Addition of Fentanyl to Ropivacaine Infusion in Continuous Thoracic Paravertebral Infusion Does Not Improve Its Analgesic Effect Following Modified Radical Mastectomy: A Randomized Controlled Trial.

A randomized controlled trial was conducted to evaluate pain scores in patients given continuous thoracic paravertebral (TPV) block with ropivacaine alone or with fentanyl in modified radical mastectomy (MRM). Forty female patients ASA classes 1 and 2, aged 18 to 60 years, undergoing MRM were recruited. Preanesthesia with 0.5% ropivacaine, 20 mL, was injected at the T4 TPV space. After 2 hours, patients were randomly assigned to receive a 0.1 mL/kg/h infusion of either 0.2% ropivacaine (group R) or 0.19% ropivacaine plus fentanyl, 2 µg/mL (group RF). Postoperatively, patient-controlled analgesia (PCA) with fentanyl was provided. Visual analog scale (VAS) pain scores at rest and movement were significantly less in group RF at 8 AM on postoperative day 1 (R vs RF: rest: 2 [interquar-tile range, 0-7] vs 1 [0-6]; P = .016; movement: 2.5 [1-8] vs 2 [1-8], P= .042) and on movement 60 minutes postoperatively (R vs RF: 2 [0-9] vs 2 [1-2]; P = .01). Mean total fentanyl consumed via PCA in group R was significantly more (206 ± 31.68 µg vs RF 82.5 ± 35.07 µg, P < .001). Mean total fentanyl consumed via PCA plus TPV infusion was comparable (R: 206 ± 31.68 µg vs RF: 211 ± 25.52 µg, P < .2). Because the mean VAS score was below 3 in all timeframes, addition of fentanyl to ropivacaine in continuous TPV infusion in MRM had no clinical advantage.

Central bronchial carcinoid: Management of a case and anesthetic perspectives.

Obstructing lesions of the central airways present with a variety of symptoms and are often associated with pneumonia or asthma-like states. Anesthesia to these patients often presents challenges right from the preoperative stabilization of underlying lung condition, mask ventilation in the supine position to maintaining oxygenation and ventilation in the intraoperative and postoperative period. We present here a case of a young woman with a central bronchial tumor with significant airway obstruction with potential for major bleeding and subsequent anesthetic management without lung sacrificing measures and cardiopulmonary bypass assistance.

Rapid Resolution of Donor-Derived Glomerular Fibrin Thrombi After Deceased Donor Kidney Transplantation.

The aim of this study was to determine the clinical and histologic outcomes related to transplanting kidneys from deceased donors with glomerular fibrin thrombi (GFT). We included all cases transplanted between October 2003 and October 2014 that had either a preimplantation biopsy or an immediate postreperfusion biopsy showing GFT. The study cohort included 61 recipients (9.9%) with GFT and 557 in the control group without GFT. Delayed graft function occurred in 49% of the GFT group and 39% in the control group (p = 0.14). Serum creatinine at 1, 4, and 12 months and estimated GFR at 12 months were similar in the two groups. Estimated 1-year graft survival was 93.2% in the GFT group and 95.1% in the control group (p = 0.22 by log-rank). Fifty-two of the 61 patients in the GFT group (85%) had a 1-month protocol biopsy, and only two biopsies (4%) showed residual focal glomerular thrombi. At the 1-year protocol biopsy, the prevalence of moderate to severe interstitial fibrosis and tubular atrophy was 24% in the GFT group and 30% in the control group (p = 0.42). We concluded that GFT resolves rapidly after transplantation and that transplanting selected kidneys from deceased donors with GFT is a safe practice.

Measles Outbreak in High Risk Areas of Delhi: Epidemiological Investigation and Laboratory Confirmation.

