A splenic 'cyst': histology confirmed splenic sarcoma.

Primary malignant fibrous histiocytoma, now classified as pleomorphic undifferentiated sarcoma, is the most common soft-tissue sarcoma in adult life. Primary splenic pleomorphic undifferentiated sarcoma is extremely rare and aggressive, and is associated with a poor prognosis; only 14 cases of splenic pleomorphic undifferentiated sarcoma have been documented in the English literature. We discuss a case of a 56-year-old woman with iron-deficiency anaemia, early satiety and left upper-quadrant pain, who was preoperatively diagnosed with a large splenic cyst following thorough investigation. This was excised in an elective procedure. Unfortunately, histology confirmed splenic pleomorphic undifferentiated sarcoma. Following a review and summary of the literature, we discuss key differentials between splenic cysts and splenic pleomorphic undifferentiated sarcoma. This case highlights that iron-deficiency anaemia is unusual in splenic cysts and more sinister causes must be considered.

Effect of resection of localized pancreaticobiliary adenocarcinoma on angiogenic markers and tissue factor related pro-thrombotic and pro-angiogenic activity.

In this study, 52 patients were studied to elucidate the relative impact of resection of localized pancreaticobiliary adenocarcinoma (PBC) on circulating factors of tumour-associated angiogenesis e.g. tissue factor bearing microparticles (TFMP) and vascular endothelial growth factor (VEGF) and their clinicopathological significance to angiogenesis markers in cancer tissue from PBC patients. Angiogenesis array analysis on serum samples revealed that surgical resection of tumour lesion in PBC patients affects the levels of a panel of angiogenesis-related molecules, including VEGF that was verified by ELISA to significantly reduce (median & IQR: 1003(369-2000) vs. 457(159-834) pg/ml; p<0.05). Correspondingly, a significant decrease in the angiogenic activity (decreased capillary tube formation; p<0.05) of serum samples after the surgery was also found. Despite a decrease in number of circulating TFMP after surgery, this did not reach statistical significance; there was a significant reduction in pro-coagulant activity (prolonged prothrombin time, p<0.001) post-operatively. In addition, the activity of total microparticles (MP activity assay, p<0.05) was decreased significantly. Immunohistochemical staining of tumour tissue revealed a strong correlation between the microvessel density (MVD) and VEGF expression. Also, higher levels of circulating TFMP or TF related activity (prothrombin time) correlated significantly with TF expression and MVD on tumour tissues from PBC patients. These findings suggest that in pancreaticobiliary adenocarcinoma TF related angiogenesis drivers are equally significant to VEGF ones, raising the clinical question of whether the effectiveness of angiogenesis targeting studies could be improved through the 'dual' targeting of these pathways in PBC.

Rare benign pathologies mimicking malignancy: A cautionary tale for Whipple's resections.

Benign pathologies demonstrated after a Whipple's resection (pancreatoduodenectomy) for pancreatic and peri-ampullary lesions are relatively uncommon. Here we report two cases where a Whipple's procedure was undertaken for suspected pancreaticobiliary cancer and where the final histology revealed, in each case, a rare benign lesion. The first case confirmed a cholesterol polyp in the distal common bile duct whilst the second case revealed ampullary intramural ectopic gland hyperplasia. Although pre-operative imaging helps in differentiating some benign lesions from malignant lesions, rare benign pathology may still mimic malignant conditions leading to a Whipple's resection.

Case hepatic endometriosis: a continuing diagnostic dilemma.

BACKGROUND: Intraparenchymal endometriosis of liver is rare. It may present as liver tumour and the diagnosis is not usually established till after surgery. CASE OUTLINE: A 48-year-old postmenopausal woman presented with right upper quadrant pain and a cystic liver mass. Liver function tests and tumour markers (alphaFP, CEA, CA 19-9, and CA 125) were normal. Radiological imaging (USS, CT and MRI) suggested a thick walled cystic mass involving segments IV and VIII with complex intracystic septations. Frozen section at operation suggested a benign cystadenoma. The cyst was enucleated using a CUSA (Cavitron ultrasonic aspirator). The final histology confirmed endometriosis. DISCUSSION: Eleven cases of hepatic endometrioma have been reported and only four in postmenopausal women. Preoperative diagnosis poses a challenge and so far none of the cases have been diagnosed preoperatively. Surgery remains the treatment of choice. Accurate diagnosis at time of operation may avoid extensive liver surgery and its associated morbidity.

