Gemcitabine Plus Nab-Paclitaxel as Second-Line Chemotherapy following FOLFIRINOX in Patients with Unresectable Pancreatic Cancer: A Single-Institution, Retrospective Analysis.

INTRODUCTION: Patients with advanced pancreatic cancer have a poor prognosis. FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) have been established as first-line treatment, but they have not been confirmed as second-line treatment after FFX. The aim of this study was to evaluate the safety and efficacy of GnP as second-line therapy after FFX in patients with unresectable pancreatic cancer. METHODS: Twenty-five patients with unresectable pancreatic cancer were enrolled. The patients were treated with GnP after FFX between September 2015 and September 2019. Tumor response, progression-free survival (PFS), overall survival (OS), and incidence of adverse events were evaluated. RESULTS: The response rate, disease control rate, median PFS, and median OS were 12%, 96%, 5.3 months, and 15.6 months, respectively. The common grade 3 or 4 adverse events were neutropenia (76%) and anemia (16%). CONCLUSIONS: GnP after FOLFIRINOX is expected to be one of the second-line recommendations for patients with unresectable pancreatic cancer.

17ß-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells.

High-density lipoprotein (HDL) mediates reverse cholesterol transport. In this process, the human homolog of the B class, type I scavenger receptor (SR-BI), CD36, and LIMPII analogous-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1, and 17ß-estradiol (E2) modulates nitric oxide (NO) synthesis. In this study, we elucidated the effect of E2 on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis and reporter gene assay in HUVECs incubated with E2. eNOS activity was assessed by detection of phosphorylation (Ser 1179) of eNOS. We investigated the effect of the constitutively active form or dominant negative form of protein kinase C on hSR-BI/CLA-1 promoter activity. Our results showed that E2 increased the endogenous expression of hSR-BI/CLA-1. E2 also enhanced the activity of the hSR-BI/CLA-1 promoter and the expression of its mRNA. However, bisindolylmaleimide I, an inhibitor of protein kinase C, blocked the stimulatory effect of E2 on hSR-BI/CLA-1 promoter activity. Moreover, constitutively active PKC increased the activity of the hSR-BI/CLA-1 promoter, and a dominant-negative mutant of PKC prevented E2 from stimulating promoter activity. In cells treated with E2, HDL stimulated the phosphorylation of serine 1179 of eNOS in HUVECs. These results suggested that E2 upregulates the expression of the endothelial hSR-BI/CLA-1 via the PKC pathway, which may be a novel mechanism of the anti-atherosclerotic potential of E2 in vascular endothelial cells.

Synergistic effect between Juzen-taiho-to, a Japanese traditional herbal medicine, and gemcitabine single-agent chemotherapy for advanced biliary tract cancer.

This is the first report of the successful treatment of advanced biliary tract cancer with gemcitabine single-agent chemotherapy in combination with Juzen-taiho-to (JTT), a Japanese traditional herbal medicine. An 84-year-old woman was referred to our hospital with general fatigue and appetite loss; she was diagnosed with advanced biliary tract cancer and accompanying colonic invasion and hepatic metastasis. The patient's response to combination chemotherapy was extremely good, and her tumors disappeared. Recent studies have confirmed the occurrence of spontaneous and induced antitumor immune responses, carried out by tumor-infiltrating lymphocytes in the tumor microenvironment. The availability, antigen presentation, and proliferation of these immune cells are increased by cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-2. Recently, JTT has gained recognition as a biological response modifier that has stimulatory effects on systemic immune responses such as enhancement of cytokine expression (GM-CSF, IL-2, etc.). In addition, some chemotherapy agents, such as anthracyclines and gemcitabine, are effective boosters of the immune response through tumor-specific antigen overexpression after apoptotic tumor cell destruction. These findings suggest that JTT enhances the antitumor effects of gemcitabine, in particular its tumor-specific effects on immune response, and these drugs are a good combination for advanced biliary tract cancer therapy.

Xanthogranuloma of the intrasellar region presenting in pituitary dysfunction: a case report.

