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The pancreatic cancer microenvironment is crucial in cancer development, progression and drug resistance. Cancer-stromal interactions have been recognized as important targets for cancer therapy. However, identifying relevant and druggable cancer-stromal interactions is challenging due to the lack of quantitative methods to analyze the whole cancer-stromal interactome. Here we studied 14 resected pancreatic cancer specimens (8 pancreatic adenocarcinoma (PDAC) patients as a cancer group and 6 intraductal papillary-mucinous adenoma (IPMA) patients as a control). Shotgun proteomics of the stromal lesion dissected with laser captured microdissection (LCM) was performed, and identified 102 differentially expressed proteins in pancreatic cancer stroma. Next, we obtained gene expression data in human pancreatic cancer and normal pancreatic tissue from The Cancer Genome Atlas database (n = 169) and The Genotype-Tissue Expression database (n = 197), and identified 1435 genes, which were differentially expressed in pancreatic cancer cells. To identify relevant and druggable cancer-stromal-interaction targets, we applied these datasets to our in-house ligand-receptor database. Finally, we identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients. Furthermore, we examined FN1 and ITGA3 protein expression in pancreatic cancer tissues using tissue microarrays (TMAs) of 271 PDAC cases, and demonstrated that FN1-ITGA3 had unfavorable prognostic impact for PDAC patients. [ABSTRACT FROM AUTHOR]

Highlights • Cancer of unknown primary (CUP) is metastatic without a known primary. • Investigated the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. • S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to monotherapy. • S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model. Abstract Cancer of unknown primary (CUP) is metastatic disease without a known primary and therefore very difficult to identify effective therapy. Previously, we demonstrated partial efficacy of Salmonella typhimurium A1-R (S. typhimurium A1-R) alone and carboplatinum alone (CAR) on a CUP patient tumor in the patient-derived xenograft (PDOX) model. The aim of the present study was to investigate the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. The CUP tumors were implanted orthotopically into the left supraclavicular fossa of nude mice to match the site from which they were resected from the patient. CUP PDOX models were divided randomly into the following 4 groups after the tumor volume reached 100 mm3: G1: untreated group; G2: CAR (30 mg/kg, i.p., weekly, 2 weeks); G3: S. typhimurium A1-R (5x107 CFU/body, i.v., weekly, 2 weeks).; G4: S. typhimurium A1-R combined with CAR (S. typhimurium A1-R; 5x107 CFU/body, i.v., weekly, 2 weeks; CAR, 30 mg/kg, i.p., weekly, 2 weeks). Each group comprised 7 mice. All mice were sacrificed on day 15. Tumor volume and body weight were measured twice a week. S. typhimurium A1-R and CAR moderately inhibited tumor growth compared to the untreated group on day 15 (P < 0.001 and P < 0.001, respectively). S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to S. typhimurium A1-R monotherapy or CAR monotherapy on day 15 (P = 0.004 and P = 0.001, respectively). The present report demonstrates that S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model. [ABSTRACT FROM AUTHOR]

Background The impact of associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) on tumor growth activity was investigated. Methods A BALB/c mouse model (male, 8–10 weeks old) of liver metastasis labeled by red fluorescent protein was established. Changes in future liver remnant (FLR) volumes, tumor growth activity, and levels of cytokines and growth factors in liver tissues during the treatment period were compared among the models involving ALPPS, portal vein ligation (PVL), or sham operation. Results The ratio of the FLR volume to body weight at 24 h after the procedure was greater for ALPPS (4.45 ± 0.12 × 10 −2 ) than for PVL (3.79 ± 0.12 × 10 −2 ; P = 0.003) and sham operation (3.18 ± 0.16 × 10 −2 ; P < 0.001). No differences in tumor progression in the FLR were observed at any time point after the procedures. Within the deportalized liver (DL), although tumor progression was observed during a later period after ALPPS (9 days postoperative) and PVL (12 days postoperative), no acceleration of tumor growth after ALPPS was observed in an early period similar to PVL. Conclusion ALPPS induces a rapid increase in FLR volume and avoids remnant tumor progression during the early postoperative period. [ABSTRACT FROM AUTHOR]

Background: We compared tumor growth activity during treatment associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) with that in classical 2-stage hepatectomy.Methods: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), and tumor growth activity during the treatment period were compared between 12 patients treated with ALPPS and 20 patients treated with 2-stage hepatectomy for colorectal liver metastases. This study was registered in UMIN Clinical Trials Registry (registration number, UMIN000018622).Results: The FLR hypertrophy ratio at 1 week after the first operation was greater in the ALPPS group (1.43 ± 0.24) than the 2-stage group (1.21 ± 0.28, P = 0.043). The mean kinetic growth rate (mKGR) of tumors in the ALPPS group (0.548 ± 7.29 mL/day) did not differ significantly from that in the 2-stage group (-3.53 ± 7.02 mL/day) in the first week after the initial procedure (P = 0.210). However, mKGR between 1 and 3 weeks after the first procedure (1.29 ± 2.34 mL/day) was significantly greater than that in first week after the procedure in the 2-stage group (P = 0.034).Conclusions: ALPPS induces a rapid FLR volume increase while avoiding remnant tumor progression. [ABSTRACT FROM AUTHOR]

