Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents.
Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents.
J Med Chem. 2010 Feb 11;53(3):1347-56
Authors: He R, Chen Y, Chen Y, Ougolkov AV, Zhang JS, Savoy DN, Billadeau DD, Kozikowski AP
Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro with the lowest IC(50) value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogues by embellishing the terminal phenyl ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogues was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compounds 4h and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC(50) = 50 nM) and MiaPaca-2 (IC(50) = 40 nM) cancer cell lines, respectively. Compound 4a was found to reactivate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
PMID: 20055418 [PubMed - indexed for MEDLINE]
Immunohistochemical and electron microscopic studies of a case of duodenal gangliocytic paraganglioma.
Immunohistochemical and electron microscopic studies of a case of duodenal gangliocytic paraganglioma.
Med Mol Morphol. 2009 Dec;42(4):245-9
Authors: Ohtsuki Y, Watanabe R, Kimura M, Okamoto T, Murakami S, Mizukami Y, Takeji M, Okada Y, Hayashi Y, Lee GH, Furihata M
Gangliocytic paraganglioma (GPG) is a rare tumor, occurring almost exclusively in the duodenum. In the present case, a submucosal tumor 2.5 x 2 x 1.5 cm in size was located on the anal side of the papilla of Vater, with clear margins and without capsule on cut-surface examination. Tumor cells included three types of cells: ganglion-like cells (GCs), endocrine cells (ECs), and Schwann cells (SCs). The GCs were large with eccentric nuclei with large nucleoli and clear abundant cytoplasm. ECs were detected in small nests, surrounded by bundles of SCs. Immunohistochemically, GCs were positive for synaptophysin, neuron-specific enolase (NSE), and CD56. ECs were positive for chromogranin A, NSE, somatostatin, pancreatic polypeptide, and CD56, and were associated with S100 protein-positive SCs. On fine structural examination, ECs contained numerous membrane-bounded secretory granules, 250-450 nm in diameter, in their cytoplasm, surrounded by a branched, complex basal lamina. SCs possessed basal lamina along their long interlacing cytoplasmic processes. The histogenesis of GPG most likely involves proliferation and differentiation of pluripotent stem cells in the duodenal crypts in the duodenum as a true tumor, although it is also possible that the retroperitoneal components of both GCs and SCs proliferate, together with ECs, from ventral primordial tissue of the pancreas in the duodenum. The immunohistochemical and ultrastructural findings of a case of GPG are reported, focusing on three major cellular components: GCs, ECs, and SCs.
PMID: 20033372 [PubMed - indexed for MEDLINE]
Immunohistochemical analyses of E-cadherin, beta-catenin, CD44s, and CD44v6 expressions, and Ki-67 labeling index in intraductal papillary mucinous neoplasms of the pancreas and associated invasive carcinomas.
Immunohistochemical analyses of E-cadherin, beta-catenin, CD44s, and CD44v6 expressions, and Ki-67 labeling index in intraductal papillary mucinous neoplasms of the pancreas and associated invasive carcinomas.
Med Mol Morphol. 2009 Dec;42(4):222-9
Authors: Okimura A, Hirano H, Nishigami T, Ueyama S, Tachibana S, Fukuda Y, Yamanegi K, Ohyama H, Terada N, Nakasho K
We examined the expressions of adhesion molecules (E-cadherin, beta-catenin, CD44s, and CD44v6) and Ki-67 labeling index (Ki-67 LI) in low- and moderate-grade dysplasia and invasive carcinoma components in ten noninvasive intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and eight invasive carcinomas associated with IPMNs of the pancreas using immunohistochemical methods. There was no significant difference in regard to the proportion of components expressing either E-cadherin or beta-catenin in more than 70% of the tumor cells between the low- and moderate-grade dysplasia components. In contrast, the proportion of those in invasive carcinoma components was significantly lower than in low- or moderate-grade dysplasia components. Also, there was no significant difference in the proportion of components expressing CD44s or CD44v6 in more than 5% of tumor cells among low-grade dysplasia, moderate-grade dysplasia, and invasive carcinoma components. In contrast, the Ki-67 LI values increased in the order of low-grade dysplasia, moderate-grade dysplasia, and invasive carcinoma components, with significant differences among them. The present results indicate that carcinoma components are associated with a decrease in tumor cells expressing E-cadherin and beta-catenin and have the highest proliferative activity.