OBJECTIVE: To describe epidemiological and laboratory characteristics of the measles outbreaks recorded in the urban slums of Delhi (designated as high risk areas under the Polio program), from February through July 2014. METHODS: As a part of surveillance and containment measures, an extensive field investigation for measles case search (WHO definition) through 'house to house survey' was conducted by district health teams and field volunteers of National Polio Surveillance Project (NPSP), WHO, Delhi from February through July, 2014. The data generated by the health teams was collected and analyzed. RESULTS: About 1.1 million households in the high risk areas of Delhi were surveyed for epidemiological investigations. A total of 1337 suspected measles cases were reported. The case fatality rate (CFR) was 1.2 %. Statistical analysis showed significant relation between age of the child (measles case) and immunization status. Higher numbers of reported cases were above 5 y and less than 9 mo of age. Measles IgM was detected in 132 cases and D8 strain was isolated on genotyping. CONCLUSIONS: The outbreak was predominantly localized to the high risk areas (urban slums) of the city. Low CFR was reported during the outbreaks. The outbreaks highlight the need to extend the reach of immunization services to urban slums and strengthen measles surveillance including laboratory based surveillance.

Transplanting Kidneys from Deceased Donors With Severe Acute Kidney Injury.

Our aim was to determine outcomes with transplanting kidneys from deceased donors with acute kidney injury, defined as a donor with terminal serum creatinine ≥2.0 mg/dL, or a donor requiring acute renal replacement therapy. We included all patients who received deceased donor kidney transplant from June 2004 to October 2013. There were 162 AKI donor transplant recipients (21% of deceased donor transplants): 139 in the standard criteria donor (SCD) and 23 in the expanded criteria donor (ECD) cohort. 71% of the AKI donors had stage 3 (severe AKI), based on acute kidney injury network (AKIN) staging. Protocol biopsies were done at 1, 4, and 12 months posttransplant. One and four month formalin-fixed paraffin embedded (FFPE) biopsies from 48 patients (24 AKI donors, 24 non-AKI) underwent global gene expression profiling using DNA microarrays (96 arrays). DGF was more common in the AKI group but eGFR, graft survival at 1 year and proportion with IF/TA>2 at 1 year were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (p-value <0.005; FDR <10%), but by 4 months there were no differences. Transplanting selected kidneys from deceased donors with AKI is safe and has excellent outcomes.

VAC Therapy in Large Infected Sacral Pressure Ulcer Grade IV-Can Be an Alternative to Flap Reconstruction?

Vacuum-assisted closure (VAC) therapy is a new entrant in wound care after growth factors and alginate or hydrocolloid dressing, in the treatment of pressure ulcers. We have been using this technique for diabetic foot ulcers. A young nondiabetic man presented with a large sacral bed sore after high doses of ionotropes in an intensive care unit for treating severe hypotension. His wound was debrided, and instead of flap surgery in such infected wound, he was treated with VAC therapy. The complete wound healing was achieved in 6 weeks and at half the cost of flap surgery. Moreover, the chances of flap failure and its related complications were eliminated.

Cryosurgery and ligation (Cryo-plication) of symptomatic hemorrhoids - "an ideal procedure". Initial experience and review of literature.

Haemorrhoidal disease has been in limelight again due to emerging newer modalities of treatment over the last decade. The range varies from simple rubber band ligation to stapled rectopexy. But a rational and ideal approach is still unclear. This study aims to analyze the ideal modality in today's scenario of managing haemorrhoidal disease. A prospective study on 12 patients, was carried out over 24 months in a surgical unit of a tertiary care hospital. The pain, bleeding, rectal discharge, anal stenosis were observed. Results show that the Cryoplication procedure had no anal stenosis, minimal bleeding, less pain and cost was effective. When compared with other contemporary modalities it has lesser complications and short and easy learning curve.

CCL19 reduces tumour burden in a model of advanced lung cancer.

