AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs).
METHODS: The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed.
RESULTS: All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis.
CONCLUSION: Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation.
Pancreatic neuroendocrine tumor; Pancreatic neuroendocrine carcinoma; Nonfunctioning; Lymphadenectomy; Treatment
AIM: To evaluate the clinical utility of hepatic clearance (HC) measured with technetium-99m-diethylenetriaminepenta-acetic acid-galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) to estimate the degree of liver fibrosis.
METHODS: Seventy-eight consecutive patients who underwent initial hepatectomy due to hepatocellular carcinoma were enrolled in this study. Indocyanine green clearance (ICG R15), quantitative indices estimated by 99mTc-GSA [the receptor index (LHL15 and HH15) and HC via SPECT analysis], and conventional liver function tests were performed before hepatectomy. Correlations among the quantitative indices for liver functional reserve, conventional liver function tests, and the degree of liver fibrosis were evaluated.
RESULTS: The degree of liver fibrosis was correlated with ICG R15, HH15, LHL15, and HC. HC showed the best correlation with conventional liver function tests. According to multivariate analysis, HC and LHL15 were significant independent predictors of severe fibrosis. HC was the most valuable index for predicting severe fibrosis.
CONCLUSION: HC measured with 99mTc-GSA SPECT is a reliable index for assessing liver fibrosis before hepatectomy.
Fibrosis; Technetium-99m-diethylenetriaminepenta-acetic acid-galactosyl human serum albumin; Single-photon emission computed tomography; Hepatic clearance; Liver resection
The symptoms of gallbladder cancer (GBC) are vague and non-specific. Therefore, GBC is often detected at an advanced or metastatic stage. The most effective treatment for GBC is surgical resection, however the majority of GBC cases are unresectable at the time of diagnosis. Therefore, numerous GBC patients undergo chemotherapy. This study reports the case of a 60-year-old female with GBC who underwent successful surgical curative resection following a single dose of the chemotherapeutic agent, S-1, twice daily for 4 weeks followed by a 14-day rest period for 36 months. S-1 is a novel orally administered drug composed of a combination of the 5-fluorouracil (5-FU) prodrug, tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and oteracil potassium in a 1:0.4:1 molar concentration ratio. The focus of the present study was the candidate factors that affect the therapeutic efficacy of S-1-based chemotherapy. In particular, the gene expression involved in the S-1 metabolic pathway was investigated by assessing the intratumoral dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) and orotate phosphoribosyltransferase gene expression. The surgical specimen exhibited high intratumoral DPD gene expression levels compared with those observed in previously reported non S-1 responsive cases of biliary tract cancer. Due to the results obtained in the current study, we hypothesize that CDHP enhanced the antitumor efficacy of 5-FU by inhibiting the excess DPD protein produced by the tumor.
gallbladder cancer; S-1; gene expression
Endothelial-cell–derived Sema3A promotes axonal outgrowth and plasticity and thereby regulates neurohormone release in the adult rodent brain in response to the ovarian cycle.
Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3aloxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction.
In the developing embryo, endothelial cells release chemotropic signals such as Semaphorin 3A (Sema3A) that, upon activation of its receptor Neuropilin-1 (Nrp1), regulate neuronal migration and axon guidance. However, whether endothelial cells in the adult brain retain the ability to secrete molecules that influence neuronal function is unknown. Here we show in the adult brain of rodents that vascular endothelial cells release Sema3A and that the amount released is regulated by the ovulatory cycle. Sema3A, in turn, promotes the outgrowth of axons of hypothalamic neurons that express Neuropilin-1 towards the endothelial wall of portal blood vessels. These neurons release there the neuropeptide that controls reproduction: gonadotropin-releasing hormone (GnRH). Notably, this endothelial-cell-mediated sprouting of GnRH axons regulates neuropeptide release at a key stage of the estrous cycle, the proestrus, when the surge of GnRH triggers ovulation. Thus, by promoting GnRH axonal growth in the adult brain, Sema3A/Neuropilin-1 plays a pivotal role in orchestrating the central control of reproduction. Our results suggest a model in which vascular endothelial cells are dynamic signaling components that relay peripheral information to the brain to control key physiological functions, including species survival.