INTRODUCTION: Differentiation of cystic mass lesions of the sellar and parasellar regions may pose a diagnostic dilemma for physicians, neurosurgeons, radiologists and pathologists involved in treating patients with these entities. A considerable number of tumors previously identified as craniopharyngiomas may, in fact, have been xanthogranulomas. We report a case of pituitary dysfunction caused by xanthogranuloma of the intrasellar region. CASE PRESENTATION: A 47-year-old man of Japanese descent presented to our institution with a tumor located exclusively in the intrasellar region which manifested as severe hypopituitarism. MRI revealed a clearly defined intrasellar mass that was heterogeneously hyperintense on T1-weighted images and markedly hypointense on T2-weighted images. We preoperatively diagnosed the patient with Rathke's cleft cyst or non-functioning pituitary adenoma. Although the tumor was completely removed using a transsphenoidal approach, the improvement of the patient's endocrine function was marginal, and continued endocrine replacement therapy was needed. Postoperatively, a histological examination revealed the tumor to be a xanthogranuloma of the intrasellar region. His visual field defects and headache improved. CONCLUSION: Because diagnosis depends on surgical intervention and xanthogranulomas of the intrasellar region are very rare, the natural history of xanthogranuloma is still unknown. Therefore, this entity is difficult to diagnose preoperatively. We suggest that xanthogranuloma should be included in the differential diagnosis, even in the case of sellar lesions, to formulate appropriate postoperative management and improve endocrine outcomes.

The transcription factor prolactin regulatory element-binding protein mediates prolactin transcription induced by thyrotropin-releasing hormone in GH3 cells.

The prolactin regulatory element-binding protein (PREB) is a transcription factor that regulates prolactin (PRL) promoter activity in the rat anterior pituitary. PRL gene expression and secretion are regulated by various hormones and growth factors, including dopamine, epidermal growth factor, and thyrotropin-releasing hormone (TRH). We examined the effect of TRH on PREB expression in pituitary cells. Western blots probed with a PREB-specific antiserum showed that the relative abundance of PREB in GH3 cells increased on treatment with TRH in a dose-dependent manner. The relative abundance of PREB mRNA also increased in a dose-dependent manner after treatment with TRH. TRH induced the expression of the luciferase reporter protein under the PREB promoter control. We used inhibitors of certain signal transduction pathways to show that TRH-induced PREB induction is sensitive to the protein kinase A (PKA) inhibitor. TRH stimulated the activity of the wild-type PRL promoter, whereas mutation of the PREB core-binding element on the PRL promoter reduced this ability. In summary, we have shown that TRH stimulated PREB expression in GH3 cells via the PKA pathway. PREB can function as a transcriptional regulator of PRL promoter activity and might be involved in TRH-induced PRL gene transcription.

Transcriptional factor prolactin regulatory element-binding protein-mediated gene transcription of ABCA1 via 3',5'-cyclic adenosine-5'-monophosphate.

OBJECTIVE: Prolactin regulatory element-binding (PREB) protein is a transcription factor that regulates prolactin promoter activity in the rat anterior pituitary. The PREB protein is not only expressed in the anterior pituitary but also in the cardiovascular system, including vascular smooth muscle cells (SMCs). However, the role of PREB in SMCs is not clearly understood. The ATP-binding cassette transporter A1 (ABCA1) regulates lipid efflux from peripheral cells to apolipoproteins. In the present study, we have examined the role of PREB in regulating ABCA1 expression mediated by 3',5'-cyclic adenosine-5'-monophosphate (cAMP). METHODS AND RESULTS: PREB was expressed in the rats SMC line CRL-2018. ABCA1 expression was found to be regulated by cAMP, which stimulated the expression of PREB in a dose-dependent manner. Conversely, over-expression of PREB, which was induced by a PREB-expressing adenovirus, increased the expression of the ABCA1 protein in CRL-2018 cells. In addition, PREB stimulated the activity of the luciferase reporter protein that was under the control of the ABCA1 promoter. Chromatin immunoprecipitation assay showed that PREB mediates its transcriptional activity by directly binding to the ABCA1 promoter region. Finally, we used siRNA to inhibit PREB expression in the cells and demonstrated that the knockdown of PREB expression attenuated the effects of cAMP on ABCA1 expression. CONCLUSIONS: In summary, our data showed that PREB regulates the cAMP-mediated transcription of the ABCA1 gene in vascular SMCs.

Scavenger receptor class BI mediates the anti-apoptotic effect of erythropoietin.