PMID: 20033368 [PubMed - indexed for MEDLINE]
Circulatory collapse in a patient with gastrinoma after metoclopramide administration.
Circulatory collapse in a patient with gastrinoma after metoclopramide administration.
Hong Kong Med J. 2009 Dec;15(6):478-81
Authors: Lau KK, Chan KW, Lok CM, Lam AW, Lee HH, Luk WF, Mak CM, Ching CK, Lo J, Li SM, Chan AY
A patient who was given metoclopramide for vomiting and diarrhoea developed circulatory collapse with his blood pressure dropping to 50/20 mm Hg. A gastrinoma was diagnosed histologically. The extent of the tumour was defined by octreotide scanning and magnetic resonance imaging. Metoclopramide was again given for colicky abdominal pain and the patient developed circulatory collapse a second time. A laparotomy involving extensive resection of the tumour was performed. The MEN1 mutation was not detected in blood or tumour tissue. Follow-up octreotide scanning did not show any residual tumour. Possible causes for the circulatory collapse are discussed. Our case is probably the first patient with gastrinoma to develop circulatory collapse after being given metoclopramide.
PMID: 19966355 [PubMed - indexed for MEDLINE]
Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1).
Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1).
Hum Mutat. 2010 Jan;31(1):E1089-101
Authors: Turner JJ, Christie PT, Pearce SH, Turnpenny PD, Thakker RV
Phenocopies may confound the clinical diagnoses of hereditary disorders. We report phenocopies in Multiple Endocrine Neoplasia type 1 (MEN1), an autosomal dominant disorder, characterised by the combined occurrence of parathyroid, pituitary and pancreatic tumours. We studied 261 affected individuals from 74 families referred with a clinical diagnosis of MEN1 and sought inconsistencies between the mutational and clinical data. We identified four patients from unrelated families with phenocopies. Patients 1 and 2 from families with MEN1, developed prolactinomas as the sole endocrinopathy but they did not harbour the germline MEN1 mutation present in their affected relatives. Patient 3, had acromegaly and recurrent hypercalcaemia following parathyroidectomy, whilst patient 4 had parathyroid tumours and a microprolactinoma. Patients 3 and 4 and their relatives did not have MEN1 mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium-sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome due to a hyperparathyroidism type 2 deletional-frameshift mutation (c.1239delA), respectively. Phenocopies may mimic MEN1 either by occurrence of a single sporadic endocrine tumour in a patient with familial MEN1, or occurrence of two endocrine abnormalities associated with different aetiologies. Phenocopies arose in >5% of MEN1 families, and awareness of them is important in the clinical management of MEN1 and other hereditary disorders.
PMID: 19953642 [PubMed - indexed for MEDLINE]
The ADMR receptor mediates the effects of adrenomedullin on pancreatic cancer cells and on cells of the tumor microenvironment.
The ADMR receptor mediates the effects of adrenomedullin on pancreatic cancer cells and on cells of the tumor microenvironment.
PLoS One. 2009;4(10):e7502
Authors: Ramachandran V, Arumugam T, Langley R, Hwang RF, Vivas-Mejia P, Sood AK, Lopez-Berestein G, Logsdon CD
BACKGROUND: Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC). METHODS AND FINDINGS: AM receptors ADMR and CRLR were present in HPSC, HUVEC and MLECs while PDAC cells possessed only ADMR receptors as assessed by RT-PCR and western blotting. All cell lines expressed and secreted AM as indicated by ELISA. The growth of each of the cell lines was stimulated by exogenous AM and inhibited by the antagonist AMA. AM also stimulated in vitro angiogenesis assessed by polygon formation of endothelial cell lines. SiRNA-mediated silencing of ADMR, but not CRLR, reduced basal growth of all cells examined and reduced polygon formation of endothelial cells in vitro. Orthotopic tumors developed with shADMR bearing cancer cells had dramatically reduced primary tumor volume (>90%) and lung and liver metastasis compared to shControl bearing cells. To validate ADMR as a potential therapeutic target, in vivo studies were conducted using neutral nanoliposomes to systemically deliver human siRNA to ADMR to silence human cancer cells and mouse siRNA to ADMR to silence mouse tumor stromal cells. Systemic silencing of both human and mouse ADMR had no obvious adverse effects but strongly reduced tumor development. CONCLUSION: ADMR mediates the stimulatory effects of AM on cancer cells and on endothelial and stellate cells within the tumor microenvironment. These data support the further development of ADMR as a useful target treatment of pancreatic cancer.
