Satisfaction with Care and Satisfaction with Decision Making are Similar Regardless of Staffing Model in a Neurocritical Care Unit.

INTRODUCTION: Patient-centered care, particularly shared medical decision making, is difficult to measure in critically ill patients where decisions are often made by a designated surrogate, often receiving information from multiple providers with varying degrees of training. The purpose of this study was to compare short-term satisfaction with care and decision making in patients or surrogates between two neurocritical care units [one staffed by a neurocritical care attending and advanced practice providers (APPs) and one staffed by a neurocritical care attending and resident/fellow trainees] using the Family Satisfaction in the ICU (FS-ICU) survey. METHODS: Over a 6-month period, the FS-ICU was administered on a tablet device to patients or surrogates at least 24 h after admission and stored on REDCap database. RESULTS: One hundred and thirty-four patients or surrogates completed the FS-ICU. The response rates were 59.97% and 46.58% in the APP and trainee units, respectively. There were no differences in patient age, sex, ventilator days or ICU length of stay. Overall, there were no differences in satisfaction with care or perceived shared medical making between the units. Respondents who identified their relationship with the patient as "other" (not a spouse, parent, nor a sibling) were less satisfied with care. Additionally, surrogates who identified as parents of the patient were more satisfied with degree of shared medical decision making. CONCLUSION: This study showed that: (1) collecting FS-ICU in a neurocritical care unit is feasible, (2) overall there is no difference in short-term satisfaction with care or shared decision making between a NICU staffed with trainees compared to one staffed with APPs, and (3) parents of patients have a higher short-term satisfaction with degree of shared medical decision making.

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, targets cancer stem cells and impedes resistance to antiangiogenic therapy in mouse models of breast cancer.

Antiangiogenic therapies inhibit the development of new tumor blood vessels, thereby blocking tumor growth. Despite the advances in developing antiangiogenic agents, clinical data indicate that these drugs have limited efficacy in breast cancer patients. Tumors inevitably develop resistance to antiangiogenics, which is attributed in part to the induction of intra-tumoral hypoxia and stabilization of hypoxia-inducible factor 1α (HIF-1α), a transcription factor that promotes tumor angiogenesis, invasion, metastasis, and cancer stem cell (CSC) self-renewal. Here, we tested whether inhibiting HIF-1α can reverse the stimulatory effects of antiangiogenic-induced hypoxia on breast CSCs. Breast cancer cells grown under hypoxic conditions were treated with the dual topoisomerase-1 (TOPO-1) and HIF-1α inhibitor camptothecin and assessed for their CSC content. In a preclinical model of breast cancer, treatment with bevacizumab was compared to the combination treatment of bevacizumab with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload or CRLX101 monotherapy. While exposure to hypoxia increased the number of breast CSCs, treatment with CPT blocked this effect. In preclinical mouse models, concurrent administration of CRLX101 impeded the induction of both HIF-1α and CSCs in breast tumors induced by bevacizumab treatment. Greater tumor regression and delayed tumor recurrence were observed with the combination of these agents compared to bevacizumab alone. Tumor reimplantation experiments demonstrated that the combination therapy effectively targets the CSC populations. The results from these studies support the combined administration of dual TOPO-1- and HIF-1α-targeted agents like CRLX101 with antiangiogenic agents to increase the efficacy of these treatments.

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia.

Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/ß-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.

Near-infrared tissue oximetry and digital image analysis: quantification of renal ischaemia in real time during partial nephrectomy.