A scavenger receptor of the B class (SR-BI)/human homolog of SR-BI, CD36, and LIMP II analogous-1 (CLA-1), has been identified as a receptor for high-density lipoprotein (HDL). Mice lacking SR-B1 develop anemia, plausibly explained by the observation that the erythrocyte life-span in these animals is reduced. Erythropoietin (EPO) is known to promote survival of erythroid cells, in large part through protection from apoptosis. We have examined the role of EPO on hSR-BI/CLA-1 expression and erythrocyte apoptosis. Endogenous expression of hSR-BI/CLA-1 was increased by exposure to EPO. EPO increased transcriptional activity of hSR-BI/CLA-1 promoter. The stimulatory effect of EPO on hSR-BI/CLA-1 promoter activity was abrogated by LY294002, specific inhibitor of phosphatidylinositol-3 kinase (PI3K). Constitutively active Akt stimulates the activity of the hSR-BI/CLA-1 promoter and a dominant-negative mutant of Akt abolished the ability of EPO to stimulate promoter activity. Finally, EPO in combination with HDL protected the cell from apoptosis, which suggests that hSR-BI/CLA-1 induced by EPO might contribute to the erythrocyte life-span.

Suprasellar germinoma masquerading as lymphocytic hypophysitis associated with central diabetes insipidus, delayed sexual development, and subsequent hypopituitarism.

We report the case of an 18-year-old woman with suprasellar germinoma masquerading as lymphocytic hypophysitis, which was associated with central diabetes insipidus, delayed sexual development, and hypopituitarism. Magnetic resonance imaging revealed an enlarged pituitary gland, thickened pituitary stalk, and a mass lesion in the inferior hypothalamus; these findings are typical of lymphocytic hypophysitis. Despite the administration of prednisolone therapy for 3 months, an enlarged irregular cystic mass lesion developed in the pituitary stalk and inferior hypothalamus. Open cranial surgery of the posterior pituitary revealed the presence of a germinoma. Therefore, chemotherapy and stereotactic radiation therapy were administered, resulting in complete remission of the germinoma. This case illustrates that the presence of an intrasellar mass lesion in association with pituitary stalk thickening can often cause difficulties in differential diagnosis. We believe that lymphocytic hypophysitis in pubertal children may be the first sign of a host reaction to an occult germinoma.

Acute leukemia of ambiguous lineage, biphenotype, without CD34, TdT or TCR-rearrangement.

Biphenotypic acute leukemia (BAL) is a rare entity that comprises 0.5-3% of all acute leukemias and probably arises from multipotent progenitor cells. The optimal approach for BAL therapy is unknown. Thus, it is important to elucidate the origin of the neoplastic cells for determination of the appropriate therapy. We report the case of a 41-year-old man with BAL having myeloid and T-lymphoid lineage phenotypes. Strangely, neither CD34 nor TdT expression nor rearrangement of TCR-alpha/beta, delta/gamma genes were shown. This pattern is rarely encountered and suggests that the blast cells were possibly considered immature with aspects of differentiation indicating myeloid lineage, rather than T-lymphoid lineage.

Co-existence of glucagonoma with recurrent insulinoma in a patient with multiple endocrine neoplasia-type 1 (MEN-1).

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the anterior pituitary, and the endocrine pancreas. Our patient was a 58-year-old man who manifested typical features of MEN-1 including primary hyperparathyroidism, lung carcinoid, and lipomas and insulinoma. He was admitted to our hospital because of recurrent hypoglycemia and a growth of pancreatic tumors. The first operation for insulinoma was performed when he was 20 years old. We found a germline mutation of the MEN1 gene (E45G, exon 2) in this patient. According to these examinations and his clinical course, the patient was diagnosed as having a recurrence of insulinoma. He subsequently underwent surgery for the pancreatic tumors. The majority of these tumor cells were immunohistochemically positive for insulin and negative for glucagon. A few nodules showed immunohistochemical staining positivity for glucagon but they were negative for insulin. Although it is uncommon for patients with MEN1 to exhibit insulinoma and glucagonoma, this case suggests the need for careful analysis of pancreatic tumors in patients with MEN1.

A case of non-Hodgkin's lymphoma primary arising in both adrenal glands associated with adrenal failure.

It is known that adrenal insufficiency is one of the complications in primary adrenal lymphoma, especially those with bilateral adrenal involvement. A 73-year-old man was referred for general fatigue and high fever to the nearest hospital. The patient was transferred to our hospital for evaluation of bilateral adrenal tumors and hyponatremia. He was diagnosed as having non-Hodgkin's lymphoma (NHL) with primaries arising in both adrenal glands. Primary adrenal lymphoma (PAL) is a rare extra-nodal NHL. Although an appropriate treatment of this disease has not been established, our case has demonstrated that the combination of rituximab and THP-COP chemotherapy could be administered, and that it improved clinical manifestations. This case raises the suggestion that malignant lymphoma should be suspected in patients with bilateral adrenal tumors that present with progressive adrenal insufficiency.

The prolactin regulatory element-binding regulates of the 11beta-hydroxylase gene.