PMID: 19847298 [PubMed - indexed for MEDLINE]
Nicotine promotes tumor growth and metastasis in mouse models of lung cancer.
Nicotine promotes tumor growth and metastasis in mouse models of lung cancer.
PLoS One. 2009;4(10):e7524
Authors: Davis R, Rizwani W, Banerjee S, Kovacs M, Haura E, Coppola D, Chellappan S
BACKGROUND: Nicotine is the major addictive component of tobacco smoke. Although nicotine is generally thought to have limited ability to initiate cancer, it can induce cell proliferation and angiogenesis in a variety of systems. These properties might enable nicotine to facilitate the growth of tumors already initiated. Here we show that nicotine significantly promotes the progression and metastasis of tumors in mouse models of lung cancer. This effect was observed when nicotine was administered through intraperitoneal injections, or through over-the-counter transdermal patches. METHODS AND FINDINGS: In the present study, Line1 mouse adenocarcinoma cells were implanted subcutaneously into syngenic BALB/c mice. Nicotine administration either by intraperitoneal (i.p.) injection or transdermal patches caused a remarkable increase in the size of implanted Line1 tumors. Once the tumors were surgically removed, nicotine treated mice had a markedly higher tumor recurrence (59.7%) as compared to the vehicle treated mice (19.5%). Nicotine also increased metastasis of dorsally implanted Line1 tumors to the lungs by 9 folds. These studies on transplanted tumors were extended to a mouse model where the tumors were induced by the tobacco carcinogen, NNK. Lung tumors were initiated in A/J mice by i.p. injection of NNK; administration of 1 mg/kg nicotine three times a week led to an increase in the size and the number of tumors formed in the lungs. In addition, nicotine significantly reduced the expression of epithelial markers, E-Cadherin and beta-Catenin as well as the tight junction protein ZO-1; these tumors also showed an increased expression of the alpha(7) nAChR subunit. We believe that exposure to nicotine either by tobacco smoke or nicotine supplements might facilitate increased tumor growth and metastasis. CONCLUSIONS: Our earlier results indicated that nicotine could induce invasion and epithelial-mesenchymal transition (EMT) in cultured lung, breast and pancreatic cancer cells. This study demonstrates for the first time that administration of nicotine either by i.p. injection or through over-the-counter dermal patches can promote tumor growth and metastasis in immunocompetent mice. These results suggest that while nicotine has only limited capacity to initiate tumor formation, it can facilitate the progression and metastasis of tumors pre-initiated by tobacco carcinogens.
PMID: 19841737 [PubMed - indexed for MEDLINE]
The reg4 gene, amplified in the early stages of pancreatic cancer development, is a promising therapeutic target.
The reg4 gene, amplified in the early stages of pancreatic cancer development, is a promising therapeutic target.
PLoS One. 2009;4(10):e7495
Authors: Legoffic A, Calvo E, Cano C, Folch-Puy E, Barthet M, Delpero JR, Ferrés-Masó M, Dagorn JC, Closa D, Iovanna J
BACKGROUND: The aim of our work was to identify the genes specifically altered in pancreatic adenocarcinoma and especially those that are altered early in cancer development. METHODOLOGY/PRINCIPAL FINDINGS: Gene copy number was systematically assessed with an ultra-high resolution CGH oligonucleotide microarray in DNA from samples of pancreatic cancer. Several new cancer-associated variations were observed. In this work we focused on one of them, involving the reg4 gene. Gene copy number gain of the reg4 gene was confirmed by qPCR in 14 cancer samples. It was also found with increased copy number in most PanIN3 samples. The relationship betweena gain in reg4 gene copy number and cancer development was investigated on the human pancreatic cancer cell line Mia-PaCa2 xenografted under the skin of nude mice. When cells were transfected with a vector allowing reg4 expression, they generated tumors almost twice larger in size. In addition, these tumors were more resistant to gemcitabine treatment than control tumors. Interestingly, weekly intraperitoneal administration of a monoclonal antibody to reg4 halved the size of tumors generated by Mia-PaCa2 cells, suggesting that the antibody interfered with a paracrine/autocrine mechanism involving reg4 and stimulating cancer progression. The addition of gemcitabine resulted in further reduction, tumors becoming 5 times smaller than control. Exposure to reg4 antibody resulted in a significant decrease in intra-tumor levels of pAkt, Bcl-xL, Bcl-2, survivin and cyclin D1. CONCLUSIONS/SIGNIFICANCE: It was concluded that adjuvant therapies targeting reg4 could improve the standard treatment of pancreatic cancer with gemcitabine.
