me3 (P = 0.010, HR 3.743, 95% CI 1.370-10.228) expression was significantly associated with shorter OS. CONCLUSION: We detected PRC expression in various sarcomas and demonstrated its independent negative prognostic role, suggesting the PRC axis as promising therapeutic target for treating sarcoma.

The prognostic value of volume-based parameters using 18F-FDG PET/CT in gastric cancer according to HER2 status.

BACKGROUND: We aimed to find the clinical value of metastatic tumor burden evaluated with F18-FDG PET/CT in gastric cancer patients, considering the human epidermal growth factor receptor 2 (HER2) status. METHODS: We retrospectively reviewed 124 patients with locally advanced or metastatic gastric cancer at Yonsei Cancer Center between January 2006 and December 2014 who had undergone baseline FDG PET/CT before first-line chemotherapy. We measured the maximum standardized uptake value from the primary tumor (SUVmax) and whole-body (WB) PET/CT parameters, including WB SUVmax, WB SUVmean, WB metabolic tumor volume (WB MTV), and WB total lesion glycolysis (WB TLG), in all metabolically active metastatic lesions (SUV threshold ≥2.5 or 40% isocontour for ≤2.5), and we determined their association with patient survival outcomes. RESULTS: SUVmax was higher in HER2-positive gastric cancers (median 12.1, range 3.4-34.6) compared to HER-2 negative (7.4, 1.6-39.1, P < 0.001). Among all patients, WB TLG > 600, which is indicative of a high metastatic tumor burden, showed worse progression-free survival (PFS) [hazard ratio (HR), 2.003; 95% CI, 1.300-3.086; P = 0.002] and overall survival (OS) (HR, 3.001; 95% CI, 1.950-4.618; P < 0.001) than did WB TLG ≤ 600. Among HER2-positive gastric cancer patients treated with trastuzumab, higher metabolic tumor burden predicted worse OS, but not PFS. CONCLUSIONS: HER2-positive gastric cancers had higher SUVmax compared to HER2-negative gastric cancers. In both HER2-negative patients and -positive patients receiving trastuzumab, FDG PET/CT volume-based parameters may have a role in further stratifying the prognosis of stage IV gastric cancer.

Cumulative Metformin Use and Its Impact on Survival in Gastric Cancer Patients After Gastrectomy.

OBJECTIVE: The aim of this study was to evaluate the association between metformin and survival of gastric cancer (GC) patients. BACKGROUND: Metformin has recently received attention as a potential anticancer treatment. However, no study has shown the survival benefit of metformin for GC patients. METHODS: A total of 1974 GC patients who underwent curative gastrectomy were compared for survival according to groups; 132 diabetic patients treated with metformin, 194 diabetic patients without metformin, and 1648 non-diabetic patients. RESULTS: During the median follow-up period of 6.2 years (interquartile range, 4.7-7.8 years), 381 patients (19.3%) died, including 302 (15.3%) who died from GC. The non-diabetic patients had significantly better recurrence-free survival (RFS; P < 0.0001), cancer-specific survival (CSS; P = 0.006), and overall survival (OS; P < 0.0001). However, the diabetic patients treated with metformin had a significantly better prognosis than those who were not (OS: hazard ratio [HR] = 0.584, 95% confidence interval [CI], 0.369-0.926; CSS: HR = 0.57, 95% CI, 0.334-0.975; RFS: HR = 0.633, 95% CI, 0.410-0.977), and metformin treatment prolonged survival in diabetic patients to a rate comparable to that in non-diabetic patients. In multivariable analysis using the Cox proportional hazard model with time-dependent covariates, each cumulative 6 months of metformin use was significantly associated with a decreased risk of recurrence, cancer-specific mortality, and all-cause mortality (RFS: HR = 0.864, 95% CI, 0.797-0.937; CSS: HR = 0.865, 95% CI, 0.782-0.958; OS: HR 0.870, 95% CI, 0.801-0.945). CONCLUSIONS: The increased cumulative duration of metformin use decreased the recurrence, all-cause mortality, and cancer-specific mortality rates among GC patients with diabetes who underwent gastrectomy.

Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma.

BACKGROUND: The PD-1/PD-L1 axis plays a paramount role in the immune escape of tumor cells by negative regulation of T-cell functions. The aim of the present study was to characterize the PD-L1 expression pattern and its clinical implication in soft-tissue sarcomas (STS). METHODS: We analyzed PD-L1 expression in 82 STS patients with 5 subtypes: rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma, epithelioid sarcoma, and mesenchymal chondrosarcoma. RESULTS: The median age at diagnosis was 26 (range: 1-78) and the male to female ratio was 1.6. The majority (80 %) of patients showed locoregional disease rather than metastatic disease at diagnosis. Thirty-five cases (43 %) showed PD-L1 expression and the proportion of PD-L1 expression was significantly different according to histologic subtypes (P = 0.004); highest in epithelioid sarcoma (100 %, 7/7), followed by synovial sarcoma (53 %, 10/19), rhabdomyosarcoma (38 %, 12/32), and Ewing sarcoma (33 %, 6/18), while it was not expressed in mesenchymal chondrosarcoma (0 %, 0/6). STS patients with PD-L1 expression had worse overall survival compared with those without PD-L1 expression (5-year survival rate: 48 % vs. 68 %, P = 0.015). The Cox proportional hazard model adjusted for histologic subtype, initial metastasis, and PD-L1 expression showed that PD-L1 expression was significantly associated with shorter overall survival (P = 0.037, HR 2.57, 95 % CI 1.060-6.231). CONCLUSION: We have confirmed PD-L1 expression in various STS of young population and demonstrated its independent negative prognostic role, thereby suggesting the PD-1/PD-L1 axis as a potential therapeutic target for the treatment of young STS patients.

Recursive partition analysis of peritoneal and systemic recurrence in patients with gastric cancer who underwent D2 gastrectomy: Implications for neoadjuvant therapy consideration.

BACKGROUND AND OBJECTIVES: To classify patients with nonmetastatic advanced gastric cancer who underwent D2-gastrectomy into prognostic groups based on peritoneal and systemic recurrence risks. METHODS: Between 2004 and 2007, 1,090 patients with T3-4 or N+ gastric cancer were identified from our registry. Recurrence rates were estimated using a competing-risk analysis. Different prognostic groups were defined using recursive partitioning analysis (RPA). RESULTS: Median follow-up was 7 years. In the RPA-model for peritoneal recurrence risk, the initial node was split by T stage, indicating that differences between patients with T1-3 and T4 cancer were the greatest. The 5-year peritoneal recurrence rates for patients with T4 (n = 627) and T1-3 (n = 463) disease were 34.3% and 9.1%, respectively. N stage and neural invasion had an additive impact on high-risk patients. The RPA model for systemic relapse incorporated N stage alone and gave two terminal nodes: N0-2 (n = 721) and N3 (n = 369). The 5-year cumulative incidences were 7.7% and 24.5%, respectively. CONCLUSIONS: We proposed risk stratification models of peritoneal and systemic recurrence in patients undergoing D2-gastrectomy. This classification could be used for stratification protocols in future studies evaluating adjuvant therapies such as preoperative chemoradiotherapy. J. Surg. Oncol. 2016;114:859-864. © 2016 2016 Wiley Periodicals, Inc.

Prognostic significance and frequency of EGFR expression and amplification in surgically resected advanced gastric cancer.