Prolactin regulatory element-binding (PREB) protein is a transcription factor not only in pituitary but also adrenal gland. Steroid 11beta-hydroxylase (CYP11B1), a member of the cytochrome p-450 superfamily, is responsible for the last step of glucocorticoid biosynthesis in the adrenal cortices of many kinds of animals. In the present study, we have examined the role of PREB in regulating CYP11B1. CYP11B1 expression was found to be regulated by cAMP, which stimulated the expression of PREB. In addition, PREB induced the expression of the luciferase reporter protein that was under the control of the CYP11B1 promoter. Electrophoretic mobility shift analysis (EMSA) showed that PREB mediates its transcriptional effect by binding to the PREB-responsive cis-element (PRCE) of the CYP11B1 promoter. The knockdown of PREB expression attenuated the effects of cAMP on CYP11B1 expression. In summary, our data showed that in the adrenal gland, PREB regulates the transcription of the CYP11B1 gene via cAMP.

The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1alpha gene expression of ATL cells.

OBJECTIVE: Adult T-cell leukemia (ATL) is a mature CD4(+) T-cell malignancy caused by infection with human T-lymphotrophic virus type-1 and is associated with a marked hypercalcemia in many patients. Recently, it has been proposed that macrophage inflammatory protein-1alpha (MIP-1alpha) is the clinical hallmark of hypercalcemia in ATL. In this study, we investigated the effect of extracellular calcium on MIP-1alpha secretion in ATL cells and the role of Ca(2+)/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of MIP-1alpha. MATERIALS AND METHODS: MIP-1alpha protein levels in the culture supernatant collected from ATL cells were measured by enzyme-linked immunosorbent assay. Reporter plasmid containing the MIP-1alpha promoter was transfected to ATL cells, and the promoter activity was measured by luciferase assay. RESULTS: The addition of calcium to the culture medium enhanced the secretion of MIP-1alpha from ATL cells, which was inhibited by the CaM-KK inhibitor. The transfection of CaM-KIV stimulated MIP-1alpha promoter activity, and the upstream kinase CaM-KK enhanced the stimulatory effect of CaM-KIV on the promoter activity. Mutation in the cyclic adenosine 5' monophosphate response element (CRE) within the MIP-1alpha promoter significantly reduced the effect of CaM-KIV, and CRE mutant promoter activity was not significantly enhanced by the addition of calcium to the culture medium as compared to wild-type promoter activity. CONCLUSION: Hypercalcemia enhances MIP-1alpha secretion in ATL cells, and this mechanism requires the involvement of CaM-KK/CaM-KIV cascade through the CRE. These findings raise a possibility that the inhibitory effect of CaM-KK/CaM-KIV cascade may be a potential therapeutic target for ATL.

Hyperglycemia suppresses hepatic scavenger receptor class B type I expression.

Hyperglycemia is a major risk factor for atherosclerotic disease. Hepatic scavenger receptor class B type I (SR-BI) binds HDL particles that mediate reverse cholesterol transport and thus lowers the risk of atherosclerosis. Here we examined glucose regulation of SR-BI gene expression in both HepG2 cells and whole animals. Results showed that hepatic SR-BI mRNA, protein, and uptake of cholesterol from HDL were halved following 48 h of exposure to 22.4 vs. 5.6 mM glucose. As in the case of the cell culture model, hepatic expression of SR-BI was lower in diabetic rats than in euglycemic rats. Transcriptional activity of the human SR-BI promoter paralleled endogenous expression of the gene, and this activity was dependent upon the dose of glucose. Next, we used inhibitors of select signal transduction pathways to demonstrate that glucose suppression of SR-BI was sensitive to the p38 MAPK inhibitor. Expression of a constitutively active p38 MAPK inhibited SR-BI promoter activity in the presence or absence of glucose. A dominant-negative p38 MAPK abolished the inhibitory effect of glucose on promoter activity. Deletional analysis located a 50-bp fragment of the promoter that mediated the effects of glucose. Within this DNA fragment there were several specificity protein-1 (Sp1) binding sites, and cellular knockdown of Sp1 abrogated its suppression by glucose. Together, these results indicate that the glucose suppression of SR-B1 expression is partially mediated by the activation of the p38 MAPK-Sp1 pathway and raise the possibility that the inhibition of hepatic SR-BI expression under high-glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.

D-Psicose inhibits the expression of MCP-1 induced by high-glucose stimulation in HUVECs.