Objective We compared histologic findings in nonneoplastic portions of liver resected during surgery associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) with those from hepatectomy after portal vein embolization (PVE). Summary background data Effects of congestion and ischemia in ALPPS on hepatocyte regeneration are incompletely understood, as are those on hepatocyte maturity. Methods Specimens obtained from 8 patients treated with ALPPS and from 14 patients treated with hepatectomy after PVE were examined by light and electron microscopy. Results Extrapolated kinetic growth of the future liver remnant (FLR) for ALPPS was 14.4 ± 4.8 mL/d, which was faster than for PVE (3.6 ± 2.2 mL/d; P < .001). Microscopically, the FLR showed greater hepatocyte cell density and smaller hepatocyte size in ALPPS than in PVE ( P < .01 for each). Bright-appearing hepatocytes and sinusoidal narrowing were more frequent in ALPPS (50% and 50%) than in PVE (0% and 8.3%; P = .025 for each). In the deportalized ventral aspect of the anterior section, hepatocyte atrophy, hepatocyte degeneration or necrosis, sinusoidal dilation, fibrosis, and congestion were more frequent in ALPPS than in PVE ( P = .001, P = .002, P < .001, and P < .001, respectively). Electron microscopy frequently showed vacant-appearing hepatocytic cytoplasm filled with glycogen granules in the FLR in ALPPS. Fewer cytoplasmic organelles and lipofuscin granules were observed in ALPPS than in PVE. Conclusion In the FLR, regenerative hepatocytes in ALPPS were morphologically immature compared with PVE. ALPPS should be performed with caution, considering limited functional increase in the FLR reflecting immaturity of the regenerative hepatocytes. [ABSTRACT FROM AUTHOR]

Background: Tumor reduction by present-day prehepatectomy chemotherapy can render initially unresectable disease resectable. However, little is known about whether effects on liver metastases with radiologically defined “attachment to or invasion of” major intrahepatic vessels differ between chemotherapy regimens with or without monoclonal antibodies. We compared histologically the relationships between liver tumors and major intrahepatic vessels after chemotherapy according to regimens used to treat colorectal liver metastasis. Methods: In 38 patients who underwent chemotherapy and hepatectomy with pretreatment images showing metastases attached to or invading major intrahepatic vessels, 62 metastases showed attachment to or invasion of 88 vessels. After resection, attachment, invasion, and separation were determined histopathologically in resected specimens. Results: Thirteen patients received cytotoxic drug combinations alone, whereas 25 were treated with regimens including a monoclonal antibody (bevacizumab in 15 and cetuximab in 10). By imaging, 16% (5/32) of vessels in patients receiving cytotoxic drugs alone, 23% (8/35) of vessels in those also receiving bevacizumab, and 48% (10/21) of vessels in those also receiving cetuximab showed detachment after chemotherapy (P = .015 for cetuximab versus cytotoxic and P = .039 for cetuximab versus bevacizumab). Excluding 8 vessels not evaluated histologically, 23 of 31 vessels in the cytotoxic group remained attached or invaded, as did 16 of 29 in the bevacizumab group and 8 of 20 vessels in the cetuximab group (P = .05 versus cytotoxic). Conclusion: Prehepatectomy chemotherapy regimens including monoclonal antibodies, particularly anti-epidermal growth factor receptor antibodies, eradicated attachment or invasion between vessels and metastases more frequently. Individualized strategies for prehepatectomy chemotherapy based on intrahepatic location of metastases may offer advantages according to proximity of the metastases to the major intrahepatic vessels. [Copyright &y& Elsevier]

Background: Although short- and long-term results have been described in previous reports of 2-stage hepatectomy, growth activity in metastases resected at the first versus second hepatectomy has not been compared. Methods: We analyzed growth activity of liver metastases from colorectal cancers resected at first and second hepatectomy by real-time reverse-transcription polymerase chain reaction and immunohistochemistry in 21 patients undergoing 2-stage hepatectomy to justify the 2-stage approach. Results: Of 24 patients planned to undergo 2-stage hepatectomy for colorectal liver metastases, 21 had completion of both stages. Although maximum tumor size and serum carcinoembryonic antigen before and after the first procedure did not differ, volume of the future liver remnant increased after the first procedure. Ki67 and proliferating cell nuclear antigen positivity rates were comparable between initially and subsequently resected tumors (P = .09 and P = .83, respectively). Expression of mRNA (relative to glyceraldehyde-3-phosphate dehydrogenase mRNA) in initially versus subsequently resected tumors for cyclin D1 (4.27 ± 1.29 vs 6.52 ± 2.23; P = .90), cyclin E1 (24.18 ± 16.81 vs 10.53 ± 2.28; P = .60), hepatocyte growth factor (3.16 ± 1.42 vs 0.58 ± 0.15; P = .11), basic fibroblast growth factor (5.42 ± 1.54 vs 5.92 ± 3.33; P = .13), epidermal growth factor (19.56 ± 14.76 vs 9.07 ± 4.54; P = .74), and transforming growth factor-α (2.63 ± 1.02 vs 2.07 ± 1.15; P = .29) showed no differences between the 2 time points. Conclusion: Two-stage hepatectomy did not seem to induce tumor growth activity or growth factor expression. The 2-stage strategy in combination with effective preoperative chemotherapy is a valuable strategy for colorectal metastases. [ABSTRACT FROM AUTHOR]