Epstein-Barr virus-induced molecule 1 ligand chemokine (CCL19) is a CC chemokine that chemoattracts both dendritic cells (DC) and T lymphocytes. We evaluated the antitumour efficacy of CCL19 in a murine model of spontaneous bronchoalveolar cell carcinoma. These transgenic mice (CC-10 TAg) express the SV40 large T antigen under the Clara Cell promoter, develop bilateral, multifocal, pulmonary carcinomas and die at 4 months owing to progressive pulmonary tumour burden. To mimic therapy in late-stage disease, 3-month-old transgenic mice were treated with recombinant CCL19 (0.5 microg dose(-1)) by intranodal (axillary lymph node region) injection three times per week for 4 weeks. CCL19 treatment led to a marked reduction in tumour burden with extensive mononuclear infiltration of the tumours compared to diluent treated controls. Flow cytometric analyses showed significant increases in CD4 and CD8T cell subsets as well as DC in the lungs of CCL19-treated mice. Lung tissue cytokine profiles showed a shift towards immune stimulatory molecules with a decrease in the immunosuppressive cytokine TGF-beta. Our findings show that CCL19 may serve as a potential immune stimulator and provide a strong rationale for the evaluation of CCL19 in cancer immunotherapy.

Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer.

Radioiodide is an effective therapy for thyroid cancer. This treatment modality exploits the thyroid-specific expression of the sodium iodide symporter (NIS) gene, which allows rapid internalization of iodide into thyroid cells. To test whether a similar treatment strategy could be exploited in nonthyroid malignancies, we transfected non-small cell lung cancer (NSCLC) cell lines with the NIS gene. Although the expression of NIS allowed significant radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells, we hypothesized that coexpression of both NIS and TPO genes would overcome this deficiency. Our results show that transfection of NSCLC cells with both human NIS and TPO genes resulted in an increase in radioiodide uptake and retention and enhanced tumor cell apoptosis. These findings suggest that single gene therapy with only the NIS gene may have limited efficacy because of rapid efflux of radioiodide. In contrast, the combination of NIS and TPO gene transfer, with resulting TPO-mediated organification and intracellular retention of radioiodide, may lead to more effective tumor cell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer.

Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44.

Elevated tumor cyclooxygenase (COX-2) expression is associated with increased angiogenesis, tumor invasion, and suppression of host immunity. We have previously shown that genetic inhibition of tumor COX-2 expression reverses the immunosuppression induced by non-small cell lung cancer (NSCLC). To assess the impact of COX-2 expression in lung cancer invasiveness, NSCLC cell lines were transduced with a retroviral vector expressing the human COX-2 cDNA in the sense (COX-2-S) and antisense (COX-2-AS) orientations. COX-2-S clones expressed significantly more COX-2 protein, produced 10-fold more prostaglandin E(2), and demonstrated an enhanced invasive capacity compared with control vector-transduced or parental cells. CD44, the cell surface receptor for hyaluronate, was overexpressed in COX-2-S cells, and specific blockade of CD44 significantly decreased tumor cell invasion. In contrast, COX-2-AS clones had a very limited capacity for invasion and showed diminished expression of CD44. These findings suggest that a COX-2-mediated, CD44-dependent pathway is operative in NSCLC invasion. Because tumor COX-2 expression appears to have a multifaceted role in conferring the malignant phenotype, COX-2 may be an important target for gene or pharmacologic therapy in NSCLC.

Secondary lymphoid tissue chemokine mediates T cell-dependent antitumor responses in vivo.