PMID: 19834624 [PubMed - indexed for MEDLINE]
Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells.
Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells.
PLoS One. 2009;4(10):e7464
Authors: Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, Chari R, Shames DS, Tang X, MacAulay C, Varella-Garcia M, Vooder T, Wistuba II, Lam S, Brekken R, Toyooka S, Minna JD, Lam WL, Gazdar AF
BACKGROUND: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes. METHODOLOGY/PRINCIPAL FINDINGS: We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival. CONCLUSIONS: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.
PMID: 19826477 [PubMed - indexed for MEDLINE]
Non-redundant role for IL-12 and IL-27 in modulating Th2 polarization of carcinoembryonic antigen specific CD4 T cells from pancreatic cancer patients.
Non-redundant role for IL-12 and IL-27 in modulating Th2 polarization of carcinoembryonic antigen specific CD4 T cells from pancreatic cancer patients.
PLoS One. 2009;4(10):e7234
Authors: Tassi E, Braga M, Longhi R, Gavazzi F, Parmiani G, Di Carlo V, Protti MP
BACKGROUND: Pancreatic cancer is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We previously reported that pancreatic cancer patients have a selective Th2 skew in the anti-carcinoembryonic antigen (CEA) CD4(+) T cell immunity, which correlates with the presence of a predominant GATA-3(+) tumor lymphoid infiltrate. This has negative effects in both effective anti-tumor immunity and further favoring fibrinogenesis. Aim of this study was to evaluate whether the Th2 polarization of CEA-specific CD4(+) T cells from pancreatic cancer patients is stable or can be reverted by immunomodulating cytokines. METHODOLOGY/PRINCIPAL FINDINGS: We first evaluated the influence of IL-12 and IL-27, as single agents and in association, on the polarization of CEA-specific Th2 CD4(+) T cell clones from a pancreatic cancer patient. We found that only the combination of IL-12 and IL-27 modified the polarization of Th2 effectors by both reduction of IL-5, GM-CSF and IL-13 and induction of IFN-gamma production, which lasted after cytokine removal. Second, we evaluated the effect of the combined treatment on polyclonal CEA-specific CD4(+) T cells in short-time re-stimulation assays. In agreement with the data obtained with the clones, we found that the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4(+) T cells and enhanced pre-existing Th1 type immunity. CONCLUSIONS/SIGNIFICANCE: Collectively, our results demonstrate that tumor antigen specific Th2 CD4(+) T cells in pancreatic cancer are endowed with functional plasticity. Hence, loco-regional cytokines delivery or targeted therapy based on antibodies or molecules directed to the tumor stroma might improve anti-tumor immunity and ameliorate fibrosis, without systemic toxicity.
PMID: 19798410 [PubMed - indexed for MEDLINE]
Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.
Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.
