Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia.

PURPOSE: Beta lactams are standard empirical therapy for febrile neutropenia (FN). The aim of this study was to evaluate the efficacy and safety of cefepime monotherapy compared with cefoperazone/sulbactam plus amikacin (CS + A) for empirical treatment of high risk FN. METHODS: One hundred seventy-five patients with 336 FN episodes were randomized to receive either cefepime (2 g q8h for adults and 50 mg/kg q8h for children) or CS (2 g q8h for adults and 50 mg/kg q8h for children) plus amikacin (15 mg/kg once a day). Positive response was defined as afebrile within 72 h of starting antibiotics, persistent afebrile status more than 48 h and no requirement of second-line antibiotics and antifungal agents. RESULTS: Three hundred thirty-six episodes were assessable for efficacy (168 cefepime, 168 CS + A). The positive response to antibiotics was identical for cefepime (53%) and CS + A (53%). Positive response was similar in MDI (microbiologically documented infection), 50 vs. 35% (p = 0.248), CDI (clinically documented infection), 50 vs. 35% (p = 0.259), combination CDI + MDI, 25 vs. 15% (p = 0.400), FUO (fever of unknown origin), 68 vs. 72% (p = 0.577) respectively in the two groups. The successful discontinuation of antibiotics at 72 h in FUO was similar in both groups (60 vs. 59%, p = 0.544). Total drug-related adverse events were similar in both groups (8 vs. 6%) except renal dysfunction was high in CS + A (1 vs. 7 events). Mortality was the same between two groups (8 vs 7%). CONCLUSIONS: Cefepime monotherapy and CS + A had similar efficacy as first-line therapy for FN. Discontinuation of empirical antibiotics is safe and feasible approach in selected group of FUO patients.

Gemcitabine and carboplatin in metastatic nonsmall cell lung cancer: Experience from a tertiary cancer center in South India.

BACKGROUND: Gemcitabine and carboplatin combination is widely used as one of the first-line chemotherapeutic regimens in patients with metastatic nonsmall cell lung cancer patients. METHODOLOGY: A total of 112 patients with metastatic disease were recruited. They were on standard 21-day gemcitabine 1.2 g/m2 and carboplatin AUC 5 dosing schedule. Each patient received at least four cycles and a maximum of 6 cycles of treatment. The patients were followed up, and the demographic, efficacy and toxicity profiles were analyzed. RESULT: The mean age was 53.81±9.85 with 71 male and 41 female patients. Response assessment was done in 82 patients, and the objective response rate was found to be 47.6% with 39 partial responders, 20 patients with stable disease and 23 patients with progressive disease. The median overall survival was 12 months (95% CI 9.89-14.11). We found anemia (62.5%) to be more prominent than the other toxicities followed by thrombocytopenia and vomiting (31.3%). The nonhematological toxicities were minimal and manageable. CONCLUSION: Treatment with gemcitabine and carboplatin is efficacious with manageable toxicity profile in the real world non-clinical trial setting.

Study of gefitinib maintenance in unselected patients with metastatic primary lung adenocarcinoma: A descriptive study.

BACKGROUND: Maintenance treatment of patients with advanced nonsmall cell lung cancer (NSCLC) without disease progression after first-line chemotherapy is a subject of ongoing research. The aim of this study was to investigate the efficacy, safety, and tolerability of the epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor, i.e., gefitinib in the maintenance setting irrespective of EGFR status. METHODS: Patients aged 18 years or older of Indian origin, who had a life expectancy of >12 weeks with histologically or cytologically confirmed Stage IV NSCLC, the WHO performance status of 0-2, and who had completed four to six cycles of first-line platinum-based doublet chemotherapy without disease progression or unacceptable toxic effects were included in the study. The primary endpoint of the study was progression-free survival in the intention-to-treat population. RESULTS: Twenty-five patients with a median age of 55 years (40-68) were included in the study. The median progression-free survival (PFS) for the entire group was 8 months (95% confidence interval [CI] =1.45-14.54) had not reached for EGFR-positive patient, but in the EGFR negative cohort, the PFS was 4.98 months (hazard ratio = 0.092, 95% CI = 3.4-6.5, P = 0.01). The median overall survival (OS) of the study group was 15 months (95% CI = 3.7-26.4), all patients with EGFR positive were alive (100% survival). The median OS for EGFR negative group was about 6.3 months. The major toxicity observed was rash/acne in 15 patients, pruritus in 7 patients, and one patient had Grade 4 pneumonitis. CONCLUSION: Gefitinib maintenance is safe, well-tolerated therapy, produces significant PFS and OS benefit in EGFR mutation-positive patient. It is definitely not a choice for EGFR negative group. In EGFR unknown group, the role of maintenance still needs to be explored.

