Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Combining passive immunotherapy with an antibody to the disialoganglioside GD2 (ch14.18/SP2/0) and cytokines with 13-cis-retinoic acid for post-myeloablative maintenance therapy increased survival in high-risk NB, but the overall prognosis for these children is still in need of improvement. Fenretinide (4-HPR) is a synthetic retinoid that has shown clinical activity in recurrent NB and is cytotoxic to a variety of cancer cells, in part via the accumulation of dihydroceramides, which are precursors of GD2. We investigated the effect of 4-HPR on CHO-derived, ch14.18-mediated anti-NB effector functions, complement-dependent cytotoxicity (CDC), and antibody-dependent and antibody-independent cellular cytotoxicity (ADCC and AICC, respectively). Here, we demonstrate for the first time that pretreatment of fenretinide-resistant NB cells with 4-HPR significantly enhanced ch14.18/CHO-mediated CDC and ADCC and AICC by both human natural killer cells and peripheral blood mononuclear cells. Treatment with 4-HPR increased GD2 and death receptor (DR) expression in resistant NB cells and induced an enhanced granzyme B and perforin production by effector cells. Blocking of ganglioside synthesis with a glucosylceramide synthase inhibitor abrogated the increased ADCC response but had no effect on the AICC, indicating that GD2 induced by 4-HPR mediates the sensitization of NB cells for ADCC. We also showed that 4-HPR induced increased GD2 and DR expression in a resistant NB xenograft model that was associated with an increased ADCC and AICC response using explanted tumor target cells from 4-HPR-treated mice. In summary, these findings provide an important baseline for the combination of 4-HPR and passive immunotherapy with ch14.18/CHO in future clinical trials for high-risk NB patients.     

Microtubule-associated protein tau genetic variations are uncommon cause of frontotemporal dementia in south India

Microtubule-associated protein tau (MAPT) positive neuropathology is the characteristic feature of majority of frontotemporal dementia (FTD) cases, which is due to the mutations or haplotypic variations in the gene encoding MAPT (MAPT). The present study was aimed at determining the frequency of genetic variations in MAPT in a south Indian FTD cohort. The frequency of mutations were determined in 116 FTD, 8 progressive supranuclear palsy (PSP) and 3 corticobasal syndrome (CBS) patients and haplotype diversity were analyzed in a study cohort comprising 116 FTD, 8 PSP, 3 CBS, 194 other dementia groups, 78 mild cognitive impairment (MCI) and 130 cognitively normal individuals and report no pathogenic mutations in FTD/PSP/CBS or haplotypic association with disease risk in FTD or other dementia patients. These findings suggest that there may be other genetic or epigenetic factors contributing to the pathogenesis of FTD in the south Indian population.     

Contrasting Inflammatory Responses in Severe and Non-severe Community-acquired Pneumonia

The objective of this study was to compare systemic and local cytokine profiles and neutrophil responses in patients with severe versus non-severe community-acquired pneumonia (CAP). Hospitalized patients with CAP were grouped according to the pneumonia severity index (PSI), as non-severe (PSI?<?91 points) or severe (PSI?≥?91 points). Blood and sputum samples were collected upon admission. Compared to non-severe CAP patients, the severe CAP group showed higher plasma levels of pro- and anti-inflammatory cytokines but in contrast, lower sputum concentrations of pro-inflammatory cytokines. Blood neutrophil functional responses were elevated in CAP patients compared to healthy controls. However, neutrophils from severe CAP patients showed reduced respiratory burst activity compared to the non-severe group. Results indicate that patients with severe CAP fail to mount a robust local pro-inflammatory response but exhibit instead a more substantial systemic inflammatory response, suggesting that a key driver of CAP severity may be the ability of the patient to generate an optimal local inflammatory response.     

Le Fort-based maxillofacial transplantation: current state of the art and a refined technique using orthognathic applications

Following encouraging results from the first 6 maxillofacial allotransplants, there has been a dramatic rise in interest worldwide. Numerous groups are now devoting resources to increase the frequency of these complex procedures, and with this, the craniomaxillofacial surgeon should become familiar with the emerging state of the art. This article reviews the evolution of Le Fort-based cadaveric studies pertaining to maxillofacial allotransplantation, briefly describes the clinical reports through 2010, and introduces a refined technique applying orthognathic applications. Preliminary studies over the last 5 years have highlighted the challenges associated with transplanting skeletal components, and clinical results presented thus far have been extremely promising. However, a notable area for improvement is suboptimal facial-skeletal harmony and profile in the context of sagittal skeletal projection and maxillomandibular relation. To our knowledge, orthognathic planning as applied to osteocutaneous face transplantation has not been described. Many recipients seen thus far demonstrate some degree of malocclusion and suboptimal harmony, as expected, given the donor-to-recipient skeletal/jaw discrepancies. Given that the goal is to improve function as well as form, the importance of orthognathic planning cannot be overstated with respect to optimizing harmony, profile, and occlusion. Preoperative planning, including generation of donor/recipient dental cast models, as described herein for the first time, is essential.     

Initiating a minimally invasive cardiac surgery program–challenges and solutions

Background

Cardiac Surgery has evolved over past 50 years and has become a mature discipline. Minimally Invasive Cardiac Surgery techniques (MICS), warmly welcomed in the developed world, are still to take root in the developing countries. Minimally invasive approach represents a challenge in that it requires a new learning curve and carries apprehension about compromising the surgical results. As for the established surgeon, MICS necessitates a departure from the comfort zone and considerable metamorphosis.

Methods

Cardiac surgery has been carried at our centre for nearly two decades. Completing first year of our minimally invasive program we did 70 cardiac surgical cases from June 2011 to August 2012. These included 25 Mitral Valve Replacements (MVR), 30 Atrial Septal Defect closures (ASD), 10 Aortic Valve Replacement(AVR) and 5 Coronary Artery Bypass Grafting (CABG).

Results

There was no peri-op mortality. There were 2 conversions to standard sternotomy both in the early part of our learning curve. One patient developed right lower limb edema related to femoral vein cannulation.10 patients had minor air leak which settled spontaneously. There was one incidence of deep surgical site infection. The mean cross clamp time for ASD closure, MVR and AVR were 26.13 min, 51.10 min and 58.66 min respectively. The median Intensive Care Unit (ICU) stay was 2 days and the median hospital stay was 4 days.

Conclusion

The Cardiac surgery stage in the developing countries is ripe for the era of MICS. The unique patient population here stands to benefit most from it. Careful patient selection aiming to “tailor the operation to the patient and not the patient to the operation” is the crux of a successful MICS program.