OBJECTIVE: The aim of this study is to find the frequency and the role of epidermal growth factor receptor expression as a prognostic biomarker in gastric cancer. METHODS: We evaluated the prognostic value and frequency of epidermal growth factor receptor expression and amplification using immunohistochemistry and silver in situ hybridization in a large cohort of curatively resected gastric cancer. RESULTS: Of the total of 935 cases, 294 (31.4%), 101 (10.8%) and 36 (3.9%) patients showed epidermal growth factor receptor 1+, 2+ and 3+ expression on immunohistochemistry, respectively. Epidermal growth factor receptor-positive (2+/3+) patients more frequently had intestinal type than epidermal growth factor receptor-negative (0/1+) patients (82.5 vs. 44.1%, P < 0.001). After adjusting for sex, age, stage and adjuvant chemotherapy, epidermal growth factor receptor-positive patients had a favorable overall survival outcome compared with epidermal growth factor receptor-negative patients (hazard ratio, 0.734; 95% confidence interval, 0.541-0.997; P = 0.047), especially in Stage III disease (hazard ratio, 0.676; 95% confidence interval, 0.472-0.968; P = 0.033). Among the 393 cases available for  in situ hybridization, the correlation between immunohistochemistry and in situ hybridization was statistically significant (P = 0.001). Thirteen patients with gene amplification (3.3%) did not show different survival outcome with others (P = 0.359). CONCLUSION: Epidermal growth factor receptor positivity was an independent favorable prognostic factor for gastric cancer, especially in Stage III disease.

Proper timing of adjuvant chemotherapy affects survival in patients with stage 2 and 3 gastric cancer.

BACKGROUND: Adjuvant chemotherapy improves survival in patients with gastric cancer. However, the relationship between the timing of adjuvant chemotherapy and survival has not been investigated. METHODS: Patients with D2-resected stage 2 and 3 gastric cancer that received adjuvant chemotherapy from 2005 to 2011 at Yonsei University Health System were included. The patients were grouped according to intervals between surgery and adjuvant chemotherapy. RESULTS: Among 840 patients, the interval from surgery to the start of adjuvant therapy was less than 4 weeks in 337 (40.1 %) patients (early group), 4-8 weeks in 467 (55.6 %) patients (intermediate group), and more than 8 weeks in 36 (4.3 %) patients (late group). The 5-year RFS was 55.7 % in the early group, 54.4 % in the intermediate group, and 43.6 % in the late group (p = 0.076). The corresponding 5-year OS rates were 63.4, 62.8, and 51.7 % (p = 0.037). CONCLUSIONS: There is insufficient evidence to suggest starting adjuvant chemotherapy within 4 weeks after surgery for patients with D2 resected stage 2 and 3 gastric cancer. However, delayed treatment of adjuvant chemotherapy after 8 weeks showed worse survival outcomes than early and intermediate treatment initiation, suggesting that adjuvant chemotherapy should be considered start within 8 weeks after radical resection.

PTEN deficiency as a predictive biomarker of resistance to HER2-targeted therapy in advanced gastric cancer.

BACKGROUND: To investigate the role of the phosphoinositide 3-kinase (PI3K) pathway activation in human epidermal growth factor receptor 2 (HER2)-targeted therapy. METHODS: We evaluated the predictive roles of PI3K, catalytic alpha (PIK3CA), and phosphatase and tensin homolog (PTEN) in HER2-based therapy (either trastuzumab or lapatinib). PTEN expression and PIK3CA mutation were analyzed using immunohistochemistry and pyrosequencing. RESULTS: Forty-eight patients received trastuzumab (n = 39) or lapatinib (n = 9) combination chemotherapy. PTEN loss was found in 47.9% (n = 23), but no PIK3CA mutations were identified. Twenty-six (54.1%) patients responded to HER2-based therapy, without a significant difference between patients with PTEN loss and those without (52.2 vs. 56.0%). Among the patients with responsive disease, time to best response did not differ by PTEN status, but the duration of response was significantly shorter for patients with PTEN loss (median 4.2 vs. 6.1 months, p = 0.04). In addition, patients with PTEN loss had a significantly shorter progression-free survival time (median 4.9 vs. 7.3 months, p = 0.047). CONCLUSIONS: PTEN deficiency is an important predictive marker for early resistance to HER2 inhibitor treatment in gastric cancer patients. This finding may be useful for the development of drug combinations and identification of patients who need a modified treatment strategy.