Comparison of efficacy of neoadjuvant chemotherapy FEC 100 and Docetaxel 75 versus AC and Docetaxel in locally advanced breast cancer: a randomized clinical study.

The aim of the study was to assess and compare the clinical and pathological response and the toxicity profile between neoadjuvant chemotherapy FEC followed by docetaxel versus AC followed by docetaxel in locally advanced breast cancer patients. Between June 2013 and June 2014, 148 patients diagnosed with LABC were randomized into two groups with 74 in each group. Group 1 received AC (adriamycin 60 mg/m(2), cyclophosphamide 600 mg/m(2)) followed by docetaxel 100 mg/m(2) with primary GCSF prophylaxis and group 2 received FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) followed by docetaxel 75 mg/m(2). MRM/BCS was performed for all patients after NACT and assessed for pathological response. Toxicity profile was assessed according to CTCAE version 4. All baseline parameters were equally matched between the two regimens. 90 % of patients completed NACT and underwent surgery. pCR rates were 31 % in group 1 and 34 % in group 2 without any difference. Any grade of hand-foot syndrome was significantly high in group 1 as compared to group 2. Grade 3 and grade 4 neutropenia and febrile neutropenia were significantly high in group 1 as compared to group 2. Median follow-up was 13.7 months (range, 2.9-25 months). There was no difference in the 2-year PFS between group 1 and group 2 (70.9 vs. 73.8 %, respectively) and OS (87.8 vs. 91.8 %, respectively) in our study population. Chemotherapy with FEC followed by docetaxel can be considered as an optimal neoadjuvant regimen in LABC as compared to AC followed by docetaxel.

Resection of hepatocellular carcinoma: the effect of surgical margin and blood transfusion on long-term survival. Analysis of 209 consecutive patients.

BACKGROUND/AIMS: Certain prognostic factors affect the postoperative mortality and long-term survival of patients following hepatic resection for hepatocellular carcinoma (HCC) and may change the surgical strategy. METHODOLOGY: 209 consecutive patients underwent hepatic resection for HCC in our hospital. Seventy-three patients underwent major resection and 136 underwent minor resections. We looked for correlations between clinical, biological, surgical and pathological factors and postoperative mortality, disease-free survival and overall survival. RESULTS: The postoperative mortality rate was 7.7% (it fell to 0% in the last two years). The cumulative overall five-year survival rate was 27% and the overall disease-free survival rate was 7.3%. Multivariate analysis identified: (1) two independent prognostic factors for postoperative mortality: age and tumor size; (2) one risk factor for tumor recurrence: intraoperative blood transfusion, and (3) three independent prognostic factors for overall survival: infiltrative tumor type, surgical margin <10 mm and intraoperative blood transfusion. CONCLUSIONS: In addition to routine staging of the tumor, the preoperative evaluation of HCC patients should include tests to determine whether the tumor is infiltrative or expansive and whether it will be possible to obtain a surgical margin (>10 mm). This procedure should make it possible to propose an appropriate neoadjuvant treatment only to these patients. The prevention of intraoperative bleeding or blood transfusion should improve the disease-free and overall survival rates in HCC patients.

Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin.

The coordinated migration and maturation of dendritic cells (DCs) such as intraepithelial Langerhans cells (LCs) is considered critical for T cell priming in response to inflammation in the periphery. However, little is known about the role of inflammatory mediators for LC maturation and recruitment to lymph nodes in vivo. Here we show in human dermatopathic lymphadenitis (DL), which features an expanded population of LCs in one draining lymph node associated with inflammatory lesions in its tributary skin area, that the Langerin/CD207(+) LCs constitute a predominant population of immature DCs, which express CD1a, and CD68, but not CD83, CD86, and DC-lysosomal-associated membrane protein (LAMP)/CD208. Using LC-type cells generated in vitro in the presence of transforming growth factor (TGF)-beta1, we further found that tumor necrosis factor (TNF)-alpha, as a prototype proinflammatory factor, and a variety of inflammatory stimuli and bacterial products, increase Langerin expression and Langerin dependent Birbeck granules formation in cell which nevertheless lack costimulatory molecules, DC-LAMP/CD208 and potent T cell stimulatory activity but express CCR7 and respond to the lymph node homing chemokines CCL19 and CCL21. This indicates that LC migration and maturation can be independently regulated events. We suggest that during DL, inflammatory stimuli in the skin increase the migration of LCs to the lymph node but without associated maturation. Immature LCs might regulate immune responses during chronic inflammation.

Identification of a PEST-like motif in listeriolysin O required for phagosomal escape and for virulence in Listeria monocytogenes.