The functional end products of the extant biosynthesis of tetrapyrrole macrocycles in photosynthetic organisms are hydrophobic: chlorophylls and bacteriochlorophylls. A model for the possible prebiogenesis of hydrophobic analogues of nature's photosynthetic pigments was investigated by reaction of acyclic reactants in five media: aqueous solution (pH 7, 60°C, 24 h); aqueous solution containing 0.1 M decanoic acid (which forms a turbid suspension of vesicles); or aqueous solution accompanied by dodecane, mesitylene, or a five-component organic mixture (each of which forms a phase-separated organic layer). The organic mixture was composed of equimolar quantities of decanoic acid, dodecane, mesitylene, naphthalene, and pentyl acetate. The reaction of 1,5-dimethoxy-3-methylpentan-2,4-dione and 1-aminobutan-2-one to give etioporphyrinogens was enhanced in the presence of decanoic acid, affording (following chemical oxidation) etioporphyrins (tetraethyltetramethylporphyrins) in yields of 1.4–10.8% across the concentration range of 3.75–120 mM. The yield of etioporphyrins was greater in the presence of the five-component organic mixture (6.6% at 120 mM) versus that with dodecane or mesitylene (2.1% or 2.9%, respectively). The reaction in aqueous solution with no added oil-slick constituents resulted in phase separation—where the organic reactants themselves form an upper organic layer—and the yield of etioporphyrins was 0.5–2.6%. Analogous reactions leading to uroporphyrins (hydrophilic, eight carboxylic acids) or coproporphyrins (four carboxylic acids) were unaffected by the presence of decanoic acid or dodecane, and all yields were at most ∼2% or ∼8%, respectively. Taken together, the results indicate a facile means for the formation of highly hydrophobic constituents of potential value for prebiotic photosynthesis. Key Words: Origin of life—Prebiotic—Oil slick—Porphyrinogen—Porphyrin—Pyrrole—Partition. Astrobiology 12, 1055–1068.
A primary benign schwannoma of the liver is extremely rare and is difficult to preoperatively discriminate from a malignant tumor. We compared the imaging and pathological findings, and examined the possibility of preoperatively diagnosing a benign liver schwannoma. A 72-year-old woman was admitted to our hospital because of a 4.6-cm mass in the liver. A malignant tumor was suspected, and a right hepatectomy was performed. After this, the diagnosis of a primary benign schwannoma of the liver was made through pathological examination. Contrast-enhanced ultrasonography (CEUS) with Sonazoid showed minute blood flows into the septum and solid areas of the tumor in the vascular phase; most likely due to increased arterial flow associated with infiltration of chronic inflammatory cells. In the postvascular phase, CEUS showed contrast defect of cystic areas and delayed enhancement of solid areas; most likely due to aggregation of siderophores. Because discriminating between a benign and malignant schwannoma of the liver is difficult, surgery is generally recommended. However, the two key findings from CEUS may be useful in discriminating ancient schwannoma by recognizing the hemorrhage involved in the secondary degeneration and aggregation of siderophores.
Liver schwannoma; Contrast-enhanced ultrasonography; Liver resection
Gastric tumors in patients affected by neurofibromatosis type 1 are usually carcinoids or stromal tumors, and rarely adenocarcinomas.
We report a case of an adenocarcinoma of the stomach in a 53-year-old Japanese man with neurofibromatosis type 1. An abdominal computed tomography scan and ultrasonography showed tumors in his liver. Gastric fibroscopy revealed a Borrmann type III tumor on his cardia that had spread to his esophagus and was highly suspicious for malignancy. Multiple biopsies showed an adenocarcinoma of the stomach, which was evaluated as gastric cancer, stage IV. Chemotherapy with TS-1 was performed. Our patient died four weeks after initial admission. Histological examination of a liver needle biopsy showed metastatic adenocarcinoma in his liver.
To the best of our knowledge, high serum levels of α-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 72-4, resulting from gastric adenocarcinoma, have not been reported previously in a patient with neurofibromatosis type 1. We report this rare case along with a review of the literature.
A new quassinoid, designated 2′-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2–8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre (Simaroubaceae)]. The structure of 1 was determined by spectroscopic analysis, and by semi-synthesis from glaucarubolone. Complete 1H and 13C NMR assignments of compounds 1–8 were also established from detailed analysis of two-dimensional NMR spectra, and the reported configurations in odyendene (7) and odyendane (8) were corrected. Compound 1 showed potent cytotoxicity against multiple cancer cell lines. Further investigation using various types of breast and ovarian cancer cell lines suggested that 1 does not target the estrogen receptor (ER) or progesterone receptor (PR). When tested against mammary epithelial proliferation in vivo using a Brca1/p53-deficient mice model, 1 also caused significant reduction in mammary duct branching.