Quality of life after liver resection for hepatobiliary malignancies.

BACKGROUND: Few prospective longitudinal studies have used a validated quality of life (QOL) instrument in patients undergoing liver resection for hepatobiliary malignancy. METHODS: Patients undergoing liver resection for hepatobiliary tumours in a 1-year period were enrolled. The cancer-specific European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) was completed before operation, and at 6, 12 and 36-48 months after surgery. QOL over time was analysed in relation to several clinical factors. RESULTS: A total of 103 patients were enrolled. Patient compliance was at least 75 per cent at all stages. Most functional scales and the global QOL scale showed a non-significant trend towards deterioration at 6 months and a return to preoperative level at 12 months. Physical functioning and dyspnoea deteriorated significantly at 6 months (P = 0.020 and P = 0.004 respectively) and did not recover by 12 months (P = 0.002 and P < 0.001 respectively). Pain and fatigue showed clinically significant deterioration over 12 months, which was not statistically significant. Survivors without recurrence at 36-48 months showed better QOL than those with recurrent disease. CONCLUSION: Major liver resection is associated with acceptable QOL outcomes, and QOL continues to improve in the long term in those without recurrence.

Cystic duct and Heister's "valves".

The anatomy and physiology of the cystic duct have been relatively neglected by anatomists and the function of the spiral mucosal folds or "valves" of Heister, first described in 1732, remains obscure. The gross and microscopic anatomy of the cystic duct is reviewed together with results from laboratory investigations into the function of the cystic duct and its spirally arranged folds. The duct and spiral folds contain muscle fibers responsive to pharmacologic, hormonal, and neural stimuli. There is, however, no convincing evidence of a discrete muscular sphincter within the duct. Although the cystic duct is unlikely to play a major role in gallbladder filling and emptying, it appears to function as more than a passive conduit. Coordinated, graded muscular activity in the cystic duct in response to hormonal and neural stimuli may facilitate gallbladder emptying. The principal function of the internal spiral folds that are found in man and other animals may be to preserve patency of this narrow, tortuous tube rather than to regulate bile flow.

Liver transplantation for a hilar inflammatory myofibroblastic tumor.

A 7-yr-old boy presented with obstructive jaundice secondary to an inflammatory myofibroblastic tumor centered on the hepatic hilum and extending into the liver. The tumor was further complicated by portal vein phlebitis and occlusion. Attempted resection of the tumor with portal vein reconstruction and bilioenteric drainage was unsuccessful and he required urgent orthotopic liver transplantation. In contrast to more peripheral inflammatory myofibroblastic tumors in the liver, hilar lesions are locally aggressive, causing occlusive portal phlebitis and biliary obstruction. Successful management may include the need for liver transplantation.

Awareness of post-exposure prophylaxis guidelines against occupational exposure to HIV in a Mumbai hospital.

BACKGROUND: Exposure to the human immunodeficiency virus (HIV) is a matter of concern for healthcare workers. We conducted a survey to determine the level of awareness amongst operating room personnel regarding post-exposure prophylaxis in case of needlestick injuries from confirmed or suspected cases of HIV. METHODS: A structured questionnaire was presented to 39 anaesthetists and 31 surgical residents. Questions were related to identification of high risk fluids, risk of transmission, drugs, costs and procedure to be adopted for post-exposure prophylaxis. RESULTS: Fourteen respondents (20%) were aware of the true risk of transmission. About one-third identified all high risk fluids correctly. Fifty-five respondents (78%) correctly stated that washing the site with soap and water was the initial measure, but less than a third knew whom to contact immediately after a needlestick injury. Though 45 respondents (64%) correctly stated that prophylaxis should be initiated within 1 hour of injury, none knew exactly which drugs were to be used. Thirty respondents (42%) were aware of the use of zidovudine but none were aware of the second or third drugs used for post-exposure prophylaxis. Only 4 respondents (6%) knew the correct duration of post-exposure prophylaxis. Five respondents (7%) knew that the drugs were available in medical stores and 7 knew the approximate cost of therapy. CONCLUSION: There is surprisingly poor knowledge of post-exposure prophylaxis against HIV. Ongoing awareness and training programmes are necessary to improve the same.

