Surgical Resection Is Better than Transarterial Chemoembolization for Hepatocellular Carcinoma Beyond Milan Criteria Independent of Performance Status

Background and Aims

Performance status is tightly linked with survival in patients with hepatocellular carcinoma (HCC). We investigated the impact of performance status on HCC patients beyond the Milan criteria receiving surgical resection (SR) or transarterial chemoembolization (TACE).

Methods

A total of 909 patients with HCC beyond the Milan criteria were retrospectively analyzed by using propensity score analysis.

Results

The baseline characteristics were similar between the SR and TACE group for patients with performance status 0 in the propensity model. More patients in the TACE group with performance status ≥1 had Child-Turcotte-Pugh class A compared to the SR group (p?=?0.044) in the propensity model. SR provided significantly better long-term overall survival than TACE in patients selected in the propensity model regardless of performance status (both p?TACE was associated with 2.279-fold and 3.066-fold increased risk of mortality in performance status 0 and performance status ≥1 in the propensity model (95 % confidence interval, 1.476–3.591 and 1.570–5.989), respectively.

Conclusions

For either performance status 0 or ≥1 HCC patients beyond the Milan criteria, SR provides significantly better long-term survival than TACE. SR should be considered a priority treatment in these patients independent of performance status.     

Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy

Background

The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity.

Methods

We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years.

Results

Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B.

Conclusion

Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.     

Correlation study of chronic nonbacterial prostatitis with the levels of COX-2 and PGE2 in prostatic secretion

Objective

The prostatitis syndrome is a multifactorial condition of largely unknown etiology. This study is to analyze the relationship between cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) with the chronic nonbacterial prostatitis (CNBP).

Methods

A total of 172 CNBP patients and 151 healthy males were recruited as CNBP and control group, respectively. The prostatic fluid was collected and tested by pre- and post-massage test. White blood cell (WBC) number was counted, and the contents of COX-2 and PGE2 were determined by double antibody-based sandwich enzyme-linked immuno-sorbent assay. The pain and discomfort of each patient were scored according to the National Institutes of Health chronic prostatitis symptom index.

Results

Compared with the control group, CNBP group displayed significantly higher WBC count, COX-2 level, and PGE2 level. Contents of COX-2 and PGE2 in prostatic secretion of CNBP group were positively correlated with pain scores (r = 0.855 and 0.675, respectively, P < 0.01) and total symptom scores (r = 0.674 and 0.566, respectively, P < 0.01). A significantly positive correlation between COX-2 and PGE2 levels was also discovered (r = 0.493, P < 0.05). The WBC number was not obviously correlated with the accumulations of COX-2 and PGE2 or the clinic symptoms of CNBP.

Conclusion

Increase in PGE2 concentration caused by activated COX-2 pathway may contribute to the pain or discomfort symptom of the CNBP patients. Our results indicate that selective COX-2 inhibitors have application prospect in CNBP treatment.     

Protective effects of adiponectin on uncoupling of glomerular VEGF–NO axis in early streptozotocin-induced type 2 diabetic rats

Purpose

To determine whether adiponectin could reduce microalbuminuria and provide renal protective effects by improving endothelial dysfunction and uncoupling of the glomerular vascular endothelial growth factor (VEGF)–nitric oxide (NO) axis in streptozotocin-induced type 2 diabetic rats.

Methods

Wistar rats were randomly divided into normal control group, diabetic nephropathy (DN) group induced by high-fat feeding and streptozotocin, diabetic rats injected with adenovirus-expressed adiponectin (AD-AdipoQ), and diabetic rats injected with AD-IRES-EGFP as control. Blood and urine samples were collected. Endothelium-dependent vasodilatation (EDV) of the aorta was measured. Renal tissues were collected for CD34 immunohistochemistry. Glomerular NO and VEGF levels were measured by the Griess reaction and Western blot testing, respectively.

