Surgical resection techniques for locally advanced hilar cholangiocarcinoma

Background

Resection of perihilar cholangiocarcinoma involves major hepatectomy including caudate lobectomy. It is technically challenging because of the complex, intimate and variable relationship between biliary and vascular structures in the liver hilum. Resectability rates vary from 30 to 80 % and about one third of patients have microscopically involved margins. However, adequately performed resections provide 5-year survival of 30–40 % and are worth pursuing.

Purpose

Better understanding of anatomy, better imaging, improved surgical techniques and progress in perioperative care of these patients have pushed the limits of resection of these tumours. Many of the traditional indicators of inoperability such as bilateral involvement of second-order hepatic ducts, contralateral biliary and vascular involvement, and need for arterial resection have been overcome or are being challenged. This review discusses techniques that may increase margin-free resectability of Bismuth–Corlette type III and IV perihilar cholangiocarcinoma.

Conclusion

Advanced perihilar cholangiocarcinoma requires extended liver resection and often vascular resection, despite which the margin may be compromised in about one third of patients. Right sided tumours are likely to need right trisectionectomy and portal vein resection, best served by an en bloc hilar resection or Rex-recess approach. Left-sided tumours often involve contralateral blood vessels and require left trisegmentectomy with possible right portal vein or right hepatic artery reconstruction. These tumours are best tackled by hepatobiliary surgeons with experience in microvascular techniques. Salvage procedures when arterial reconstruction is not feasible are still under evaluation.     

Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction,apoptosis and inflammation in rats: Possible mechanism of nephroprotection

Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100 mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney.     

Development of EGFR-Targeted Nanoemulsion for Imaging and Novel Platinum Therapy of Ovarian Cancer

Purpose

Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C₆-ceramide, were designed to overcome these limitations.

Methods

The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780_CP.

Results

The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFR-targeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC₅₀ in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist^®.

Conclusion

The myrisplatin/C₆-ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer.     

Assessment of atmospheric dispersion and radiological impact from the Fukushima accident in a 40-km range using a simulation approach

In this study, radiation doses and lifetime attributable health risk to the members of public in a 40-km impact zone around the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) were assessed for the airborne releases that occurred during 11–31 March 2011 from the loss of coolant accident associated with the east Japan earthquake and tsunami event. High-resolution simulations with FLEXPART-WRF Lagrangian particle dispersion model were made using available source term estimates for four significant isotopes (Cs134, Cs137, I131, Xe133). Radiation risk models were adopted to estimate the health risk for leukemia, breast, thyroid, and all solid cancers using simulated distributed lifetime organ doses. The simulations indicate occurrence of hotspots in the spatial activity deposition and radiation dose distribution with high values in the northwest and south-southwest land sectors in a 40-km radius. Large activity depositions (10⁶ to 10⁸ Bq/m² of Cs137 between 12 and 31 March 2011) and external air doses (10 to 100 μSv/h) are simulated in the above sectors. The simulated air dose rates are found to match with observed doses at 85 % of the monitor stations within a factor of 5. It is estimated that the groundshine and ingestion dose are the principal contributors of the effective dose. Simulated average effective dose during the first year of exposure varied as ~150 mSv in the first few kilometers to 2 mSv at 40 km. The risk incidence was estimated to be high for infants compared to the children and adult age group for all types of cancers. The first 0–20-km range of the FDNPP is characterized with high risk for all types of cancers, for example, 10 to 20 in 10,000 adults for leukemia. The analysis shows that the immediate implementation of countermeasures of evacuation in the 0–20-km zone, sheltering in the 20–40-km zone, and food restrictions by Japan actually reduced significant health risks to the population living near FDNPP. Simulated yearly distribution of total dose indicates that people of evacuated zone can be rehabilitated in about 16 years in the 5–10-km area and 7 years in the 10–20-km area with minimum risk, whereas the near reactor zone of 0–5 km and areas along the plume footprint up to 20 km in the northwest sector of FDNPP require special attention and reclamation measures for rehabilitation. This study demonstrates a total simulation-based approach for estimating the radiation risk for the Fukushima case and helps to assess the time attainment of low risk for inhabitation of the people in the affected areas.     

Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism

Chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive disorder characterized by short limbs. Previously, we mapped the locus responsible for the disease on the distal end of bovine chromosome 6. Here, we narrowed the critical region to approximately 2 cM by using linkage analysis, constructed a BAC and YAC contig covering this region, and identified a gene, LIMBIN (LBN), that possessed disease-specific mutations in the affected calves. One mutation was a single nucleotide substitution leading to an activation of a cryptic splicing donor site and the other was a one-base deletion resulting in a frameshift mutation. Strong expression of the Lbn gene was observed in limb buds of developing mouse embryos and in proliferating chondrocytes and bone-forming osteoblasts in long bones. These findings indicate that LBN is responsible for bovine chondrodysplastic dwarfism and has a critical role in a skeletal development.     