Association of the anticancer antibiotic chromomycin A(3) with the nucleosome: role of core histone tail domains in the binding process.

The anticancer antibiotic chromomycin A(3) is a transcription inhibitor which forms two types of complexes with Mg(2+): complex I (1:1 in terms of chromomycin A(3)-Mg(2+)) and complex II (2:1 in terms of chromomycin A(3)-Mg(2+)). These complexes are the DNA-binding ligands. With the broad objective of elucidation of the mechanism for action of this group of transcription inhibitors in eukaryotic systems, we have studied the interaction of the antibiotic with nucleosome core particles under different conditions. We have demonstrated and characterized the role of core histone proteins, particularly the N-terminal tail domains, in the association of nucleosome with both complexes of chromomycin. From a scrutiny of the spectroscopic features of the two bound complexes and comparison of the binding and associated thermodynamic parameters, we have shown the following. Core histone(s) stand(s) in the way of access of the ligand(s) to nucleosomal DNA. N-Terminal intact and chopped core particles interact differentially with the same complex. The modes of interaction of the two complexes, I and II, with the same system are different. Tryptic removal of N-terminal tail domains of core histones enhances the binding potential and access of both complexes of chromomycin to the nucleosomal DNA. Agarose gel electrophoresis of an equilibrium mixture containing either complex I or complex II and a saturating concentration of the core particle has demonstrated that both complexes have a tendency to disrupt the nucleosome structure, leading to a release of nucleosomal DNA. Compared to the N-terminal intact nucleosome, the N-terminal chopped nucleosome is more susceptible to disruption. Therefore, we suggest from the above results that the N-terminal tail domains, which have an important role in eukaryotic gene expression, stand in the way of a free access of external agents such as anticancer drugs to the eukaryotic genome. The significance of the results to understand the molecular basis of the transcription inhibitory capacity of chromomycin is discussed.

Interactions of chromomycin A3 and mithramycin with the sequence d(TAGCTAGCTA)2.

Anti-cancer antibiotics, chromomycin A3 (CHR) and mithramycin (MTR) inhibit DNA directed RNA synthesis in vivo by binding reversibly to template DNA in the minor groove with GC base specificity, in the presence of divalent cations like Mg2+. Under physiological conditions, (drug)2Mg2+ complexes formed by the antibiotics are the potential DNA binding ligands. Structures of CHR and MTR differ in their saccharide residues. Scrutiny of the DNA binding properties reveal significant differences in their sequence selectivity, orientation and stoichiometry of binding. Here, we have analyzed binding and thermodynamic parameters for the interaction of the antibiotics with a model oligonucleotide sequence, d(TAGCTAGCTA)2 to understand the role of sugars. The oligomer contains two potential binding sites (GpC) for the ligands. The study illustrates that the drugs bind differently to the sequence. (MTR)2Mg2+ binds to both sites whereas (CHR)2Mg2+ binds to a single site. UV melting profiles for the decanucleotide saturated with the ligands show that MTR bound oligomer is highly stabilized and melts symmetrically. In contrast, with CHR, loss of symmetry in the oligomer following its association with a single (CHR)2Mg2+ complex molecule leads to a biphasic melting curve. Results have been interpreted in the light of saccharide dependent differences in ligand flexibility between the two antibiotics.

Interaction of mithramycin with chromatin.

Mithramycin (MTR) is an anti-cancer antibiotic that blocks the macromolecular biosynthesis via reversible interaction with DNA template in the presence of bivalent metal ion such as Mg2+. In absence of DNA, mithramycin forms two types of complexes with Mg2+, complex I (with 1:1 stoichiometry in terms of MTR: Mg2+) and complex II (with 1:2 stoichiometry in terms of MTR: Mg2+). In an eukaryotic system, the drug would interact with chromatin, a protein-DNA complex. We have employed the spectroscopic techniques such as absorption and fluorescence to study the interaction of MTR: Mg2+ complexes with rat liver chromatin. In this report, we have shown that the two types of ligands have different binding potentials with the same chromatin. This supports our proposition that complexes I and II, are different molecular species. We have also shown that the histone protein(s) reduce the binding potential and the number of available sites for both ligands.

Differential interactions of antitumor antibiotics chromomycin A(3) and mithramycin with d(TATGCATA)(2) in presence of Mg(2+).