The hly-encoded listeriolysin O (LLO) is a major virulence factor secreted by the intracellular pathogen Listeria monocytogenes, which plays a crucial role in the escape of bacteria from the phagosomal compartment. Here, we identify a putative PEST sequence close to the N-terminus of LLO and focus on the role of this motif in the biological activities of LLO. Two LLO variants were constructed: a deletion mutant protein, lacking the 19 residues comprising this sequence (residues 32-50), and a recombinant protein of wild-type size, in which all the P, E, S or T residues within this motif have been substituted. The two mutant proteins were fully haemolytic and were secreted in culture supernatants of L. monocytogenes in quantities comparable with that of the wild-type protein. Strikingly, both mutants failed to restore virulence to a hly-negative strain in vivo. In vitro assays showed that L. monocytogenes expressing the LLO deletion mutant was strongly impaired in its ability to escape from the phagosomal vacuole and, subsequently, to divide in the cytosol of infected cells. This work reveals for the first time that the N-terminal portion of LLO plays an important role in the development of the infectious process of L. monocytogenes.

IkappaBepsilon-deficient mice: reduction of one T cell precursor subspecies and enhanced Ig isotype switching and cytokine synthesis.

Three major inhibitors of the NF-kappaB/Rel family of transcription factors, IkappaBalpha, IkappaBbeta, and IkappaBepsilon, have been described. To examine the in vivo role of the most recently discovered member of the IkappaB family, IkappaBepsilon, we generated a null allele of the murine IkappaBepsilon gene by replacement of all coding sequences with nlslacZ. Unlike IkappaBalpha nullizygous mice, mice lacking IkappaBepsilon are viable, fertile, and indistinguishable from wild-type animals in appearance and histology. Analysis of beta-galactosidase expression pattern revealed that IkappaBepsilon is mainly expressed in T cells in the thymus, spleen, and lymph nodes. Flow cytometric analysis of immune cell populations from the bone marrow, thymus, spleen, and lymph nodes did not show any specific differences between the wild-type and the mutant mice, with the exception of a reproducible 50% reduction of the CD44-CD25+ T cell subspecies. The IkappaBepsilon-null mice present constitutive up-regulation of IgM and IgG1 Ig isotypes together with a further increased synthesis of these two isotypes after immunization against T cell-dependent or independent Ags. The failure of observable augmentation of constitutive nuclear NF-kappaB/Rel-binding activity is probably due to compensatory mechanisms involving IkappaBalpha and IkappaBbeta, which are up-regulated in several organs. RNase-mapping analysis indicated that IL-1alpha, IL-1beta, IL-1Ra, and IL-6 mRNA levels are constitutively elevated in thioglycolate-elicited IkappaBepsilon-null macrophages in contrast to GM-CSF, G-CSF, and IFN-gamma, which remain undetectable.

Listeriolysin O-dependent activation of endothelial cells during infection with Listeria monocytogenes: activation of NF-kappa B and upregulation of adhesion molecules and chemokines.

The facultative intracellular bacterium Listeria monocytogenes is an invasive pathogen that crosses the vascular endothelium and disseminates to the placenta and the central nervous system. Its interaction with endothelial cells is crucial for the pathogenesis of listeriosis. By infecting in vitro human umbilical vein endothelial cells (HUVEC) with L. monocytogenes, we found that wild-type bacteria induced the expression of the adhesion molecules (ICAM-1 and E-selectin), chemokine secretion (IL-8 and monocyte chemotactic protein-1) and NF-kappa B nuclear translocation. The activation of HUVEC required viable bacteria and was abolished in prfA-deficient mutants of L. monocytogenes, suggesting that virulence genes are associated with endothelial cell activation. Using a genetic approach with mutants of virulence genes, we found that listeriolysin O (LLO)-deficient mutants inactivated in the hly gene did not induce HUVEC activation, as opposed to mutants inactivated in the other virulence genes. Adhesion molecule expression, chemokine secretion and NF-kappa B activation were fully restored by a strain of Listeria innocua transformed with the hly gene encoding LLO. The relevance in vivo of endothelial cell activation for listerial pathogenesis was investigated in transgenic mice carrying an NF-kappa B-responsive lacZ reporter gene. NF-kappa B activation was visualized by a strong lacZ expression in endothelial cells of capillaries of mice infected with a virulent haemolytic strain, but was not seen in those infected with a non-haemolytic isogenic mutant. Direct evidence that LLO is involved in NF-kappa B activation in transgenic mice was provided by injecting intravenously purified LLO, thus inducing stimulation of NF-kappa B in endothelial cells of blood capillaries. Our results demonstrate that functional listeriolysin O secreted by bacteria contributes as a potent inflammatory stimulus to inducing endothelial cell activation during the infectious process.