Results

Injections of AD-AdipoQ significantly increased serum adiponectin levels and reduced the urinary albumin-to-creatinine ratio in diabetic rats (P < 0.05). The levels of plasma glucose, serum insulin, high-sensitivity C-reactive protein, and malondialdehyde were significantly reduced in diabetic rats after injections of AD-AdipoQ (P < 0.05). Severe EDV impairment was observed in the DN group, which was improved by AD-AdipoQ. CD34 expression in the glomeruli was also higher in diabetic rats, indicating increased proliferation of glomerular endothelial cells. However, AD-AdipoQ improved the increased proliferation of endothelial cells in the glomeruli. Diabetic rats showed increased glomerular VEGF levels and reduced NO levels. This uncoupling of the VEGF–NO axis was partially improved by AD-AdipoQ.

Conclusion

Adiponectin reduces the degree of microalbuminuria and has renal protective effects by improving endothelial dysfunction and uncoupling of the glomerular VEGF–NO axis in early diabetic nephropathy.     

Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ

Purpose

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods

We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results

Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion

We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.     

CCR2 Elimination in Mice Results in Larger and Stronger Tibial Bones but Bone Loss is not Attenuated Following Ovariectomy or Muscle Denervation

Bone loss due to age and disuse contributes to osteoporosis and increases fracture risk. It has been hypothesized that such bone loss can be attenuated by modulation of the C–C chemokine receptor 2 (CCR2) and/or its ligands. The objectives of this study were to examine the effects of genetic elimination of CCR2 on cortical and trabecular bones in the mouse tibia and how bone loss was impacted following disuse and estrogen loss. Female CCR2 knockout (CCR2^?/?) and wildtype mice underwent ovariectomy (OVX) or denervation of musculature adjacent to the tibia (DEN) to induce bone loss. Cortical and trabecular structural properties as well as mechanical properties (i.e., strength) of tibial bones were measured. Compared to wildtype mice, CCR2^?/? mice had tibiae that were up to 9 % larger and stronger; these differences could be explained mainly by the 17 % greater body mass (P < 0.001) of CCR2^?/? mice. The majority of the tibia’s structural and functional responses to OVX and DEN were similar regardless of the lack or presence of CCR2, indicating that CCR2 is not protective against bone loss per se. These findings indicate that while CCR2^?/? mice do have larger and stronger bones than do wildtype mice, there is minimal evidence that CCR2 elimination provides protection against bone loss during disuse and estrogen loss.     

Ileal Effect on Blood Glucose,HbA1c,and GLP-1 in Goto-Kakizaki Rats

Background

There have been enumerable studies on the effects of glucagon-like peptide-1 (GLP-1) on satiety and pancreatic islet function, stimulating the advocacy of surgical transposition of the ileum (rich in GLP-1-generating L-cells) higher in the gastrointestinal tract for earlier stimulation. In the Goto-Kakizaki rat with naturally occurring type 2 diabetes, we studied the influence of ileal exclusion (IE) and ileal resection (IR) on blood glucose, hemoglobin A1c (HbA1c), and GLP-1.

Methods

In six control (Ctrl), 10 IE, and 10 IR rats, over 12 weeks of follow-up, we determined blood glucose, HbA1c, and GLP-1.

Results

Two animals in the IE and IR groups did not survive to week 13. Both operated groups weighed more than the Ctrl group at baseline and at 13 weeks; thus, IE and IR did not retard weight gain (p?HbA1c percentages at week 13: 14.7?±?28 Ctrl, 11.7?±?3.4 IE, 13.8?±?3.5 IR (%?±?SEM). The end-study GLP-1 values (pM?±?SEM) were 5?±?0.9 Ctrl, 33?±?8.9 IE, and 25?±?6.7 IR. P values for intergroup differences were IE vs. Ctrl 0.02, IR vs. Ctrl 0.02, and IE vs. IR 0.59.

