Home-based color card screening for biliary atresia: the first steps for implementation of a nationwide newborn screening in Germany.

INTRODUCTION: Biliary atresia is a rare neonatal disease and the most common indication for pediatric liver transplantation. Kasai portoenterostomy is the initial treatment, aiming to prevent liver transplantation. Beyond age at Kasai, few prognostic factors are known. Multiple countries have established screening methods to reduce the age at Kasai and recent analysis shows significant better outcomes for screening cohorts. In 2016, we established a decentralized stool color card screening in Lower Saxony and we present our first 2 years of experiences. METHODS: In cooperation with a major German health insurance company and the Medical Association of Lower Saxony, we established the screening project, printed 120,000 color cards, and distributed them to all maternity hospitals. Program advertises were printed in newspapers and medical journals. After the first year, the project was evaluated. Thirty maternity hospitals and local practitioners were contacted via telephone, Internet, intranet, and pediatric journals. RESULTS: One out of seventy-six maternity hospitals (1.3%) refused to participate in the screening. 30 hospitals (40%) were contacted and 93.5% of the interviewed staff reported that stool color cards were handed out regularly and discussed with the parents. Only 20% of local practitioners assessed neonatal cholestasis to be a relevant problem during daily practice, and 55% regarded a stool color card screening to be useful. CONCLUSIONS: In the second year, we extended the screening project to outpatient maternity clinics. Based on the responses of local practitioners, we regard the voluntary screening as insufficient and we have contacted the Federal Joint Committee for the initiation of a nationwide obligatory stool color card screening.

Effects of exercise on inflammation in patients receiving chemotherapy: a nationwide NCORP randomized clinical trial.

PURPOSE: A growing body of research suggests that inflammation plays a role in many chemotherapy-related toxicities such as fatigue, anxiety, and neuropathy. Regular exercise can change levels of individual cytokines (e.g., reducing IL-6, increasing IL-10); however, it is not known whether exercise during chemotherapy affects relationships between cytokines (i.e., whether cytokine concentrations change collectively vs. independently). This study assessed how 6 weeks of exercise during chemotherapy affected relationships between changes in concentrations of several cytokines. METHODS: This is a secondary analysis of a randomized trial studying 6 weeks of moderate-intensity walking and resistance exercise during chemotherapy compared with chemotherapy alone. At pre- and post-intervention, patients provided blood to assess serum concentrations of cytokines IL-1ß, IL-6, IL-8, IL-10, and IFN-γ, and receptor sTNFR1. We investigated relationships between cytokines using the correlations between changes in cytokine concentrations from pre- to post-intervention. RESULTS: We obtained complete data from 293 patients (149 randomized to exercise). Exercise strengthened the correlation between concentration changes of IL-10 and IL-6 (r = 0.44 in exercisers vs. 0.11 in controls; p = 0.001). We observed the same pattern for IL-10:IL-1ß and IL-10:sTNFR1. Exercise also induced an anti-inflammatory cytokine profile, per reductions in pro-inflammatory IFN-γ (p = 0.044) and perhaps IL-1ß (p = 0.099, trend-level significance). CONCLUSIONS: Our hypothesis-generating work suggests that regular exercise during 6 weeks of chemotherapy may cause certain cytokine concentrations to change collectively (not independently). This work enhances our understanding of relationships between cytokines and complements traditional analyses of cytokines in isolation. Future work should test for replication and relationships to patient outcomes. TRIAL REGISTRATION: Clinical Trials.gov, # NCT00924651, http://www.clinicaltrials.gov .

Effects of a Home-based Exercise Program on Anxiety and Mood Disturbances in Older Adults with Cancer Receiving Chemotherapy.