The antitumor antibiotics chromomycin A(3) (CHR) and mithramycin (MTR) are known to inhibit macromolecular biosynthesis by reversibly binding to double stranded DNA with a GC base specificity via the minor groove in the presence of a divalent cation such as Mg(2+). Earlier reports from our laboratory showed that the antibiotics form two types of complexes with Mg(2+): complex I with 1:1 stoichiometry and complex II with 2:1 stoichiometry in terms of the antibiotic and Mg(2+). The binding potential of an octanucleotide, d(TATGCATA)(2), which contains one potential site of association with the above complexes of the two antibiotics, was examined using spectroscopic techniques such as absorption, fluorescence, and circular dichroism. We also evaluated thermodynamic parameters for the interaction. In spite of the presence of two structural moieties of the antibiotic in complex II, a major characteristic feature was the association of a single ligand molecule per molecule of octameric duplex in all cases. This indicated that the modes of association for the two types of complexes with the oligomeric DNA were different. The association was dependent on the nature of the antibiotics. Spectroscopic characterization along with analysis of binding and thermodynamic parameters showed that differences in the mode of recognition by complexes I and II of the antibiotics with polymeric DNA existed at the oligomeric level. Analysis of the thermodynamic parameters led us to propose a partial accommodation of the ligand in the groove without the displacement of bound water molecules and supported earlier results on the DNA structural transition from B --> A type geometry as an obligatory requirement for the accommodation of the bulkier complex II of the two drugs. The role of the carbohydrate moieties of the antibiotics in the DNA recognition process was indicated when we compared the DNA binding properties with the same type of Mg(2+) complex for the two antibiotics.

Interaction of antitumor drug, mithramycin, with chromatin.

Mithramycin (MTR) is an anticancer drug that blocks macromolecular biosynthesis via reversible interaction with DNA in the presence of bivalent cation such as Mg2+. Mithramycin forms two types of complexes with Mg2+: complex I (1:1 in terms of MTR:Mg2+) and complex II (2:1 in terms of MTR:Mg2+). In vivo antibiotic would interact with chromatin, a protein-DNA complex. For the first time we have demonstrated and characterized the association of both complexes of MTR with chromatin and nucleosome core. From an evaluation and comparison of the binding and thermodynamic parameters and CD spectra of bound complexes, we have shown the following. Histone(s) stand in the say of the access of the ligand(s) to chromosomal DNA. Chromatin and core particle interact differentially with the same ligand. Mode of interaction of the two complexes, I and II, with the same system is different. Significance of these results to understand the transcription inhibitory property of the drug in eukaryotic chromosome is discussed.

Cardiomediastinal tamponade and shock following three-stage transthoracic oesophagectomy.

Massive gastric tube dilatation causing cardiomediastinal tamponade is an unusual cause of obstructive shock after transthoracic oesophagectomy. A 55-year-old female was operated for total transthoracic oesophagectomy. Twelve hours after the surgery, she developed hypotension and raised central venous pressure unresponsive to fluid infusion and ionotropes. X-ray chest showed a massively dilated stomach, which was causing intrathoracic tamponade. Suction applied to the nasogastric tube led to aspiration of 150-200 ml of fluid and a large volume of air, which led to resolution of the haemodynamic instability. A simple manoeuvre like nasogastric suction in postoperative case of oesophagectomy can serve as a diagnostic as well as therapeutic tool. It must be performed before resorting to invasive and expensive examination or intervention.

Interaction of microtubules with active principles of Xanthium strumarium.

Indigenous variety of Xanthium strumarium (X. strumarium) was screened for its antimitotic activity using the microtubule-tubulin system isolated from mammalian tissue. A preliminary phytochemical screening of the whole extracts of the plant was carried out followed by partial purification of the whole extract of X.strumarium. The separated fractions obtained were identified and used for in vitro polymerization studies. The whole as well as partially separated chemical constituents of X. strumarium showed effective inhibition of tubulin polymerization. The results thus suggest that X. strumarium may possess antimitotic components.

Role of Mg2+ in the interaction of anticancer antibiotic, chromomycin A3 with DNA: does neutral antibiotic bind DNA in absence of the metal ion?