Eur J Gastroenterol Hepatol. 2010 Feb;22(2):246-52
Authors: Said R, O'Reilly EM, Blumgart L, Shia J, Abou-Alfa GK
Cushing's syndrome and Zollinger-Ellison syndrome occur occasionally as a result of neuroendocrine cancers. The concurrence of the two syndromes has been considered to confer a poor clinical and therapeutic outcome. In this study, we are reviewing two patients with pancreatic islet cell carcinomas and with both Zollinger-Ellison and Cushing's syndromes, one followed up for more than 5 years, and the other still receiving therapy, 5 years since diagnosis. A literature review showed that surgery has limited utility as the majority of these patients had metastases at the time of diagnosis. Proton-pump inhibitors, ketoconazole, and somatostatin antagonists have a major role in controlling symptoms. Interferon and systemic chemotherapeutic agents play a role in the management of metastatic and fast-growing cases. Chemoembolization and bland embolization show encouraging results in controlling liver metastases. The latter was used effectively and more than once in the two patients presented herein. On the basis of recent molecular genetics studies, target therapy may be helpful, however, ongoing trials will define it's utility. As the data confers a worse prognosis versus other pancreatic neuroendocrine tumors, the relatively favorable outcome of the two patients reported herein may reflect the impact of multiple therapeutic modalities.
PMID: 19770666 [PubMed - indexed for MEDLINE]
The 'Whip-Stow' procedure: an innovative modification to the whipple procedure in the management of premalignant and malignant pancreatic head disease.
The 'Whip-Stow' procedure: an innovative modification to the whipple procedure in the management of premalignant and malignant pancreatic head disease.
Am Surg. 2010 Jan;76(1):70-2
Authors: Jeyarajah DR, Khithani A, Curtis D, Galanopoulos CA
Pancreaticoduodenectomy (PD) is the standard of care in the treatment of premalignant and malignant diseases of the head of the pancreas. Variability exists in anastomosis with the pancreatic remnant. This work describes a safe and easy modification for the pancreatic anastomosis after PD. Ten patients underwent the "Whip-Stow" procedure for the management of the pancreatic remnant. PD combined with a Puestow (lateral pancreaticojejunostomy [LPJ]) was completed using a running single-layer, 4-0 Prolene obeying a duct-to-mucosa technique. LPJ and pancreaticogastrostomy (PG) historical leak rates are reported to be 13.9 and 15.8 per cent, respectively. Mortality, leak, and postoperative bleeding rates were 0 per cent in all patients. The Whip-Stow was completed without loops or microscope with a 4-0 single-layer suture decreasing the time and complexity of the anastomosis. Average time was 12 minutes as compared with the 50 minutes of a 5 or 6-0 interrupted, multilayered duct-mucosa anastomosis. Benefits included a long-segment LPJ. In this study, the Whip-Stow procedure has proven to be a safe and simple approach to pancreatic anastomosis in selected patients. This new technique provides the benefit of technical ease while obeying the age old principles of obtaining a wide duct to mucosa anastomosis.
PMID: 20135943 [PubMed - indexed for MEDLINE]
Weekly epirubicin as salvage therapy in patients with gemcitabine-resistant advanced pancreatic cancer.
Weekly epirubicin as salvage therapy in patients with gemcitabine-resistant advanced pancreatic cancer.
J Chemother. 2009 Dec;21(6):698-700
Authors: Cereda S, Rognone A, Mazza E, Fugazza C, Ceraulo D, Villa E, Reni M
PMID: 20071296 [PubMed - indexed for MEDLINE]
CEA and CA-19.9 serum tumor markers as prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.
CEA and CA-19.9 serum tumor markers as prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.
J Chemother. 2009 Dec;21(6):673-80
Authors: Tsavaris N, Kosmas C, Papadoniou N, Kopteridis P, Tsigritis K, Dokou A, Sarantonis J, Skopelitis H, Tzivras M, Gennatas K, Polyzos A, Papastratis G, Karatzas G, Papalambros A
Most pancreatic adenocarcinoma patients present with locally advanced or metastatic disease at diagnosis. in this retrospective study the authors evaluated the prognostic significance of the CEA and CA-19.9 serum tumor markers in advanced (unresectable) pancreatic cancer in correlation to other prognostic factors (demographic data, clinical parameters, treatment modality) and survival time using univariate and multivariate methods, in 215 patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma. median survival was 29.0 weeks, with 21.9% of patients surviving 36 weeks. Among 24 potential prognostic variables, 19 were associated with shorter survival. Multivariate analysis indicated that ten factors had a significant independent effect on survival: chemotherapy, surgery, tumor localization, elevated C-reactive protein, elevated CeA, CA 19-9 (>30 x nl), jaundice at diagnosis, weight loss >10%, distant metastases, and Karnofsky performance status. Patients who had only palliative therapy had a hazard ratio of 8.94 versus those who underwent palliative surgery and chemotherapy. Although certain clinical, biochemical and biological factors remain important predictors of survival in patients with advanced pancreatic cancer, CA-19.9 serum tumor marker levels retain independent prognostic value for poor survival.