BACKGROUND/OBJECTIVE: Exercise interventions improve anxiety and mood disturbances in patients with cancer. However, studies are limited in older adults with cancer. We assessed the effects of exercise on anxiety, mood, and social and emotional well-being in older patients with cancer during their first 6 weeks of chemotherapy. DESIGN: Exploratory secondary analysis of a randomized controlled trial (RCT). SETTING: Community oncology practices. PARTICIPANTS: Older patients (aged 60 years or older) undergoing chemotherapy (N = 252). INTERVENTION: Patients were randomized to Exercise for Cancer Patients (EXCAP) or usual care (control) for the first 6 weeks of chemotherapy. EXCAP is a home-based, low- to moderate-intensity progressive walking and resistance training program. MEASUREMENTS: Analysis of covariance, with study arm as the factor, baseline value as the covariate, and study arm × baseline interaction, was used to evaluate arm effects on postintervention anxiety (State Trait Anxiety Inventory [STAI]), mood (Profile of Mood States [POMS]), and social and emotional well-being (Functional Assessment of Cancer Therapy-General subscales) after 6 weeks. RESULTS: Median age was 67 years; 77% had breast cancer. Statistically significant group differences were observed in the STAI score (P = .001), POMS score (P = .022), social well-being (P = .002), and emotional well-being (P = .048). For each outcome, EXCAP patients with worse baseline scores had larger improvements at 6 weeks; these improvements were clinically significant for STAI score and social well-being. CONCLUSIONS: Among older cancer patients receiving chemotherapy, a 6-week structured exercise program improved anxiety and mood, especially among those participants with worse baseline symptoms. Additional RCTs are needed to confirm these findings and evaluate the appropriate exercise prescription for managing anxiety, mood, and well-being in this patient population. J Am Geriatr Soc 67:1005-1011, 2019.

Arterioportal shunting, splanchnic capillary perfusion, and the effects of colloids during capnoperitoneum in neonatal and adolescent pigs.

BACKGROUND: Clinical and experimental data indicate that neonates are sensitive to the CO2 pneumoperitoneum. An impaired splanchnic perfusion during laparoscopy in adults has been reported. We recently confirmed that intravenous colloids improve macrocirculatory function in neonates. We aimed to determine the impact of CO2 pneumoperitoneum on the perfusion of splanchnic organs in the young including effects of colloid application. METHODS: Male piglets (n = 25) were divided into four groups: (1) neonatal controls, (2) neonates with crystalloid restitution, (3) neonates with colloidal restitution, and (4) adolescents with crystalloid restitution. Animals were ventilated and subjected to a 3-h, 10 mmHg CO2 pneumoperitoneum followed by 2 h resuscitation. Hepatic, splanchnic, and arteriovenous shunt perfusion was assessed via central and portal venous catheters. Capillary organ flow was detected by fluorescent microspheres. The rate of bile flow was measured. RESULTS: The neonatal crystalloid group showed a significant decrease in the intestinal capillary perfusion at the end of the recovery period. This was not detectable in the adolescent and colloid group. There was a significant increase in microcirculatory arterioportal shunt flow during the CO2 pneumoperitoneum in both neonatal groups but not in the sham and adolescent groups (p < 0.05). Hepatic arterial perfusion increased after insufflation in all groups and dropped during capnoperitoneum to levels of about 70% baseline. There was no significant impairment of splanchnic perfusion or bile flow as a result of the pneumoperitoneum in all groups. CONCLUSIONS: Capillary perfusion of the abdominal organs was stable during capnoperitoneum and recovery in adolescents and neonates with colloid restitution, but not with crystalloid restitution. Significant arterioportal shunting during capnoperitoneum could affect hepatic microcirculation in neonates. Our data confirm that moderate pressure capnoperitoneum has no major effect on the perfusion of abdominal organs in neonates with adequate substitution.

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

IMPORTANCE: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. OBJECTIVE: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. DESIGN, SETTING, AND PARTICIPANTS: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. MAIN OUTCOMES AND MEASURES: Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. RESULTS: In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. CONCLUSIONS AND RELEVANCE: Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Minimal invasive lung support via umbilical vein with a double-lumen cannula in a neonatal lamb model: a proof of principle.