OBJECTIVE: To determine the feasibility of using near-infrared tissue oximetry (TO) and digital image analysis for assessing renal function and to quantify local renal ischaemia in a porcine model. MATERIALS AND METHODS: Tissue oximetry was performed and red/blue (R/B) colour ratios were determined on renal units of Yorkshire swine. Interval measurements were taken before clamping the renal hilum, during warm ischaemia, and after unclamping using a ViOptix T.Ox™ Tissue Oximeter and Matlab(®) digital image analysis. Matlab software analysed images from the laparoscopic camera and determined an R/B ratio to track renal ischaemia. The tissue oximeter used direct infrared light and was placed adjacent to the kidney parenchymal surface. The data were divided into preclamp, clamp and post-clamp, and compared between methodologies. RESULTS: The R/B ratio showed a higher rate of change compared with TO during clamp time in both the 15-min experiment (R/B = 96.0 vs. TO = 52.1 unit/reference) and the 30-min experiment (R/B = 97.6 vs. TO = 45.9). The R/B ratio showed a higher rate of change compared with TO at 1 min after clamping in the 15-min experiment (R/B = 80.1 vs. TO = 12.4). Both detection devices showed similar changes in pre- and post-clamp measurements in the 15- min experiment (R/B = 1.6 vs. TO = 3.8) and the 30-min experiment (R/B = 4.7 vs. TO =-4.5). In the 30-min experiment the R/B ratio showed a significant difference between preclamp, clamp, and post-clamp states (P= 0.026). CONCLUSIONS: Both TO and digital image analysis were able to calculate an ischaemic drop in tissue oxygen saturation during periods of acute renal ischaemia. The findings suggest that the R/B ratio observed during histogram analysis shows a greater sensitivity compared with TO in quantifying renal ischaemia.

Posterior reconstruction before anastomosis improves the anastomosis time during robot-assisted radical prostatectomy.

BACKGROUND AND OBJECTIVES: Our goal was to evaluate posterior reconstruction of the rhabdosphincter during robot-assisted radical prostatectomy and determine whether this technique decreased anastomotic time of a surgeon in training to perform vesicourethral reconstruction. METHODS: We reviewed the first 25 robot-assisted prostatectomies performed by 2 urology surgeons in training (surgeon 1 and surgeon 2). The patient populations were matched for age, Gleason score, clinical stage, and PSA. Whereas surgeon 1 performed the vesicourethral anastomosis without posterior reconstruction, surgeon 2 reapproximated Denonvilliers' fascia of the posterior bladder to the rhabdosphincter. Time for each surgeon to complete the anastomosis and clinical factors was compared. RESULTS: Surgeon 1 had a median anastomosis time of 25 minutes (range, 17 to 48), whereas surgeon 2 had a median anastomosis time of 15 minutes (range, 10 to 30) (P<0.001). Biopsy Gleason score, pathological tumor stage, perineural invasion, median age at the time of surgery, PSA, prostate weight, and estimated blood loss were not significantly different between surgeons (P>0.05). Pathological Gleason score (P=0.045) and total console time (surgeon 1-216 minutes, surgeon 2-176 minutes; P=0.002) were significantly different between surgeons. CONCLUSION: Posterior reconstruction prior to anastomosis decreases anastomosis time for robotic surgeons in training.

Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling.

Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.

Trastuzumab resistance induces EMT to transform HER2(+) PTEN(-) to a triple negative breast cancer that requires unique treatment options.

Although trastuzumab is an effective treatment in early stage HER2(+) breast cancer the majority of advanced HER2(+) breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2(+) breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2(+) cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2(+) to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2(+) cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2(+) PTEN(-) cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2(+) cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-κB positive feedback loop whereas parental HER2(+) cells did not respond. This data suggests that trastuzumab resistance in HER2(+) PTEN- breast cancer induces EMT and subtype switching, which requires unique treatment options.

Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity.

Developmental pathways such as Notch play a pivotal role in tissue-specific stem cell self-renewal as well as in tumor development. However, the role of Notch signaling in breast cancer stem cells (CSC) remains to be determined. We utilized a lentiviral Notch reporter system to identify a subset of cells with a higher Notch activity (Notch(+)) or reduced activity (Notch(-)) in multiple breast cancer cell lines. Using in vitro and mouse xenotransplantation assays, we investigated the role of the Notch pathway in breast CSC regulation. Breast cancer cells with increased Notch activity displayed increased sphere formation as well as expression of breast CSC markers. Interestingly Notch(+) cells displayed higher Notch4 expression in both basal and luminal breast cancer cell lines. Moreover, Notch(+) cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts, whereas Notch(-) cells failed to generate tumors. γ-Secretase inhibitor (GSI), a Notch blocker but not a chemotherapeutic agent, effectively targets these Notch(+) cells in vitro and in mouse xenografts. Furthermore, elevated Notch4 and Hey1 expression in primary patient samples correlated with poor patient survival. Our study revealed a molecular mechanism for the role of Notch-mediated regulation of breast CSCs and provided a compelling rationale for CSC-targeted therapeutics.