PMID: 20071292 [PubMed - indexed for MEDLINE]
Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.
Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.
Clin Cancer Res. 2009 Dec 1;15(23):7405-11
Authors: Rathkopf D, Dickson MA, Feldman DR, Carvajal RD, Shah MA, Wu N, Lefkowitz R, Gonen M, Cane LM, Dials HJ, Winkelmann JL, Bosl GJ, Schwartz GK
PURPOSE: Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner. EXPERIMENTAL DESIGN: We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. RESULTS: Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders. CONCLUSIONS: Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.
PMID: 19934304 [PubMed - indexed for MEDLINE]
Diagnosis and staging of primary ovarian cancer: correlation between PET/CT, Doppler US, and CT or MRI.
Diagnosis and staging of primary ovarian cancer: correlation between PET/CT, Doppler US, and CT or MRI.
Gynecol Oncol. 2010 Mar;116(3):389-94
Authors: Nam EJ, Yun MJ, Oh YT, Kim JW, Kim JH, Kim S, Jung YW, Kim SW, Kim YT
PURPOSE: To compare the diagnostic accuracy of positron emission tomography/computed tomography (PET/CT), pelvic Doppler ultrasonography (US), abdomino-pelvic computed tomography (CT), and pelvic magnetic resonance imaging (MRI) for detection of ovarian cancer and to assess the role of PET/CT in evaluating the dissemination of ovarian cancer. PATIENTS AND METHODS: One hundred thirty-three women suspected to have ovarian cancer were enrolled in a prospective study before surgery between March 2005 and August 2007. The accuracy of each modality in detection of malignancy was estimated by computing the relevant areas under a receiver operating characteristics curve. Histopathologic results served as the reference standard. RESULTS: Histopathology showed benign tumors in 25 patients, borderline tumors in 13 patients, and malignant tumors in 95 patients. In distinguishing malignant/borderline from benign ovarian tumors, the accuracy of PET/CT (0.921) was higher than that of pelvis US (0.830) and abdomino-pelvic CT or pelvis MRI (0.749; P=0.013). Radiologic staging by PET/CT was concordant with surgical staging in 78% of patient and PET/CT revealed 15 (15.8%) unpredicted extra-abdominal lymph node metastasis in 95 patients with ovarian cancer. In addition, PET/CT detected new, unexpected co-existing malignant tumors in five (3.8%) cases including two thyroid tumors, two breast tumors, and one pancreatic neuroendocrine cancer. CONCLUSION: PET/CT is superior to pelvis US, abdomino-pelvic CT, and pelvic MRI for diagnosis of malignant ovarian tumors and is useful in revealing metastatic ovarian cancer and co-existing malignant tumors. Therefore, we suggest that PET/CT could be used during pre-operative evaluation of patients suspected to have ovarian cancer.
PMID: 19926121 [PubMed - indexed for MEDLINE]
Randomized study comparing endoscopic ultrasound-guided Trucut biopsy and fine needle aspiration with high suction.
Randomized study comparing endoscopic ultrasound-guided Trucut biopsy and fine needle aspiration with high suction.