PURPOSE: Acute respiratory distress syndrome, with the need for invasive mechanical ventilation (MV) remains a major cause of neonatal mortality and morbidity. Although venovenous extracorporeal lung support (VV-ECLS) has become a standard of care procedure in neonatal patients with acute pulmonary failure there are no reports regarding the use of a double-lumen cannula for extracorporeal minimal invasive lung support via the umbilical vein. METHODS: A neonatal lamb model was used (n = 3). Umbilical vein was cannulated with a double-lumen catheter allowing venovenous extracorporeal gas exchange. Cannula was positioned with its tip in the right atrium. VV-ECLS was started and ventilation was stopped. Providing oxygenation and CO2 removal solely through VV-ECLS hemodynamics, blood gases were measured. RESULTS: Total VV-ECLS without MV was applied to all three neonatal lambs. Time on venovenous ECLS was 60, 120 and 120 min. Initial pCO2 was 60, 56 and 65 mmHg compared to 31, 32 and 32 mmHg at the end of VV-ECLS. Initial pO2 was 30, 27 and 26 mmHg compared to 22, 19 and 23 mmHg. Initial lactate was 5, 10 and 3.7 mmol/l compared to 13.3, 12.6 and 11.3 mmol/l at the end of VV-ECLS. MAP at baseline was 51, 52 and 65 mmHg compared to 36, 38 and 41 mmHg at the end of VV-ECLS. In all three lambs inotropes were admitted to maintain MAD >35 mmHg. CONCLUSION: Even without mechanical ventilation we were able to sufficiently remove pCO2 with our new minimal invasive VV-ECLS using a double-lumen catheter via the umbilical vein, supporting the idea of a lung protective strategy in neonatal acute respiratory failure. pO2 was measured 22, 19 and 23 mmHg, respectively, at the end of VV-ECLS, at least partially caused by recirculation phenomenon, which could possibly be improved by different cannula design. Inotropic support was necessary during VV-ECLS to achieve targeted MAD > 35 mmHg. While technically feasible, this new approach might allow further research in the field of extracorporeal lung support and therefore will follow the concept of a lung protective strategy in acute neonatal respiratory failure.

Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib-Responsive Non-Small Cell Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is clearly beneficial in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance develops uniformly and the benefit of continuation of EGFR TKI therapy beyond progression remains unclear. MATERIALS AND METHODS: This was a randomized phase II study of chemotherapy (arm A: pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients with progressive NSCLC following clinical benefit from erlotinib. In arm B, chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days 2-19 of each cycle to minimize negative pharmacodynamic interactions. The primary endpoint was that continuation of erlotinib in this patient population could extend progression-free survival (PFS) by 50%. RESULTS: A total of 46 patients were randomized (arm A: 24; arm B: 22). Patient characteristics were well balanced except there were more female patients in arm A (p = .075). The median PFS of patients in arm A was 5.5 months and for those in arm B, 4.4 months (p = .699). The response rates were 13% and 16% in arms A and B, respectively (p = .79). EGFR status data were available for 39 of the 46 patients and no significant difference in PFS was seen for continuing ERL beyond progression in mutation-positive patients. Substantially more toxicity was seen in arm B than arm A. CONCLUSION: There was added toxicity but no benefit with the continuation of ERL beyond progression along with chemotherapy as compared with chemotherapy alone. IMPLICATIONS FOR PRACTICE: The benefits of continuing erlotinib upon progression alongside conventional chemotherapy are unclear. This randomized phase II study, initiated prior to the establishment of routine epidermal growth factor receptor (EGFR) mutation testing, addressed this clinically relevant issue through randomizing patients with prior clinical benefit from erlotinib (thereby enriching for EGFR-mutated tumors) upon progression in the second- or third-line setting to conventional chemotherapy (single-agent pemetrexed or docetaxel) with or without continued erlotinib. The results showed no benefit to continuing erlotinib beyond progression, while significantly more side effects were noted in the combination arm. Along with other recently presented study findings, these results argue against the routine practice of continuing erlotinib in this setting.

Liver fibrosis during the development of biliary atresia: Proof of principle in the murine model.

BACKGROUND: The murine model of biliary atresia (BA) is used for examining the pathogenesis of BA. The aim of the study was description of the morphological features and illustrating the detailed development of fibrosis using the Biliary Atresia Research Consortium (BARC) system. METHODS: Neonatal mice were injected intraperitoneally with rhesus rotavirus (RRV) strain (N=17). Healthy mice were the control group (N=29). All mice were sacrificed at 7 or 14days after birth. Two pathologists examined the morphological features using the BARC system; CK19, αSMA and collagen type I were assessed by immunohistochemistry. RESULTS: In RRV mice, portal fibrous expansion with focal bile duct proliferation and strong portal cellular infiltrate was found in contrast to healthy mice. In RRV mice, CK19 bile duct staining was significantly less or absent (p<0.01), with stronger portal staining of collagen type I (p=0.02). Expansion of staining for αSMA was more in RRV mice (p<0.01), but αSMA portal staining was stronger in healthy mice (p=0.02). CONCLUSIONS: The morphological features observed in the murine model of BA correspond with the BA characteristics according to the BARC criteria. Fibrosis is an important feature of the model. Therefore, this murine model is useful for investigating the pathogenesis of BA.