Conclusions

Neither IE nor IR resulted in a decrease in the mean GLP-1 level. On the contrary, the exclusion or resection of the L-cell rich ileum raised GLP-1 levels 5- to 6-fold. This increase in the GLP-1 was not associated with the mitigation of hyperglycemia or elevated HbA1c levels.     

Univariate and multivariate analyses of preoperative factors influencing symptomatic outcomes of transoral fundoplication

Background

Preoperative factors predicting symptomatic improvement after transoral fundoplication (TF) in chronic gastroesophageal reflux disease (GERD) patients with persistent symptoms on proton-pump inhibitors (PPIs) therapy have not been elucidated fully.

Methods

Univariate and multivariate logistic regression analyses were performed on data from 158 consecutive patients who underwent TF with the EsophyX device between January 2010 and June 2012 in 14 community centers. Variables included age, gender, body mass index, GERD duration, PPIs therapy duration, presence of hiatal hernia, esophagitis, Hill grade, quality of life scores (QOL) on PPIs, % total time pH < 4, and DeMeester score on reflux testing off PPIs.

Results

All patients suffered from typical GERD symptoms. Additionally, 78 % (124/158) of patients suffered from atypical symptoms. Six percent (10/158) with recurrent GERD symptoms refractory to PPI therapy underwent revisional procedure (9 laparoscopic Nissen, 1 TF). Median follow-up was 22 (range 10–43) months. For patients with typical symptoms, univariate analyses revealed 4 preoperative factors predictive of successful outcomes: age ≥ 50 [odds ratio (OR) = 2.4, 95 % confidence interval (CI) = 1.2–4.8, p = 0.014], GERD Health-related Quality of Life score (GERD-HRQL) ≥ 15 on PPIs (OR = 6.0, CI = 1.2–29.4, p = 0.026, Reflux Symptom Index score  > 13 on PPIs (OR = 2.4, CI = 1.1–5.2, p = 0.027), and Gastroesophageal Reflux Symptom Score  ≥ 18 on PPIs (OR = 2.6, CI = 1.2–5.8, p = 0.018). Age and GERD-HRQL score remained significant predictors by multivariate analysis. For patients with atypical symptoms, only GERD-HRQL score ≥ 15 on PPIs (OR = 9.9, CI = 0.9–4.6, p = 0.036) was associated with successful outcomes.

Conclusions

Elevated preoperative QOL scores on PPIs and age ≥ 50 were most closely associated with successful outcome of TF in patients with persistent symptoms despite medical therapy.     

Impact of Femoral Neck and Lumbar Spine BMD Discordances on FRAX Probabilities in Women: A Meta-analysis of International Cohorts

There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX. We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS–FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS–FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort. The absolute ΔLS–FN was greater than 2 SD for 2.5 % of women and between 1 and 2 SD for 21 %. ΔLS–FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95 % CI = 1.04–1.15). In reclassification analyses, only 2.3–3.2 % of the women moved to a higher or lower risk category when using FRAX with ΔLS–FN compared with FN-derived FRAX alone. Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1–2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold.     

Five-year results of arthroscopic techniques for the treatment of acetabular chondral lesions in femoroacetabular impingement

Purpose

This study assesses and compares the clinical outcomes of the arthroscopic matrix-induced autologous chondrocyte implant (MACI) and autologous matrix-induced chondrogenesis (AMIC) techniques for the treatment of acetabular chondral defects between 2 and 4 cm² consequent to femoral acetabular impingement.

Methods

Fifty-seven consecutive patients were treated with the MACI (n?=?26) or AMIC (n?=?31) technique. Patients were assessed pre-operatively and up to five years using the modified Harris Hip Score (mHHS) to compare outcomes.

Results

In both the MACI and AMIC groups, significant hip score improvements were measured over baseline levels at six months post-op (81.2?±?8.4 for MACI, 80.3?±?8.3 for AMIC, both p?MACI and AMIC, respectively (NS). Subgroup analysis of both MACI and AMIC treatment outcomes for patients with an initial chondral defect larger than 3 cm² yielded comparable results at each time point.