Secondary lymphoid tissue chemokine (SLC, also referred to as Exodus 2 or 6Ckine) is a recently identified high endothelial-derived CC chemokine. The ability of SLC to chemoattract both Th1 lymphocytes and dendritic cells formed the rationale to evaluate this chemokine in cancer immunotherapy. Intratumoral injection of recombinant SLC evidenced potent antitumor responses and led to complete tumor eradication in 40% of treated mice. SLC-mediated antitumor responses were lymphocyte dependent as evidenced by the fact that this therapy did not alter tumor growth in SCID mice. Studies performed in CD4 and CD8 knockout mice also revealed a requirement for both CD4 and CD8 lymphocyte subsets for SLC-mediated tumor regression. In immunocompetent mice, intratumoral SLC injection led to a significant increase in CD4 and CD8 T lymphocytes and dendritic cells, infiltrating both the tumor and the draining lymph nodes. These cell infiltrates were accompanied by the enhanced elaboration of Th1 cytokines and chemokines monokine induced by IFN-gamma and IFN-gamma-inducible protein 10 but a concomitant decrease in immunosuppressive cytokines at the tumor site. In response to irradiated autologous tumor, splenic and lymph node-derived cells from SLC-treated tumor-bearing mice secreted significantly more IFN-gamma, GM-CSF, and IL-12 and reduced levels of IL-10 than did diluent-treated tumor-bearing mice. After stimulation with irradiated autologous tumor, lymph node-derived lymphocytes from SLC-treated tumor-bearing mice demonstrated enhanced cytolytic capacity, suggesting the generation of systemic immune responses. These findings provide a strong rationale for further evaluation of SLC in tumor immunity and its use in cancer immunotherapy.

Adenoviral gene transfer is inhibited by soluble factors in malignant pleural effusions.

Direct in vivo gene delivery is a prerequisite for many gene therapy strategies; however, efficacy has been limited by a lack of therapeutic gene transfer. In studying intrapleural malignancy as a model for the gene therapy of non-small cell lung cancer, we previously identified soluble chondroitin sulfate-proteoglycans/glycosaminoglycans (CS-PG/GAGs) in malignant pleural effusions (MPE) as factors that inhibit retroviral vector (RV) transduction. Similarly, we have observed inhibition to gene transfer in the fluid component of MPE using adenoviral (Ad) vectors. Analyses indicate that the factors responsible for the block are filterable, soluble, titrable, and heat stable (56 degrees C). Passage through microporous membranes fractionates the inhibitory factors into large (> 100 kD) components of the effusions. In contrast to RV transduction, hyaluronic acid or CS-PG/GAGs are not the inhibitors because the block is not reversed by pretreatment of the effusions with mammalian hyaluronidase, and exogenous addition of GAGs into the transduction media does not diminish Ad transduction. In considering the mechanism of action of the inhibitory factors, we observe that Ad entry, and specifically the binding of radiolabeled Ad to its target cell, is inhibited in the presence of MPE. Ad internalization may also be impaired; however, these studies exclude soluble fibronectin in MPE as a competitive inhibitor of Ad transduction. Lastly, sepharose A- mediated immunoglobulin depletion of MPE only partially reverses the block, and significant inhibition to Ad gene transfer persists at lower adenovirus:target cell ratios. Identifying the structural and functional basis for inhibition to Ad gene transfer may yield specific strategies to enable better in vivo translation of gene therapy approaches.

Intratumoral administration of adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor immunity and achieves tumor eradication.

In two murine lung cancer models adenoviral interleukin 7-transduced dendritic cells (DC-AdIL-7) were administered intratumorally, resulting in complete tumor regression. Intratumoral DC-AdIL-7 therapy was as effective as DCs pulsed with specific tumor peptide antigens. Comparison with other intratumoral therapies including recombinant IL-7, AdIL-7 vector alone, unmodified DCs, IL-7-transduced fibroblasts, or DCs pulsed with tumor lysates revealed DC-AdIL-7 therapy to be superior in achieving antitumor responses and augmenting immunogenicity. Mice with complete tumor eradication as a result of either DC-AdIL-7 or AdIL-7 therapy were rechallenged with parental tumor cells 30 days or more after complete tumor eradication. All the DC-AdIL-7-treated mice completely rejected a secondary rechallenge, whereas the AdIL-7-treated mice had sustained antitumor effects in only 20-25% of the mice. DC-AdIL-7 therapy was more effective than AdIL-7 in achieving systemic antitumor responses and enhancing immunogenicity. After complete tumor eradication, those mice treated with DC-AdIL-7 evidenced significantly greater release of splenocyte GM-CSF and IFN-gamma than did controls or AdIL-7-treated mice. After intratumoral injection, gene-modified DCs trafficked from the tumor to lymph node sites and spleen. DCs were detected in nodal tissues for up to 7 days after intratumoral injection. We report that intratumoral DC-AdIL-7 leads to significant systemic immune responses and potent antitumor effects in murine lung cancer models.