Rhabdomyolysis associated with fenofibrate monotherapy is extremely rare. Here, we report a rare case of rhabdomyolysis of the psoas muscle in an 82-year-old man with chronic myelogenous leukemia (CML). He was prescribed fenofibrate because of a hypertriglyceridemia. The patient reported generalized muscle pain and right abdominal pain while receiving fenofibrate monotherapy. An abdominal computed tomography scan and an abdominal ultrasound showed a large and low attenuation and high echogenicity, respectively, in the right middle abdominal area. Laboratory values included a serum creatine concentration of 4.1 mg/dl and a creatinine phosphokinase concentration of 5,882 IU/l. During laparotomy, a large hematoma and necrotic mass was identified in the right psoas muscle. Histological examination revealed that the resected specimens were of the psoas muscle with irregular fiber sizes, degenerating fibers surrounding the inflammatory reaction, and fiber necrosis that is typical for polymyositis. Based on these findings and the clinical history, a diagnosis of fenofibrate-induced rhabdomyolysis was made. To the best of our knowledge, no patient has ever been diagnosed with fulminant psoas rhabdomyolysis due to a fenofibrate monotherapy. This report details the rare case of rhabdomyolysis in a patient with CML associated with fenofibrate monotherapy and offers a review of the literature.
Rhabdomyolysis; Fenofibrate monotherapy; Chronic myelogenous leukemia; Psoas muscle; urgery
Pancreatic fistula is a quite rare complication in patients who undergo living donor liver transplantation (LDLT). However, in the cases that show pancreatic fistula, the limited volume of the graft and the resultant inadequate liver function may complicate the management of the fistula. As a result, the pancreatic fistula may result in the death of the patient. We present 2 cases in which endoscopic treatment was effective against pancreatic fistulas that developed after LDLT. In case 1, a 61-year-old woman underwent LDLT for primary biliary cirrhosis. Because of a portal venous thrombus caused by a splenorenal shunt, the patient underwent portal vein reconstruction, and a splenorenal shunt was ligated on postoperative day (POD) 7. The main pancreatic duct was injured during the manipulation to achieve hemostasis, thereby necessitating open drainage. However, discharge of pancreatic fluid continued even after POD 300. Endoscopic naso-pancreatic drainage (ENPD) was performed, and this procedure resulted in a remarkable decrease in drain output. The refractory pancreatic fistula healed on day 40 after ENPD. In case 2, a 58-year-old man underwent LDLT for cirrhosis caused by the hepatitis C virus. When the portal vein was exposed during thrombectomy, the pancreatic head was injured, which led to the formation of a pancreatic fistula. Conservative therapy was ineffective; therefore, ENPD was performed. The pancreatic fistula healed on day 38 after ENPD. The findings in these 2 cases show that endoscopic drainage of the main pancreatic duct is a less invasive and effective treatment for pancreatic fistulas that develop after LDLT.
Pancreatic fistula; Endoscopic treatment; Living donor liver transplantation; Complications
Carbohydrate antigen 19-9 (CA 19-9) is a sensitive marker for pancreatic and hepatobiliary malignancies. The highest frequency of elevated serum CA 19-9 levels is found among patients with pancreatic cancer. CA 19-9 has recently been demonstrated to be a marker of digestive tract malignancies. We report the case of a patient with a gastric cancer and a very high serum CA 19-9 level. During laparotomy, a large mass was found in the antrum. A distal gastrectomy with D2 dissection of the lymph nodes was performed. Histological examination, including immunohistochemistry, revealed an adenocarcinoma of the stomach producing CA 19-9. To the best of our knowledge, no patient with an extremely high serum CA 19-9 level resulting from a gastric adenocarcinoma has been reported previously.
Gastric cancer; Adenocarcinoma; CA 19-9
Recirculation of leukocytes is essential for proper immune responses. However, the molecular mechanisms that regulate leukocyte entry into the lymphatics remain unclear. Here we show that plexin-A1, a primary receptor component for class III and class VI semaphorins, is crucially involved in the entry of dendritic cells (DCs) into the lymphatics. Additionally, we show that Sema3A, but not Sema6C or Sema6D, is required for DC transmigration, and that Sema3A produced by the lymphatics promotes actomyosin contraction at the trailing edge of migrating DCs. These findings not only demonstrate that semaphorin-signals are involved in DC trafficking but also provide a novel mechanism that induces actomyosin contraction as these cells pass through narrow gaps.