Conclusions

This study suggests that both arthroscopic MACI and AMIC are valid procedures to repair medium-sized chondral defects on the acetabular side of the hip found during treatment of femoroacetabular impingement. Due to its high sustainability and minimal invasiveness, the single-stage AMIC procedure can reduce total treatment time and minimise morbidity while providing the same beneficial effects as the two-stage MACI intervention.     

Predictors that Influence Contralateral Prophylactic Mastectomy Election Among Women with Ductal Carcinoma In Situ Who Were Evaluated for BRCA Genetic Testing

Background

Patients with ductal carcinoma in situ (DCIS) are at increased risk for developing contralateral breast cancer (CBC). Consequently, more women with DCIS are electing to undergo contralateral prophylactic mastectomy (CPM). We evaluated factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA testing.

Methods

This retrospective study involved 165 women with DCIS referred for genetic counseling between 2003 and 2011. Patient characteristics were age, marital and educational status, tumor markers, nuclear grade, family history of breast cancer (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with CPM election.

Results

Of 165 patients, 44 (27 %) underwent CPM. Patients <45 years of age were more likely to elect CPM (p = 0.0098). A BRCA+ mutation was found in 17 patients (10.3 %), and BRCA+ women were more likely to elect CPM than BRCA or untested women (p = 0.0001). Patients who had a family history of OC (57.7 %) were more likely to choose CPM than those with no family history (p = 0.0004). Younger age, BRCA+, and an OC family history remained significant in the multivariate model (p < 0.008).

Conclusion

The CPM rate among patients with DCIS who undergo genetic counseling is high. Factors associated with increased likelihood of CPM among this group were age, BRCA+, and a family history of OC. Further studies are needed to evaluate patients’ perceptions of CBC risk and their role in the likelihood of CPM choice.     

Impact of steroid medication before hospital admission on barotrauma in mechanically ventilated patients with acute respiratory distress syndrome in intensive care units

Purpose

To investigate the association between steroid medication before hospital admission and barotrauma in mechanically ventilated patients with acute respiratory distress syndrome (ARDS).

Methods

An observational single-center retrospective study was conducted using patients admitted to the general intensive care unit (ICU) of a university hospital in Japan. We analyzed 149 mechanically ventilated patients with ARDS hospitalized between March 2008 and March 2011. ARDS was identified according to criteria from the Berlin Definition. Barotrauma was defined as pneumothorax, subcutaneous emphysema, or mediastinal emphysema occurring during mechanical ventilation in the ICU. The influence of steroid medication before hospital admission on barotrauma was studied using multiple logistic regression analysis.

Results

There were no differences in baseline patient characteristics except for congestive heart failure, peak pressure during mechanical ventilation, and steroid pulse therapy between the barotrauma and non-barotrauma groups. Logistic regression analysis showed that peak pressure ≥35 cmH₂O was associated with barotrauma in patients with ARDS [odds ratio (OR), 17.34; P < 0.01], whereas steroid medication before hospital admission was not a significant factor for barotrauma (OR, 1.63; P = 0.51).

Conclusions

Barotrauma in ARDS patients was associated with higher pressure during mechanical ventilation but not with steroid medication before hospital admission.     

Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK,AKT and NF-kappa B pathways in murine RAW264.7 cells