Sarcoma is a rare and recalcitrant malignancy. Although immune and novel targeted therapies have been tested on many cancer types, few sarcoma patients have had durable responses with such therapy. Doxorubicin and cisplatinum are still first-line chemotherapy after four decades. Our laboratory has established the patient-derived orthotopic xenograft (PDOX) model using surgical orthotopic implantation (SOI). Many promising results have been obtained using the sarcoma PDOX model for identifying effective approved drugs and experimental therapeutics, as well as combinations of them for individual patients. In this review, we present our laboratory's experience with PDOX models of sarcoma, and the ability of the PDOX models to identify effective approved agents, as well as experimental therapeutics. [ABSTRACT FROM AUTHOR]

Fluorescence-guided surgery (FGS) of cancer is an area of intense current interest. However, although benefits have been demonstrated with FGS, curative strategies need to be developed. Glioblastoma multiforme (GBM) is one of the most invasive of cancers and is not totally resectable using standard bright-light surgery (BLS) or current FGS strategies. We report here a curative strategy for FGS of GBM. In this study, telomerase-dependent adenovirus OBP-401 infection brightly and selectively labeled GBM with green fluorescent protein (GFP) for FGS in orthotopic nude mouse models. OBP-401-based FGS enabled curative resection of GBM without recurrence for at least 150 days, compared to less than 30 days with BLS. [ABSTRACT FROM AUTHOR]

Neuroendocrine carcinomas (NEC) (high grade Ki67 > 20%) were poor prognostic and lethal disease. Platinum-based chemotherapy is usually chosen as a first line treatment for advanced NEC. However, this efficacy is temporary and there is no standard second-line treatment. Temozolomide (TMZ) based chemotherapy is one of the effective treatment options for advanced NEC in foreign countries, however it was not approved for NEC by Japanese authorities. The aim of this study is the efficacy and safety of TMZ monotherapy for advanced NEC patients with resistant to platinum-based chemotherapy. The dose of TMZ was 200mg/m2 from day1 to 5 every 4 weeks. This study was designed as prospective Phase II. Primary end point was response rate (RR) and secondary end point was disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. We also evaluated the prevalence of O6-methylguanine DNA methyltransferase (MGMT) in NEC and correlated MGMT deficiency with treatment response to TMZ by immunohistochemistry (IHC) as accompanying study. We recruited 13 cases pathologically diagnosed poorly differentiated and/or high grade NEC (man: 6, woman: 7, median age: 65). Primary lesions were pancreas (n = 3), stomach (3), duodenum (1), colon (1), gallbladder (1), liver (1), uterus (1), bladder (1), and primary unknown (1). Median of Ki-67 leveling index was 60% (range 22-90%). RR was 15.4% and DCR rate was 23.1% (PR: 2, SD: 1, PD: 10). PFS was 55 days (95% C.I. 29.7-80.3). OS was 214 days (95% C.I. 32.7-395.3) and OS from first line treatment was 547 days (429.2-664.8). There were no severe hematological adverse events, but Grade 3 nausea was occurred only one case (7.7%). One case (9.1%) was MGMT deficiency by IHC and this case achieved partial response. TMZ monotherapy for advanced NEC was safety but marginally effective treatment for patient with resistant to platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

• Liposarcoma (LS) is a chemotherapy-resistant disease. • Developed dedifferentiated liposarcoma (DDLS) patient-derived orthotopic xenograft (PDOX) model. • Gemcitabine (GEM) combined with docetaxel (DOC) arrested the tumor growth of DDLS PDOX. • GEM combined with DOC has clinical potential for this and possibly other DDLS patients. Liposarcoma (LS) is a chemotherapy-resistant disease. The aim of the present study was to find precise therapy for a recurrent dedifferentiated liposarcoma (DDLS) in a patient-derived orthotopic xenograft (PDOX) model. The DDLS PDOX models were established orthotopically in the right inguinal area of nude mice. The DDLS PDOX models were randomized into five groups: untreated; doxorubicin (DOX); gemcitabine (GEM) combined with docetaxel (DOC); pazopanib (PAZ); and yondelis (YON). On day 15, all mice were sacrificed. Measurement of tumor volume and body weight were done two times a week. The DDLS PDOX was resistant to DOX (P > 0.184). YON suppressed tumor growth significantly compared to control group (P < 0.027). However, only GEM combined with DOC arrested the tumor growth (P < 0.001). These findings suggest that GEM combined with DOC has clinical potential for this and possibly other DDLS patients. [ABSTRACT FROM AUTHOR]