C-3 Esterifications of betulinic acid (BA, 1) and its A-ring homolog, ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4-19, including nine new compounds (4-12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4-6, 11-14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100, 76, 37, and 11% inhibition of EBA activation at 1000, 500, 100 and 10 mol ratio/TPA, respectively, with IC50 value of 285 mol ratio/32pmol TPA). Compound 6 merits further development as a cancer preventive agent.
Betulinic acid; Ceanothic acid; Antitumor-promoter; Cancer preventive agents; Epstein-Barr virus
2,3,4,5-Tetrahydro-1,3,3-trimethyldipyrrin (1) is a crucial building block in the rational synthesis of chlorins and oxochlorins. The prior 5-step synthesis of 1 from pyrrole-2-carboxaldehyde (2) employed relatively simple and well-known reactions yet suffered from several drawbacks, including limited scale (≥ 0.5 g of 1 per run). A streamlined preparation of 1 has been developed that entails four steps: (i) nitro-aldol condensation of 2 and nitromethane under neat conditions to give 2-(2-nitrovinyl)pyrrole (3), (ii) reduction of 3 with NaBH4 to give 2-(2-nitroethyl)pyrrole (4), (iii) Michael addition of 4 with mesityl oxide under neat conditions or at high concentration to give γ-nitrohexanonepyrrole 5, and (iv) reductive cyclization of 5 with zinc/ammonium formate to give 1. Several multistep transformations have been established, including the direct conversion of 2 → 1. The advantages of the new procedures include (1) fewer steps, (2) avoidance of several problematic reagents, (3) diminished consumption of solvents and reagents, (4) lessened reliance on chromatography, and (5) scalability. The new procedures facilitate the preparation of 1 at the multigram scale.
5-Methoxy-8,8,18,18-tetramethyl-2,12-di-p-tolylbacteriochlorin (MeO-BC) undergoes regioselective electrophilic bromination with NBS to give the 15-bromo analogue (MeO-BC-Br15) in 85% yield. By contrast, the bacteriochlorin lacking the 5-methoxy group (8,8,18,18-tetramethyl-2,12-di-p-tolylbacteriochlorin, H-BC) gives a mixture of two mono-bromo and two di-bromobacteriochlorins. Deuterium exchange of both bacteriochlorins (H-BC and MeO-BC) in acidic media (TFA-d) occurs preferentially at the β-pyrrole positions (3, 13) > unhindered meso-positions (5, 15 for H-BC; 15 for MeO-BC) > hindered meso-positions (10, 20). The 15-bromo-5-methoxybacteriochlorin MeO-BC-Br15 was subjected to three types of Pd-mediated coupling reactions (Suzuki, Sonogashira, Hartwig-Buchwald) to give six bacteriochlorins bearing functional groups at the 15-position (49% to 85% yield). The groups include 4-(tert-butoxycarbonylmethoxy)phenyl, 4-pyridyl, 3,5-diformylphenyl, phenylethynyl, TIPS-ethynyl, and N-benzamido. The presence of the 15-ethynyl moiety shifts the position of the long-wavelength Qy band from 732 nm to ∼753 nm. The ability to introduce a range of groups at a specific site enables synthetic bacteriochlorins to be tailored for a variety of applications.
Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA-DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anticancer assay using nine different human tumor cell lines, most of the GA-DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED50 values of 0.6, 0.8, and 0.9 μM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA-DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA-DZ conjugates are new chemical entities and represent interesting hits for anticancer drug discovery and development.
Glycyrrhetinic acid; Dehydrozingerone; Conjugation; Cytotoxicity
Stable chlorins bearing few or no substituents have been subjected to a variety of reactions including demetalation, magnesium insertion, oxochlorin formation, and bromination followed by Suzuki coupling. The kinetics of deuteration also have been determined for two oxochlorins and a series of chlorins bearing 0, 1, 2, or 3 meso-aryl substituents.
Chlorin; Deuteration; Bromination; Metalation
The availability of stable chlorins bearing few or no substituents has enabled a variety of fundamental studies. The studies described herein report absorption spectra of diverse chlorins, comparative NMR features of chlorins bearing 0–3 meso-aryl substituents, and X-ray structures of the fully unsubstituted chlorin and the oxochlorin.
Chlorin; NMR; Absorption spectra; X-ray
Five routes to stable chlorins bearing 0 or 1 meso substituents have been investigated, among which reaction of a 9-bromo-1-formyldipyrromethane and 2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin proved most effective. Application of this route afforded metallochlorins [Cu(II), Zn(II), Pd(II)] including the chlorin lacking any β-pyrrole and meso substituents.
Chlorin; Hydroporphyrin; Hydrodipyrrin; Dipyrromethane