The bone protective effects of the hydrogen molecule (H₂) have been demonstrated in several osteoporosis models while the underlying molecular mechanism has remained unclear. Osteoclast differentiation is an important factor related to the pathogenesis of bone-loss related diseases. In this work, we evaluated the effects of incubation with H₂ on receptor activator of NFκB ligand (RANKL)-induced osteoclast differentiation. We found that treatment with H₂ prevented RANKL-induced osteoclast differentiation in RAW264.7 cells and BMMs. Treatment with H₂ inhibits the ability to form resorption pits of BMMs stimulated by RANKL. Treatment with H₂ reduced mRNA levels of osteoclast-specific markers including tartrate resistant acid phosphatase, calcitonin receptor, cathepsin K, metalloproteinase-9, carbonic anhydrase typeII, and vacuolar-type H⁺-ATPase. Treatment with H₂ decreased intracellular reactive oxygen species (ROS) formation, suppressed NADPH oxidase activity, down-regulated Rac1 activity and Nox1 expression, reduced mitochondrial ROS formation, and enhanced nuclear factor E2-related factor 2 nuclear translocation and heme oxygenase-1 activity. In addition, treatment with H₂ suppressed RANKL-induced expression of nuclear factor of activated T cells c1 and c-Fos. Furthermore, treatment with H₂ suppressed NF-κB activation and reduced phosphorylation of p38, extracellular signal-regulated kinase, c-Jun-N-terminal kinase, and protein kinases B (AKT) stimulated with RANKL. In conclusion, hydrogen molecules prevented RANKL-induced osteoclast differentiation associated with inhibition of reactive oxygen species formation and inactivation of NF-κB, mitogen-activated protein kinase and AKT pathways.     

Esophageal carcinoma cell line with high EGFR polysomy is responsive to gefitinib

Purpose

It has previously been shown that gefitinib-treated patients with epidermal growth factor receptor (EGFR) gene amplification or high polysomy had a statistically significant improvement in response, time to progression, and survival in non-small cell lung cancer (NSCLC). Only few studies utilizing anti-EGFR treatment in advanced esophageal adenocarcinomas have been performed and the results have been heterogeneous. The aim of this study was to evaluate EGFR-targeted therapy with gefitinib in esophageal adenocarcinoma with a high EGFR polysomy.

Methods

Novel esophageal cell lines PT6216 and LN6216c were established from primary tumor and lymph node metastasis of a patient with highly aggressive and metastatic adenocarcinoma. Pathological examination including tumor differentiation and prognostic marker analysis, immunohistochemical EGFR expression analysis, EGFR fluorescence in situ hybridization, and mutation analysis were performed. Response of novel cell lines to gefitinib treatment was evaluated by cell proliferation and vitality assays. Fifty-four esophageal adenocarcinoma specimens were evaluated for EGFR gene copy gain.

Results

The primary tumor cell line PT6216 and the lymph node cell line LN6216c show a homogenously high polysomy for EGFR determined by FISH analysis. Cell proliferation and vitality are highly sensitive to the tyrosine kinase inhibitor gefitinib compared to esophageal control cells without a high polysomy for EGFR. High polysomy for EGFR was found in 35 % of patients.

Conclusion

We show for the first time a significant treatment response to the EGFR tyrosine kinase inhibitor gefitinib in esophageal tumor cells with a high polysomy for EGFR, suggesting a future role of anti-EGFR therapy for esophageal adenocarcinoma patients with a high EGFR polysomy.     

Effects of ethylenediaminetetraacetate (EDTA) on urinary excretion of hydroxyproline,calcium and phosphorus in the rat

The effects of ethylenediaminetetraacetate (EDTA) were studied in rats. Intravenous infusion of 4.84 mM Na₂EDTA increased the urinary excretion of calcium six-fold, phosphorus three-fold and hydroxyproline 55% in 158 g thyroparathyroidectomized (TPTXed) rats. Calcitonin (25 MRC mU/rat/h) abolished the sodium EDTA-induced increase in hydroxyproline excretion, presumptive evidence that sodium EDTA was acting on bone. To determine whether the changes induced by sodium EDTA are due to lowering of plasma calcium, rats were infused with 4.84 mM ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA), a more specific calcium chelator. EGTA increased the urinary excretion of calcium and phosphorus (P<0.001) but not hydroxyproline in thyroparathyroidectomized rats. Furthermore, when TPTXed rats were infused with calcium EDTA (4.84 mM Ca₂EDTA) in order that ionic calcium concentration would not be altered, hydroxyproline excretion was again markedly increased but phosphorus excretion was decreased by 26%. Since the displacement of the sodium ions in Na₂EDTA by calciumin vivo is instantaneous, and since calcium EDTA itself induces collagenolysis, the increase in urinary hydroxyproline excretion due to sodium EDTA cannot be attributed solely to lowering of plasma calcium. From these data two conclusions are drawn. First, sodium EDTA enhances bone breakdown independently of its effect on parathyroid hormone secretion. Second, since bone plays a major role in the maintenance of plasma calcium, interpretation of results should be made with caution in those investigations in which EDTA is used to study calcium homeostasis.     

