Purpose: Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC. Materials and Methods: Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity. Results: Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death. Conclusion Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Purpose: Retroperitoneal sarcomas (RPS) are rare malignant tumors arising from mesenchymal cells. The objective of this study was to review the treatment experiences and to identify prognostic factors for overall survival (OS) after primary resection and subsequent reoperations for recurrences. Methods: The medical records of patients who underwent resection for RPS at our institution between June 2002 and December 2016 were retrospectively reviewed. Univariate and multivariable Cox proportional hazards modeling was used to assess the prognostic factors for OS. Results: A total of 48 patients were enrolled. On multivariable analysis in primary resection group, the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) grade was a significant prognostic factor for OS (P=0.006). The patients who received chemotherapy after primary resection were significantly associated with poor prognosis (P=0.009). The 5-year OS rate after primary resection (n=48) were 58.1% and the 5-year cumulative reoperation rate after primary resection was 62.5%. After second resection for recurrence after primary resection (n=23), the 5-year OS rate was 64.3%. There was a tendency towards decreased surgery-free survival rate as the number of repeated resections for recurrent RPS increased. In the subset of patients (n=16) who underwent more than 3 repeated resections at our institute, the 5-year OS rate was 75.0%, indicating that repeated resections are not associated with worse outcome. Conclusion Only low tumor grade was an independent favorable prognostic factor for OS. Although the prognosis for RPS remains poor, repeated resections for recurrence are not associated with poor prognosis. Aggressive surgical strategies for recurred RPS patients are warranted.

Purpose: Hypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC. Materials and Methods: Patients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity. Results: Twenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death. Conclusion Evofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Purpose: Retroperitoneal sarcomas (RPS) are rare malignant tumors arising from mesenchymal cells. The objective of this study was to review the treatment experiences and to identify prognostic factors for overall survival (OS) after primary resection and subsequent reoperations for recurrences. Methods: The medical records of patients who underwent resection for RPS at our institution between June 2002 and December 2016 were retrospectively reviewed. Univariate and multivariable Cox proportional hazards modeling was used to assess the prognostic factors for OS. Results: A total of 48 patients were enrolled. On multivariable analysis in primary resection group, the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) grade was a significant prognostic factor for OS (P=0.006). The patients who received chemotherapy after primary resection were significantly associated with poor prognosis (P=0.009). The 5-year OS rate after primary resection (n=48) were 58.1% and the 5-year cumulative reoperation rate after primary resection was 62.5%. After second resection for recurrence after primary resection (n=23), the 5-year OS rate was 64.3%. There was a tendency towards decreased surgery-free survival rate as the number of repeated resections for recurrent RPS increased. In the subset of patients (n=16) who underwent more than 3 repeated resections at our institute, the 5-year OS rate was 75.0%, indicating that repeated resections are not associated with worse outcome. Conclusion Only low tumor grade was an independent favorable prognostic factor for OS. Although the prognosis for RPS remains poor, repeated resections for recurrence are not associated with poor prognosis. Aggressive surgical strategies for recurred RPS patients are warranted.

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12–15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.

Purpose: Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC. Materials and Methods: We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments. Results: In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug. Conclusion This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients.

OBJECTIVE: The aim of this study was to assess the clinical role of 18F-FDG PET/CT for the evaluation of lymph node metastasis in periorbital malignancies, compared with CT alone. MATERIALS AND METHODS: We analyzed eighteen PET/CT and CT scans in 15 patients with biopsy-proven periorbital malignancies. We compared the diagnostic capabilities of PET/CT and CT with regard to nodal metastasis by level-by-level analysis and by N staging prediction. The reference standards were surgical pathology (n = 7) from dissected lymph node specimens and the results from radiological follow-up (n = 11, mean 20.5 months; range 10-52 months). Moreover, any changes in patient care as prompted by PET/CT were recorded and compared with treatment planning for CT alone. RESULTS: PET/CT had a sensitivity of 100%, while CT had a sensitivity of 57% (p = 0.03) for nodal metastasis by level-by-level analysis. PET/CT had a specificity of 97%, positive predictive value of 93%, negative predictive value of 100%, and diagnostic accuracy of 98%, while the CT values for these same parameters were 97%, 89%, 82%, and 84%, respectively. PET/CT correctly predicted N staging with an accuracy of 100%, while CT was only 83% accurate (p = 0.01). Regarding the impact on patient care, the extent of surgery for regional lymph nodes and the treatment decision were modified by PET/CT in 39% of patients. CONCLUSION: PET/CT could provide useful information in the management of regional lymph node metastases in patients with periorbital malignancies.
Adult ; Aged ; Contrast Media ; Eye Neoplasms/pathology/*secondary ; Eyelid Neoplasms/pathology/secondary ; Female ; Fluorodeoxyglucose F18/*diagnostic use ; Humans ; Iohexol/analogs & derivatives/diagnostic use ; Lacrimal Apparatus Diseases/pathology ; Lymphatic Metastasis/diagnosis ; Male ; Middle Aged ; *Positron-Emission Tomography ; Radiopharmaceuticals/*diagnostic use ; Sensitivity and Specificity ; *Tomography, X-Ray Computed/methods