Antitumor antibiotic, Chromomycin A3 (CHR), inhibits DNA replication and transcription via reversible interaction with double stranded DNA with GC-base specificity. The interaction, at and above physiological pH, requires the presence of bivalent metal ions, such as Mg2+. Anionic antibiotic does not bind DNA in the absence of Mg2+. In this paper we have examined the structural potential of neutral CHR at pH 5.2 to bind DNA in the absence of Mg2+. We have demonstrated the ability of the neutral antibiotic to bind DNA by means of different spectroscopic techniques and evaluated the necessary thermodynamic parameters for elucidation of the molecular basis of recognition. The results are compared with the scenario when Mg2+ is present in the system, because the ultimate aim of these studies is to elucidate the role of Mg2+ in CHR-DNA recognition. Neutral CHR binds to Mg2+ with lesser affinity than its anionic form. Spectroscopic features of the drug and its Mg2+ complex indicate self association of the antibiotic in the absence and presence of Mg2+. GC-base specificity of the drug and its Mg2+ complex are retained at pH 5.2, though the modes of recognition of DNA by the two ligands are different. Minor groove width of DNA plays a role in the accommodation of the ligand(s) during the GC base specific recognition while positive charge of Mg2+ in CHR:Mg2+ complex further facilitates the association. Relatively lower affinity of the neutral drug and its Mg2+ complex for DNA can be ascribed to the self association of these ligands in the absence of DNA.

Role of mg2+ in chromomycin a3 - DNA interaction: a molecular modeling study.

Chromomycin A(3) (CHR) is an antitumor antibiotic that inhibits macromolecular biosynthesis by reversibly binding to double stranded DNA via the minor groove, with GC-base specificity. At and above physiological pH when CHR is anionic, interaction of CHR with DNA requires the presence of divalent metal ions like Mg(2+). However, at acidic pHthe molecule is neutral and it binds DNA even in absence of Mg(2+). Molecular dynamics simulation studies at 300K of neutral CHR and 1:1 CHR:Mg(2+) complexes formed at pH 5.2 and 8.0 show that hydrophobicity of CHR:Mg(2+) complex formed with the neutral drug is greater than that of the two other species. Interactions of CHR with DNA in presence and absence of Mg(2+) have been studied by simulated annealing to understand the role of Mg(2+) in the DNA binding potential of CHR. This shows that the antibiotic has the structural potential to bind to DNA even in the absence of metal ion. Evaluation of the direct interaction energy between the ligand and DNA does not explain the observed GC-base specificity of the antibiotic. When energy contributions from structural alteration of the interacting ligand and DNA as a sequel to complex formation are taken into account, atrue picture of the theoretical binding propensity emerges. This implies that DNA and/or the ligand undergo significant structural alterations during the process of association, particularly in presence of Mg(2+). Accessible surface area calculations give idea about the entropy contribution to the binding free energy which is found to be different depending upon the presence and absence of Mg(2+).

Structural basis of DNA recognition by anticancer antibiotics, chromomycin A(3), and mithramycin: roles of minor groove width and ligand flexibility.

Anticancer antibiotics, chromomycin A(3) (CHR) and mithramycin (MTR), inhibit cellular processes like transcription and replication, by binding reversibly to double-stranded DNA via minor groove, in the presence of bivalent metal ions like Mg(2+) with GC base specificity. Here, we have attempted to assess the roles of two parameters-namely DNA groove dimension and flexibility of the ligand-in the structural recognition between the ligands, (drug)(2)Mg(2+) and DNA. For the purpose we have employed three synthetic oligonucleotides with minor groove width lying between B- and A-type structures as model DNA sequences: d(GCGCGCGC)(2) in B-form, d(CCGGCGCCGG)(2) in B-form with unusual wide minor groove, and (GGGGCCCC)(2) in A-form. Association of the (drug)(2)Mg(2+) with the oligomers have been probed using spectroscopic techniques like absorbance, fluorescence, and CD. The binding and thermodynamic parameters for the different association processes have also been characterized. Major conclusions from the above studies are as follows. Groove size of the oligomers influences the conformation of the bound ligand. A saccharide dependent variation in structural rigidity of the ligands, (MTR)(2)Mg(2+) and (CHR)(2)Mg(2+), has been observed that leads to differences in the energetics of recognition of the same DNA sequence by the two ligands. In contrast to (CHR)(2)Mg(2+), higher flexibility in (MTR)(2)Mg(2+) makes its conformation in the DNA bound form less sensitive to the groove dimension of DNA.