The flaming funis.

The authors observed a Nicaraguan traditional birth attendant burn the fetal end of the umbilical cord with camphor. They review this practice and reflect on the role of foreign medical volunteers in the developing world. There is a long history to the use of camphor in rituals and medicine. No print references to burning the umbilical cord with camphor, its effectiveness, or its safety could be identified. Interviews with Nicaraguan traditional birth attendants revealed that the practice is passed from generation to generation and that it is believed to decrease infections through the medicinal properties of camphor as well as the flame it produces. It is continued in modern times because it is easy and inexpensive and because there are no clearly better and sustainable alternatives available. Gradual and culturally sensitive modernization to improve the health for mothers and babies is appropriate, but it will be a slow process. Health care volunteers in the developing world struggle with doing the best they can despite the limited resources and sometimes the local traditions. Volunteering as a medical worker in the developing world provides inspiring rewards, teaches powerful lessons, and exposes challenging conflicts.

A double-blind randomized controlled trial of continuous intravenous Ketorolac vs placebo for adjuvant pain control after renal surgery.

OBJECTIVE: To evaluate the efficacy and safety of a novel, continuous intravenous infusion of ketorolac, a powerful nonopioid analgesic, for postoperative pain control. PATIENTS AND METHODS: A prospective, double-blind, randomized, placebo-controlled trial of a continuous infusion of ketorolac tromethamine in 1 L of normal saline vs placebo was performed in 135 patients aged 18 to 75 years after laparoscopic donor nephrectomy or percutaneous nephrolithotomy completed from October 7, 2008, through July 21, 2010. Primary study end points were the 24-hour differences in visual analog pain scores and total narcotic consumption, whereas secondary end points were differences in urine output, serum creatinine level, and hemoglobin level. RESULTS: The study was stopped after randomization of 135 patients (68 in the ketorolac group and 67 in the placebo group) when interim analysis indicated that the difference in mean pain scores between the 2 groups (difference, 0.6) was smaller than the 1-point threshold set forth in the power calculations. No statistically significant change was noted in hemoglobin levels from preoperative to postoperative values (P=.13) or in postoperative serum creatinine levels (P=.13). CONCLUSION: Although continuous infusion of ketorolac produced only a modest decrease in the use of narcotics, it appears to offer a safe therapeutic option for nonnarcotic pain control. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00765128 and NCT00765232.

Laparoscopic radical nephrectomy for very large renal tumors (> or =10 cm): is there a size limit?

BACKGROUND AND PURPOSE: The role of laparoscopic radical nephrectomy (LRN) for very large renal tumors remains to be defined. We review our experience with LRN for very large (> or =10 cm) renal malignancies. PATIENTS AND METHODS: A retrospective analysis of 360 consecutive patients who underwent LRN for renal tumors between October 1999 and May 2007 in a tertiary academic center identified 11 patients with malignancies > or =10 cm. RESULTS: Median age was 67 years (range 48-80 y), operative time was 170 minutes (range 80-240 min), estimated blood loss was 150 mL (range 50-300 mL), and length of stay was 2 days (range 1-6 d). There were two minor postoperative complications (acute renal insufficiency and ileus). Median tumor size was 12 cm (range 10-21 cm). Pathologic stage for patients with renal cell carcinoma was T(2), T(3a), T(3b), and T(4), in five, three, two, and one patient(s), respectively. One patient died after brain metastasis developed. Two patients in whom pulmonary metastases developed were still alive at last follow-up. CONCLUSIONS: LRN was successfully performed in patients with renal tumors up to 21 cm. Important considerations when performing LRN include the individual clinical picture, surgeon experience, tumor location, and patient well-being. LRN for very large tumors is feasible in properly selected patients and can have significant benefits in the palliative setting.