Cytopathology. 2010 Feb;21(1):44-51
Authors: Gerke H, Rizk MK, Vanderheyden AD, Jensen CS
OBJECTIVES: Endoscopic ultrasound (EUS)-guided Trucut biopsy (TCB) enables acquisition of tissue cores for histological assessment. Because of the rigid needle and the spring mechanism, tissue acquisition can be difficult from regions that require sharp angulation of the echoendoscope. Fine needle aspiration with high suction (FNAHS) has been proposed as a method to obtain histological tissue cores while affording the flexibility to obtain specimens even with extreme endoscope angulation. The objective was to compare prospectively these two methods in their ability to obtain specimens for histological assessment and in their diagnostic accuracy, including cytological diagnosis when achieved. METHODS: Eighty lesions in 77 patients were amenable to transoesophageal, transgastric or transrectal biopsy and were randomized to TCB (n = 44) or FNAHS (n = 36). Each specimen was assessed for adequacy (scoring system where a score of 0 was no material, 1-2 was considered cytological, and 3-5 was considered histological). Follow-up information was obtained to establish a gold standard final diagnosis. RESULTS: The median histological scores for FNAHS and TCB were 2 and 5, respectively. Histological cores were obtained in 95.3% of TCB, as opposed to 27.8% in the FNAHS group (P < 0.0001). Although the diagnostic accuracy for TCB was greater than that for FNAHS (88.3% and 77.8%, respectively), this was not statistically significant (P = 0.24). CONCLUSION: If histological information is required, TCB is superior to FNAHS. The difference in diagnostic accuracy did not reach statistical significance due to low numbers and the fact that FNAHS often enabled a cytological diagnosis.
PMID: 19456845 [PubMed - indexed for MEDLINE]
Autoimmune pancreatitis.
Autoimmune pancreatitis.
Scand J Gastroenterol. 2009;44(12):1391-407
Authors: Detlefsen S, Drewes AM
BACKGROUND: Autoimmune pancreatitis (AIP) is a relatively newly recognized type of pancreatitis that is characterized by diffuse or focal swelling of the pancreas due to lymphoplasmacytic infiltration and fibrosis of the pancreatic parenchyma. MATERIAL AND METHODS: A PubMed literature search was performed using the keywords "autoimmune pancreatitis". Sometimes, bibliographies were cross-referenced and related article searches were performed once an article of interest was identified. RESULTS: Pathologically, AIP shows narrowing of the pancreatic ducts and the intrapancreatic portion of the common bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two subtypes of the disease-one showing infiltration with IgG4-positive plasma cells but lacking granulocytic epithelial lesions (GELs), the other showing GELs but lacking strong IgG4 positivity. AIP is in at least some instances the pancreatic manifestation of a clinicopathological entity of IgG4-related systemic sclerosing disease. On the basis of pancreatic imaging, together with serological measurement of IgG4 and evaluation of other organ involvement, many AIP patients can be identified. The remaining patients require further diagnostic work-up. In these patients, pancreatic core needle biopsy and, as AIP responds to steroid treatment, also a trial with steroids, can help to differentiate AIP from pancreatic cancer. OUTLOOK AND DISCUSSION: This review presents the pathological, radiologic and laboratory findings of AIP. Moreover, the treatment and pathogenesis are discussed.
PMID: 19958057 [PubMed - indexed for MEDLINE]
Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.
Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.
Eur J Gastroenterol Hepatol. 2010 Feb;22(2):246-52
Authors: Said R, O'Reilly EM, Blumgart L, Shia J, Abou-Alfa GK
Cushing's syndrome and Zollinger-Ellison syndrome occur occasionally as a result of neuroendocrine cancers. The concurrence of the two syndromes has been considered to confer a poor clinical and therapeutic outcome. In this study, we are reviewing two patients with pancreatic islet cell carcinomas and with both Zollinger-Ellison and Cushing's syndromes, one followed up for more than 5 years, and the other still receiving therapy, 5 years since diagnosis. A literature review showed that surgery has limited utility as the majority of these patients had metastases at the time of diagnosis. Proton-pump inhibitors, ketoconazole, and somatostatin antagonists have a major role in controlling symptoms. Interferon and systemic chemotherapeutic agents play a role in the management of metastatic and fast-growing cases. Chemoembolization and bland embolization show encouraging results in controlling liver metastases. The latter was used effectively and more than once in the two patients presented herein. On the basis of recent molecular genetics studies, target therapy may be helpful, however, ongoing trials will define it's utility. As the data confers a worse prognosis versus other pancreatic neuroendocrine tumors, the relatively favorable outcome of the two patients reported herein may reflect the impact of multiple therapeutic modalities.
PMID: 19770666 [PubMed - indexed for MEDLINE]
Immunohistochemical and electron microscopic studies of a case of duodenal gangliocytic paraganglioma.
Immunohistochemical and electron microscopic studies of a case of duodenal gangliocytic paraganglioma.