New gene and cell-based therapies for lung cancer.

Lung cancer is the leading cause of cancer-related mortality in men and women in the United States, in part, because of the poor treatment options available. New treatment strategies that specifically target discreet steps in the molecular and cellular pathogenesis of this disease are under development. This review highlights many of the basic defects that result in the cellular transformation and subsequent progression of lung cancer, and how the understanding of those fundamental defects lead to the formulation of rational gene-based or cell-based therapies.

Initial experience with day case laparoscopic cholecystectomy at a tertiary care hospital in India.

BACKGROUND: Cholecystectomy is one of the commonest general surgical operations. Laparoscopic cholecystectomy is currently the most favoured approach. As it is associated with less postoperative pain and ileus, it allows early discharge of patients from the hospital. Studies from the West have reported that 'day case laparoscopic cholecystectomy' is feasible and safe. In India, the current practice is to admit patients for laparoscopic cholecystectomy 24-48 hours prior to surgery and to discharge most patients within one to two days of surgery. There is no report from any Indian centre describing 'day case laparoscopic cholecystectomy'. We conducted a prospective study to assess the feasibility, safety and patients' acceptance of 'day case laparoscopic cholecystectomy' in a tertiary care hospital. METHODS: Eighty-four patients with symptomatic cholelithiasis, aged less than 65 years with ASA grade I and II, were offered day case laparoscopic cholecystectomy. Seventy-four patients consented to be included in the study. The nature of operation and likely postoperative course were explained in detail to the patients. Conventional 4-port laparoscopic cholecystectomy was attempted in all patients. The main outcome measures assessed were successful management of patients on day case basis and its acceptance by the patients. RESULTS: Sixty-eight (92%) patients underwent successful laparoscopic cholecystectomy. Fifty-five of these (81%) were successfully managed as day case procedures. There were no major complications. Three of the 55 patients (5.4%) needed re-admission and could be managed conservatively. Fifty-three (96%) patients described their experience as 'pleasant'. None of them described their experience to be 'unpleasant' or 'bad'. Fifty-four (98%) patients stated that they would recommend day case laparoscopic cholecystectomy to close friends and relatives. CONCLUSION: In selected patients, day case laparoscopic cholecystectomy is safe and feasible in a developing country.

IkappaBalpha gene transfer is cytotoxic to squamous-cell lung cancer cells and sensitizes them to tumor necrosis factor-alpha-mediated cell death.

Current paradigms in cancer therapy suggest that activation of nuclear factor-kappaB (NF-kappaB) by a variety of stimuli, including some cytoreductive agents, may inhibit apoptosis. Thus, inhibiting NF-kappaB activation may sensitize cells to anticancer therapy, thereby providing a more effective treatment for certain cancers. E-1-deleted adenoviral (Ad) vectors encoding a "superrepressor" form of the NF-kappaB inhibitor IkappaBalpha (AdIkappaBalphaSR) or beta-galactosidase (AdLacZ) were tested alone and in combination with tumor necrosis factor-alpha (TNF-alpha) in lung cancer cells for sensitization of the cells to death. Following transduction with AdIkappaBalphaSR, lung cancer cells expressed IkappaBalphaSR in a dose-dependent manner. Probing nuclear extracts of lung cancer cells with NF-kappaB-sequence-specific oligonucleotides indicated that there was a minimal amount of NF-kappaB in the nucleus at baseline and an expected and dramatic increase in nuclear NF-kappaB following exposure of cells to TNF-alpha. Control E-1-deleted AdLacZ did not promote NF-kappaB activation. Importantly, AdIkappaBalphaSR-mediated gene transfer resulted in the complete block of nuclear translocation of NF-kappaB by specific binding of its p65/relA component with transgenic IkappaBalphaSR. At the cellular level, transduction with AdIkappaBalphaSR resulted in increased cytotoxicity in lung cancer cells as opposed to transduction with equivalent doses of AdLacZ. In addition, whereas the parental cells were resistant to TNF-alpha-mediated cytotoxicity, IkappaBalphaSR-transduced cells could be sensitized to TNF-alpha. Consequently, AdIkappaBalphaSR transduction followed by exposure to TNF-alpha uniformly resulted in the death of non-small-cell lung cancer cells. These data suggest that novel approaches incorporating IkappaBalpha gene therapy may have a role in the treatment of lung cancer.