Monocyte chemoattractant protein-1 (MCP-1) is a 76-amino-acid chemokine thought to be the major chemotactic factor for monocytes. MCP-1 is found in macrophage-rich areas of atherosclerotic lesions. Recent report indicates that MCP-1 is induced by glucose-stimulation, raising the important link between diabetes mellitus and atherosclerosis. One of the rare sugars, d-psicose (d-ribo-2-hexulose) is present in small quantities in commercial carbohydrate complexes, however the physiological functions of d-psicose have not been evaluated. In this study, we examined the effects of d-psicose on MCP-1 expression in human umbilical vein endothelial cells (HUVECs). Results showed that MCP-1 mRNA and protein were stimulated following exposure to 22.4 mM glucose. Transcriptional activity of MCP-1 promoter paralleled endogenous expression of the gene and this activity was dependent on the dose of d-glucose. d-Psicose inhibited these effects. Next we used inhibitors of selected signal transduction pathways to show that high-glucose (HG) stimulated MCP-1 promoter activity was sensitive to p38-Mitogen-Activated Protein Kinase (p38-MAPK) pathway inhibitor. As expected, a dominant-negative p38-MAPK abolished the stimulatory effect of HG on the promoter activity. To incubate the cells with HG and d-psicose reduced the activation of p38-MAPK. Together, these results indicate that the d-psicose suppression of HG induced MCP-1 expression is mediated in part by inhibition of the p38-MAPK pathway and raise the possibility that d-psicose may be of therapeutic value in the treatment of diseases such as atherosclerosis.

Regulation of scavenger receptor class BI gene expression by angiotensin II in vascular endothelial cells.

High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. In this process, a scavenger receptor of the B class (SR-BI)/human homologue of SR-BI, CD36, and LIMPII analogous-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from high-density lipoprotein. In endothelial cells, high-density lipoprotein activates endothelial NO synthase via hSR-BI/CLA-1. Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis and modulates the expression of endothelial NO synthase. In the present study, we have examined the role of Ang II on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells. Our results showed that endogenous expression of hSR-BI/CLA-1 was suppressed by exposure to Ang II in human umbilical vein endothelial cells. Administration of the Ang II type-1 receptor blocker olmesartan inhibited Ang II-induced hSR-BI/CLA-1 protein repression. In Ang II-treated cells, high-density lipoprotein had no effect on endothelial NO synthase activation. Ang II decreased transcriptional activity of the hSR-BI/CLA-1 promoter. The inhibitory effect of Ang II on hSR-BI/CLA-1 promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of human umbilical vein endothelial cells to Ang II elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt inhibits the activity of the hSR-BI/CLA-1 promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the hSR-BI/CLA-1 abolished the ability of Ang II to suppress promoter activity. Together, these results indicate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway participates in Ang II suppression of hSR-BI/CLA-1 expression and suggests that the endothelial receptor for hSR-BI/CLA-1 is downregulated by the renin-angiotensin system.

Platelet derived growth factor regulates ABCA1 expression in vascular smooth muscle cells.

The ATP-binding cassette transporter A1 (ABCA1) regulates lipid efflux from peripheral cells to High-density lipoprotein. The platelet-derived growth factor (PDGF) is a potent mitogen that enables vascular smooth muscle cells to participate in atherosclerosis. In this report, we showed that PDGF suppressed endogenous expression of ABCA1 in cultured vascular smooth muscle cells. Exposure of CRL-208 cells to PDGF elicited a rapid phosphorylation of a kinase downstream from PI3-K, Akt. The constitutively active form of both p110, a subunit of PI3-K, and Akt inhibited activity of the ABCA1 promoter. In conclusion, PI3-K-Akt pathways participate in PDGF-suppression of ABCA1 expression.

High-density lipoprotein is a potential growth factor for adrenocortical cells.

The entry of cholesterol contained within high-density lipoprotein (HDL) into adrenocortical cells is mediated by a human homologue of SR-BI, CD36, and LIMPII Analogous-1 (CLA-1) and thus augmenting their growth. To address the role of CLA-1, we created a mutant mCLA that lacked the C-terminal tail. HDL CE selective uptake by cells carrying the mCLA-1 receptor was fully active and equivalent to those transfected with full-length CLA-1 (fCLA-1). Expression of mCLA inhibited the proliferation of an adrenocortical cell line and the incorporation of [(3)H]thymidine into the cells. This effect was sensitive to wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). Our transcriptional studies revealed that the inhibitory action of mCLA required the transcriptional factor AP-1 and the effect of HDL on AP-1 activation was also abrogated by wortmannin. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for adrenocortical tumor.