Potent block of Cx36 and Cx50 gap junction channels by mefloquine

Recently, great interest has been shown in understanding the functional roles of specific gap junction proteins (connexins) in brain, lens, retina, and elsewhere. Some progress has been made by studying knockout mice with targeted connexin deletions. For example, such studies have implicated the gap junction protein Cx36 in synchronizing rhythmic activity of neurons in several brain regions. Although knockout strategies are informative, they can be problematic, because compensatory changes sometimes occur during development. Therefore, it would be extremely useful to have pharmacological agents that block specific connexins, without major effects on other gap junctions or membrane channels. We show that mefloquine, an antimalarial drug, is one such agent. It blocked Cx36 channels, expressed in transfected N2A neuroblastoma cells, at low concentrations (IC(50) approximately 300 nM). Mefloquine also blocked channels formed by the lens gap junction protein, Cx50 (IC(50) approximately 1.1 microM). However, other gap junctions (e.g., Cx43, Cx32, and Cx26) were only affected at concentrations 10- to 100-fold higher. To further examine the utility and specificity of this compound, we characterized its effects in acute brain slices. Mefloquine, at 25 microM, blocked gap junctional coupling between interneurons in neocortical slices, with minimal nonspecific actions. At this concentration, the only major side effect was an increase in spontaneous synaptic activity. Mefloquine (25 microM) caused no significant change in evoked excitatory or inhibitory postsynaptic potentials, and intrinsic cellular properties were also mostly unaffected. Thus, mefloquine is expected to be a useful tool to study the functional roles of Cx36 and Cx50.     

Characterization of in vitro antimurine thymocyte globulin-induced regulatory T cells that inhibit graft-versus-host disease in vivo

Antithymocyte/antilymphocyte globulins are polyclonal antihuman T-cell antibodies used clinically to treat acute transplant rejection. These reagents deplete T cells, but a rabbit antihuman thymocyte globulin has also been shown to induce regulatory T cells in vitro. To examine whether antithymocyte globulin-induced regulatory cells might be functional in vivo, we generated a corresponding rabbit antimurine thymocyte globulin (mATG) and tested its ability to induce regulatory cells in vitro and whether those cells can inhibit acute graft-versus-host disease (GVHD) in vivo upon adoptive transfer. In vitro, mATG induces a population of CD4(+)CD25(+) T cells that express several cell surface molecules representative of regulatory T cells. These cells do not express Foxp3 at either the protein or mRNA level, but do show suppressive function both in vitro and in vivo when adoptively transferred into a model of GVHD. These results demonstrate that in a murine system, antithymocyte globulin induces cells with suppressive activity that also function in vivo to protect against acute GVHD. Thus, in both murine and human systems, antithymocyte globulins not only deplete T cells, but also appear to generate regulatory cells. The in vitro generation of regulatory cells by anti-thymocyte globulins could provide ad-ditional therapeutic modalities for immune-mediated disease.     

Retrospective Analysis of Ponticulus Posticus in Indian Orthodontic Patients-A Lateral Cephalometric Study

Background

The lateral cephalogram is the most common diagnostic radiograph used in clinical orthodontics. Significant cervical spine pathology can be detected on the routine lateral cephalogram. The aim of this study is to sensitize clinicians for examining the cervical area of lateral cephalogram carefully and thus record anatomical variations.

Materials and Methods

The presence and types of ponticuli posticus were investigated on 650 lateral cephalograms which were randomly selected from archived records at AECS Maaruti College of Dental Sciences & Research Centre, Bangalore

Results

The prevalence rate of Ponticulus Posticus in our study was found to be 11.1%. Though there was slight female predominance of 11.7% as compared to 10.4% in males, difference was not statistically significant.

Conclusion

Ponticulus posticus is a common anomaly in the Indian population. If any such anomaly is detected or suspected, it must be documented in the patient''s health record and specialist consultation must be sought. The lateral cephalogram must thus be considered as one of the baseline screening tool for detecting anomalies and pathology in the cervical spine region.     

Neuroblastoma: Outcome over a 14 year period from a tertiary care referral centre in India

Purpose

To evaluate the outcome of children with neuroblastoma (NB) from a tertiary care referral centre in India.

Method

All children with NB registered from October 1996 through July 2009 were included in the study. INSS was used for staging. All children included in the study received chemotherapy and radiation therapy appropriate for stage. Tumor resection was done when feasible. The final outcome was overall survival and it was categorized as Complete Response (CR), Partial Response (PR); No Response (NR) and Progressive Disease (PD). Analysis of three-year overall survival was done using Kaplan Meier method and Log Rank test of significance. Multivariate analysis for significance of age, site and stage was performed.

Results

144 children in the age range of 1–132 months (median 36) were enrolled. Only 38 (26.4%) children were below 12 months. 112 (77.8%) of the tumors were abdominal and 32 (22.2%) were extra-abdominal. Stage distribution was 1 + 2 in 6 (4.2%); 3 in 58 (40.3%); 4 in 68 (47.2%); 4 s in 12 (8.3%). 83 (57.6%) underwent gross complete resection. At the time of last follow-up, 100 (69.4%) were alive [60 CR (41.7%); 33 PR; 7 PD/NR] and 44 (30.6%) were dead [1CR; 11PR; 32 PD/NR]. The three-year OS was 60.7% [95 CI 50.4–69.5]. The OS was 69.7% for those < 12 months of age [95 CI 51.8–82.0] and CR was achieved in 57.9%, while for those > 12 months the OS was 55.3% [95 CI 42.2–66.6] and CR was achieved in 35.8% (p = 0.73). All 6 (100%) patients with Stage 1 and Stage 2 disease were alive and disease free. The OS was 71.5% for Stage 3[95 CI 55.3–82.7] and CR was achieved in 56.9%, while for Stage 4 the OS was 35.7%[95 CI 19.3–52.4] and CR was achieved in 17.6% (p = 0.001). The OS was 83.3% for 4 s [95 CI 48.2–95.6] and CR was achieved in 75%.

Conclusion

All the six children with Stage 1 & 2 achieved CR and were alive, while 57% of Stage 3 could achieve CR and had an OS of 71.5%. The OS (35.7%) and CR (17.6%) for Stage 4 were significantly less (p = 0.001).