Prospective multicenter study of the impact of oncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer patients.

The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%-53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

Neonatal murine macrophages show enhanced chemotactic capacity upon toll-like receptor stimulation.

BACKGROUND: The neonatal surgical patient is threatened by exuberant inflammatory reactions. Neonatal macrophages are key players in this process. We investigated the ability of neonatal macrophages to initiate a local inflammatory reaction upon exposure to different bacterial or viral ligands to toll-like receptors (TLRs). METHODS: Peritoneal wash outs from neonatal (<24 h) and adult (42 days) C57BL/6J mice were gained by peritoneal lavages. In a first set of experiments, macrophages were purified and stimulated for 6 h by four different TLR ligands. mRNA was extracted for transcriptome analysis. In a second set of experiments, lipopolysaccharide was applied into peritoneal cavities. After 6 h of incubation, the cellular composition of the inflamed cavities was evaluated by cytological staining as well as chipcytometry. RESULTS: Neonatal murine peritoneal macrophages differed significantly in the expression of pro- and anti-chemotactic genes. Functional assignment of these genes revealed enhanced chemotactic potential of neonatal macrophages and was confirmed by a higher influx of pro-inflammatory cells into neonatal peritoneal cavities. CONCLUSION: Neonatal peritoneal macrophages demonstrated an enhanced chemotactic potential upon stimulation with four TLR ligands. This was associated with an increased influx of inflammatory cells to the peritoneal cavity. This might contribute to the strong inflammatory responses of neonates and preterms.

Novel t(5;19) Translocation in a Patient with PDGFRB Associated Chronic Leukemia: Implications for Treatment Strategy.

Myeloproliferative disorders are variable disorders, based on the genetic abnormality present and the cell line progenitors that are affected. In this case, we discuss a novel gene translocation in the subset of PDGFRB mutations, first seen with prominent hyperbasophilia. This case demonstrates the possibility for lower therapeutic doses of imatinib mesylate than previously reported, in order to control leukocyte counts and reverse the genetic mutation.

Post-hot isostatic pressing: a healing treatment for process related defects and laboratory grinding damage of dental zirconia?

OBJECTIVE: Processing parameters (powder granulation, compaction, debinding, greenbody shaping, sintering) and post-sinter rough, even fine grinding are influencing the final mechanical properties of 3Y-TZP. The hypothesis of this study was that post-sinter hot isostatic pressing (post-HIP) would be beneficial for improving reliability and strength of both sintered and coarse ground sintered zirconia by closing or reducing surface and/or small volume defects. METHODS: 75 sintered bars of an experimental 3Y-TZP (3mm×4mm×45mm) with chamfered edges and 15µm diamond surface finish were provided by the manufacturer (Ivoclar Vivadent) and randomly distributed in five groups of N=15 each. G1 served as control (as received); G2 was post-HIPed at 1400°C and G3 at 1350°C, both using a pressure of 195MPa in Ar for 1h; G4 was coarse ground with 120µm diamond disk grain size; G5 was ground 120µm and post-HIPed at 1350°C at 195MPa, 1h in Ar. The specimens were fractured in air in 4 point-bending. Weibull characteristic strength (σ0) in MPa, m parameter (reliability) and confidence intervals (CI) at 90% confidence level are reported. Identification of the critical flaw was performed by SEM on the fractured surface of all specimens and XRD performed in all groups. RESULTS: G1: σ0=973 (932-1016), m=10.6 (7.45-15.1); G2: σ0=930 (871-995), m=6.9 (4.87-9.9); G3: σ0=898 (848-952), m=7.94 (5.6-11.4); G4: σ0=921 (857-991), m=6.35 (4.48-9.11); G5: σ0=881 (847-918), m=11.4 (8.03-16.3). G5 had a significantly lower σ0 than G1. No significant differences were seen in the reliability (m) among the groups. Fractography revealed critical intrinsic subsurface flaws of 10-60µm present in all groups resulting from the processing parameters. No "healing" (i.e. closing of defects by densification) resulted after post-HIP. Grinding sintered zirconia with 120µm diamond disks induced radial cracks of 10-20µm and an important pseudo-cubic phase transformation (56wt%) that was not completely removed after post-HIP. Post-HIP increased slightly the relative density by 0.1% but without improving the strength and reliability. SIGNIFICANCE: Post-HIP was not efficient in closing large (10-60µm) subsurface (volume) processing defects.