Peep and the bain circuit

The feasibility of applying positive end expiratory pressure within the Bain circuit using an Emerson PEEP valve was studied. It was determined that varying degrees of PEEP may be applied within the Bain circuit using an Emerson PEEP valve during either mechanically or manually controlled ventilation but not during spontaneous breathing. There was some loss of measured tidal volume with increasing PEEP, due primarily to compression gas losses but also from leakage throughout the system. The maximum gas loss was 100 ml per minute at PEEP 15 cm H₂O under test conditions. PEEP may be applied between the Bain tubing and the manifold. However, one should then never allow the patient to breathe spontaneously as the PEEP valve presents an obstruction to inspiratory flow. With the PEEP valve relocated between the Bain manifold and the ventilator hose it was found that application of PEEP was possible without this disadvantage, but only during mechanical ventilation.     

Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Background

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

Methods

Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

Results

The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.     

Mechanisms of graft versus host disease produced by small bowel transplantation

Mechanisms of graft versus host disease have been studied in Lew x BN animals transplanted with a Lew small bowel. Grafted mesenteric lymph nodes but not host mesenteric lymph nodes or host spleen, in small bowel transplanted rats undergoing lethal GVHD, provide a source of CTL with specific anti-recipient cytotoxic activity. Host MLN and host spleen display anti-recipient CTL activity only when GVHD is provoked by intraperitoneal lymphocyte injection. These data demonstrate that lethal GVHD after SBTx may occur in the absence of detectable cytotoxic activity in host lymphoid tissues, suggesting that other mechanisms are involved in the pathogenesis of GVHD after SBTx. GVHD after SBTx or lymphocyte transfer is associated with the appearance of TNF in the serum. The intensity and reversibility of this phenomenon correlate with both the clinical severity and the lethality of GVHD. Taken together these data highly suggest that TNF is directly involved in the pathogenesis of GVHD after SBTx.     

Comparison of Nodal Metastasis Between BRCA Mutation Carriers and Non-BRCA Mutation Carriers with Breast Cancer

Objective

This study evaluates whether nodal status differs between breast cancer patients with BRCA mutations and those confirmed not to harbor mutations.

Methods

A prospective database identified patients with breast cancer who underwent genetic testing and axillary staging. Comparative variables included age, as well as tumor characteristics such as size, grade, lymphovascular invasion (LVI), estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2-neu), and nodal status.

Results

Overall, 235 patients with breast cancer underwent genetic testing for BRCA mutations from June 2000 to May 2012. Of these patients, 74 (31.4 %) were found to express BRCA 1 and/or 2 mutations, and 161 (68.5 %) patients were verified to have no detectable BRCA mutation. Among the entire 235 patients tested, 92 (39.1 %) were found to have nodal disease. In univariable analysis, only LVI and tumor size correlated with presence of nodal metastasis. Of the 74 BRCA mutation carriers, 34 (45.9 %) had nodal metastasis compared with 58 of the 161 (36 %; p = 0.15) patients without a BRCA mutation. BRCA mutation carriers with nodal disease were more likely to have poorly differentiated tumors than those without mutations who had nodal disease (24/33 [72.7 %] vs. 27/57 [47.4 %]; p = 0.027).

Conclusion

BRCA mutations are not themselves predictive of nodal metastasis. Patients with BRCA mutations did not have a statistically significant higher prevalence of nodal metastasis than those without mutations.