Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients' blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with single agent capecitabine at 2000 mg/m2/day. LCLs were treated with increasing concentrations of 5'-DFUR, a major capecitabine metabolite, to assess patients' ex vivo sensitivity to this drug. Subsequently, ex vivo phenotype was compared to observed patient disease response and drug induced-toxicities. We acquired an independent cohort of breast cancer cell lines and LCLs derived from the same donors from ATCC, compared their sensitivity to 5'-DFUR. As seen in the patient population, we observed large inter-individual variability in response to 5'-DFUR treatment in patient-derived LCLs. Patients whose LCLs were more sensitive to 5'-DFUR had a significantly longer median progression free survival (9-month vs 6-month, log rank p-value = 0.017). In addition, this significant positive correlation for 5'-DFUR sensitivity was replicated in an independent cohort of 8 breast cancer cell lines and LCLs derived from the same donor. Our data suggests that at least a portion of the individual sensitivity to capecitabine is shared between germline tissue and tumor tissue. It also supports the utility of patient-derived LCLs as a predictive model for capecitabine treatment efficacy in breast cancer patients

Maternal and neonatal outcome in pregnancy with previous lower segment caesarean section undergoing trial of scar

Background: Women with previous LSCS often have to make a decision about mode of delivery of their second baby. As the rate of caesarean section is continuously increasing, vaginal birth after caesarean section (VBAC) is a good strategy to decrease caesarean rate. The present study was planned to assess the fetomaternal outcome in pregnancies with previous lower segment caesarean section undergoing trial of scar and to identify the factors, which can influence the outcome of trial of scar.Methods: This was a prospective observational study on 100 patients at a tertiary care institute. Pregnant women with previous LSCS were selected randomly for the study on the basis of the inclusion and exclusion criteria. Each labor monitored closely using a partogram. Decision for repeat emergency caesarean was taken by consultant. All women included in the study were followed through delivery and till discharge.Results: Out of 100 pregnant women 49 % cases had successful VBAC, 50% had emergency caesarean and one patient had laparotomy for rupture uterus. In women, who also had a prior vaginal delivery, 72% delivered vaginally, as compared to 40% of the women who did not undergo prior vaginal delivery (p value=0.003). Women who were in spontaneous labor, 59.21% delivered vaginally, whereas women who were induced, 16.6% delivered vaginally. The rate of perinatal complication was more in the patients who required an emergency CS after a failed trial. Conclusions: Our findings may encourage obstetricians to encourage VBAC in the properly screened ANC patients and decrease the rate of recommending caesarean section

TBCRC 019: A phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer

Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation

CD1a expression in psoriatic skin following treatment with propylthiouracil, an antithyroid thioureylene

BACKGROUND: The antithyroid thioureylenes, propylthiouracil (PTU) and methimazole (MMI), are effective in the treatment of patients with plaque psoriasis. The mechanism of action of the drugs in psoriasis is unknown. Since the drugs reduce circulating IL-12 levels in patients with Graves' hyperthyroidism, the effect of propylthiouracil on CD1a expression in psoriatic lesions was examined in biopsy samples of patients with plaque psoriasis. CD1a is a marker of differentiated skin antigen presenting cells (APC, Langerhans cells). Langerhans cells and skin monocyte/macrophages are the source of IL-12, a key cytokine involved in the events that lead to formation of the psoriatic plaque. METHODS: Biopsy specimens were obtained from six patients with plaque psoriasis who were treated with 300 mg propylthiouracil (PTU) daily for three months. Clinical response to PTU as assessed by PASI scores, histological changes after treatment, and CD1a expression in lesional skin before and after treatment were studied. RESULTS: Despite significant improvement in clinical and histological parameters the expression of CD1a staining cells in the epidermis did not decline with propylthiouracil treatment. CONCLUSIONS: It appears that the beneficial effect of propylthiouracil in psoriasis is mediated by mechanisms other than by depletion of skin antigen-presenting cells

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Peer reviewe

CD1a expression in psoriatic skin following treatment with propylthiouracil, an antithyroid thioureylene.

BackgroundThe antithyroid thioureylenes, propylthiouracil (PTU) and methimazole (MMI), are effective in the treatment of patients with plaque psoriasis. The mechanism of action of the drugs in psoriasis is unknown. Since the drugs reduce circulating IL-12 levels in patients with Graves' hyperthyroidism, the effect of propylthiouracil on CD1a expression in psoriatic lesions was examined in biopsy samples of patients with plaque psoriasis. CD1a is a marker of differentiated skin antigen presenting cells (APC, Langerhans cells). Langerhans cells and skin monocyte/macrophages are the source of IL-12, a key cytokine involved in the events that lead to formation of the psoriatic plaque.MethodsBiopsy specimens were obtained from six patients with plaque psoriasis who were treated with 300 mg propylthiouracil (PTU) daily for three months. Clinical response to PTU as assessed by PASI scores, histological changes after treatment, and CD1a expression in lesional skin before and after treatment were studied.ResultsDespite significant improvement in clinical and histological parameters the expression of CD1a staining cells in the epidermis did not decline with propylthiouracil treatment.ConclusionsIt appears that the beneficial effect of propylthiouracil in psoriasis is mediated by mechanisms other than by depletion of skin antigen-presenting cells

Effect of postextubation high-flow oxygen on oxygen saturation during transit from operation theater to postoperative ward – A randomized, prospective comparative study

Background and Aims: Postoperative pulmonary complications (PPCs) increase morbidity and mortality. The risk of developing PPC starts immediately after extubation. Transport time is the most influential time for the development of hypoxia. In early postoperative period, there is a decrement in PaO2 by 7–18 mmHg from baseline and may lead to severe hypoxia. This can be attributed to diffusion hypoxia, residual effect of anesthetics, pain, and impaired hemodynamics. To prevent this hypoxia, oxygen is almost invariably given with low-flow devices immediately after extubation. We conducted this trial to know the effect of postextubation high-flow oxygen on peripheral oxygen saturation during transit from operation theater to postanesthesia care unit compared to conventional oxygen therapy. Our primary outcome was to estimate and compare the incidence of desaturation in both the groups, whereas the secondary outcome was to compare time to desaturation. Methodology: A total of 156 patients were randomly allocated to receive either high-flow or conventional oxygen for 5 min immediately after extubation. Patients were shifted to postoperative ward without oxygen supplementation. Transport time, incidence of desaturation, and time required for desaturation were noted. Results: In the high-flow oxygen group, 15.6% of patients had desaturation compared to 26.9% in the conventional group. The average time for desaturation was 3.2 ± 1.7 min in the high-flow oxygen group compared to the conventional group in whom it was 2.6 ± 1.7 min, although this difference was not statistically significant. Conclusion: The incidence of desaturation was less, whereas the time taken for desaturation was longer with the use of high flow compared to conventional oxygen therapy following extubation