Med Mol Morphol. 2009 Dec;42(4):245-9
Authors: Ohtsuki Y, Watanabe R, Kimura M, Okamoto T, Murakami S, Mizukami Y, Takeji M, Okada Y, Hayashi Y, Lee GH, Furihata M
Gangliocytic paraganglioma (GPG) is a rare tumor, occurring almost exclusively in the duodenum. In the present case, a submucosal tumor 2.5 x 2 x 1.5 cm in size was located on the anal side of the papilla of Vater, with clear margins and without capsule on cut-surface examination. Tumor cells included three types of cells: ganglion-like cells (GCs), endocrine cells (ECs), and Schwann cells (SCs). The GCs were large with eccentric nuclei with large nucleoli and clear abundant cytoplasm. ECs were detected in small nests, surrounded by bundles of SCs. Immunohistochemically, GCs were positive for synaptophysin, neuron-specific enolase (NSE), and CD56. ECs were positive for chromogranin A, NSE, somatostatin, pancreatic polypeptide, and CD56, and were associated with S100 protein-positive SCs. On fine structural examination, ECs contained numerous membrane-bounded secretory granules, 250-450 nm in diameter, in their cytoplasm, surrounded by a branched, complex basal lamina. SCs possessed basal lamina along their long interlacing cytoplasmic processes. The histogenesis of GPG most likely involves proliferation and differentiation of pluripotent stem cells in the duodenal crypts in the duodenum as a true tumor, although it is also possible that the retroperitoneal components of both GCs and SCs proliferate, together with ECs, from ventral primordial tissue of the pancreas in the duodenum. The immunohistochemical and ultrastructural findings of a case of GPG are reported, focusing on three major cellular components: GCs, ECs, and SCs.
PMID: 20033372 [PubMed - indexed for MEDLINE]
Circulatory collapse in a patient with gastrinoma after metoclopramide administration.
Circulatory collapse in a patient with gastrinoma after metoclopramide administration.
Hong Kong Med J. 2009 Dec;15(6):478-81
Authors: Lau KK, Chan KW, Lok CM, Lam AW, Lee HH, Luk WF, Mak CM, Ching CK, Lo J, Li SM, Chan AY
A patient who was given metoclopramide for vomiting and diarrhoea developed circulatory collapse with his blood pressure dropping to 50/20 mm Hg. A gastrinoma was diagnosed histologically. The extent of the tumour was defined by octreotide scanning and magnetic resonance imaging. Metoclopramide was again given for colicky abdominal pain and the patient developed circulatory collapse a second time. A laparotomy involving extensive resection of the tumour was performed. The MEN1 mutation was not detected in blood or tumour tissue. Follow-up octreotide scanning did not show any residual tumour. Possible causes for the circulatory collapse are discussed. Our case is probably the first patient with gastrinoma to develop circulatory collapse after being given metoclopramide.
PMID: 19966355 [PubMed - indexed for MEDLINE]
Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.
Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.
Eur J Gastroenterol Hepatol. 2010 Feb;22(2):246-52
Authors: Said R, O'Reilly EM, Blumgart L, Shia J, Abou-Alfa GK
Cushing's syndrome and Zollinger-Ellison syndrome occur occasionally as a result of neuroendocrine cancers. The concurrence of the two syndromes has been considered to confer a poor clinical and therapeutic outcome. In this study, we are reviewing two patients with pancreatic islet cell carcinomas and with both Zollinger-Ellison and Cushing's syndromes, one followed up for more than 5 years, and the other still receiving therapy, 5 years since diagnosis. A literature review showed that surgery has limited utility as the majority of these patients had metastases at the time of diagnosis. Proton-pump inhibitors, ketoconazole, and somatostatin antagonists have a major role in controlling symptoms. Interferon and systemic chemotherapeutic agents play a role in the management of metastatic and fast-growing cases. Chemoembolization and bland embolization show encouraging results in controlling liver metastases. The latter was used effectively and more than once in the two patients presented herein. On the basis of recent molecular genetics studies, target therapy may be helpful, however, ongoing trials will define it's utility. As the data confers a worse prognosis versus other pancreatic neuroendocrine tumors, the relatively favorable outcome of the two patients reported herein may reflect the impact of multiple therapeutic modalities.
PMID: 19770666 [PubMed - indexed for MEDLINE]