Gene therapy for lung cancer.

Gene therapy has received considerable attention and some speculation as to its value. Although few patients have been treated, the preliminary results of the phase I lung cancer gene therapy clinical trials are very promising. Clinically relevant basic research in the molecular pathogenesis and immunology of lung cancer is progressing. As improved vector technologies are developed, new opportunities will be available to initiate lung cancer gene therapy trials that are based on a more detailed understanding of lung cancer biology. In conclusion, although important biologic and technical questions remain unanswered, recent research suggests that gene therapy will have a profound impact on lung cancer treatment.

Toxin gene-mediated growth inhibition of lung adenocarcinoma in an animal model of pleural malignancy.

Transduction of malignant cells with toxin genes provides a novel strategy by which to promote tumor cell destruction. Whereas the capacity of the toxin gene/prodrug combination cytosine deaminase/fluorocytosine to inhibit growth of human metastatic pulmonary adenocarcinoma cell lines in vitro is established, the in vivo efficacy of this binary system has not yet been determined. For the development of toxin gene therapy for the treatment of lung adenocarcinoma metastatic to the pleural space, a reliable, disease-specific model is required. The serosa of the rat small intestine resembles the basal lamina of the pleura and provides the basis for a more convenient model than direct injection of tumor into the pleural space. Adenocarcinoma cells are inoculated into everted denuded rat intestine configured as a sac. Immunocytochemical and histological analyses show rapid cell growth with characteristics that mimic nodular metastatic intrapleural disease. In the context of this model, systemically delivered fluorocytosine significantly inhibits the growth of cytosine deaminase-expressing human lung adenocarcinoma cells. The dosing schedule required 30 days; neither addition of an enzyme inhibitor that increases the half-life of fluorocytosine nor intralumenal drug delivery is effective in shortening (to 15 days) the protocol. We conclude that CD continues to hold promise as a toxin gene for lung adenocarcinoma gene therapy, and that prolonged prodrug administration may be required for maximum efficacy.

Transduction of non-small cell lung cancer cells by adenoviral and retroviral vectors.

Gene transfer into a panel of non-small cell lung cancer (NSCLC) cells by adenoviral (Ad) and retroviral (RV) vectors was studied. Indexed to multiplicity of infection (MOI), Ad vectors transduce squamous, adenosquamous, and malignant mesothelioma cells with greater efficiency than large cells or adenocarcinoma cells. Transduction-sensitive cells bind the Ad vector with specificity for the Ad fiber knob, and internalize vector efficiently. Transduction-refractory cells bind and internalize vector by less efficient pathways. Like Ad vectors, there is heterogeneity in RV transduction efficiencies of different NSCLC subtypes. With respect to the most common cell type metastatic to the pleural space (adenocarcinoma), amphotropic retroviral vectors transduce cells of this subtype more efficiently (at a lower MOI) than Ad. RV transduction is not solely dependent on cellular replication, and both permissive and refractory cell lines express the mRNA for the amphotropic RV receptor. These observations suggest that neither Ad nor RV vectors will suffice a priori as the optimal gene transfer vehicle, and successful gene therapy of lung cancer may require tumor-specific or patient-specific vectors.