Prevention of delayed nausea: a University of Rochester Cancer Center Community Clinical Oncology Program study of patients receiving chemotherapy.

PURPOSE: We conducted a double-blind randomized clinical trial of the following four regimens for controlling delayed nausea (DN): group 1: palonosetron + dexamethasone on day 1 with prochlorperazine on days 2 and 3; group 2: granisetron + dexamethasone on day 1 with prochlorperazine on days 2 and 3; group 3: aprepitant + palonosetron + dexamethasone on day 1 with aprepitant + dexamethasone on days 2 and 3; and group 4: palonosetron + dexamethasone on day 1 with prochlorperazine + dexamethasone on days 2 and 3. PATIENTS AND METHODS: Chemotherapy-naive patients received doxorubicin, epirubicin, cisplatin, carboplatin, or oxaliplatin. The primary end point was average nausea assessed four times daily on days 2 and 3. Primary analyses were whether nausea control would be improved by using palonosetron versus granisetron on day 1 (group 1 v group 2); by adding dexamethasone on days 2 and 3 (group 1 v group 4); and by using aprepitant versus prochlorperazine (group 3 v group 4). Statistical significance was set at P = .017. RESULTS: Two hundred thirty-four, 234, 241, and 235 evaluable patients were accrued to groups 1, 2, 3, and 4, respectively. Adjusted mean differences for the three planned analyses were as follows: palonosetron versus granisetron: -0.01 (95% CI, -0.23 to 0.20; P = .72); adding dexamethasone on days 2 and 3: 0.20 (95% CI, -0.02 to 0.41; P = .01); and using aprepitant versus prochlorperazine: -0.03 (95% CI, -0.24 to 0.19; P = .56). CONCLUSION: The addition of dexamethasone on days 2 and 3 reduced DN. Palonosetron and granisetron have similar effects on DN. The beneficial effect of adding aprepitant for control of DN was the same as adding prochlorperazine.

Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets. PATIENTS AND METHODS: Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets. RESULTS: In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients. CONCLUSION: Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

Portal venous gas detected by ultrasound differentiates surgical NEC from other acquired neonatal intestinal diseases.

BACKGROUND: The definite clinical diagnosis of acquired neonatal intestinal diseases (ANID) is a challenge, usually met by applying Bell's or, more recently, Gordon's classification. Both classifications incorporate radiological pneumatosis intestinalis (PI) as a cornerstone of the NEC diagnosis. However, PI may be absent or difficult to identify by abdominal X-ray. Portal venous gas detected by ultrasound (PVG-US) has been proposed as another characteristic of NEC, but its incidence in other entities of ANID remains unknown. OBJECTIVE: To determine whether PVG-US and Gordon's classification can help to differentiate between NEC and other ANID, especially SIP. METHODS: Retrospective analysis of the data of 83 infants, who underwent laparotomy for a clinical diagnosis of ANID was performed. The results of PVG-US and other markers of ANID were compared with the operative result, defined as the gold standard for diagnosis. RESULTS: The NEC diagnosis was confirmed in 28/83 infants and PVG-US was present in 23 (82%) of those patients prior to operation. PVG-US was detected in 2 patients without NEC (one volvulus, one SIP), resulting in an 82% sensitivity and a 96% specificity. The sensitivity and specificity of radiological PI for patients with NEC was lower (75 and 91%), but the combination of PVG-US and radiological PI increased the sensitivity for NEC detection to 89%. Gordon's classification had a sensitivity of 93% and a specificity of 92% for NEC diagnosis. CONCLUSION: Screening for PVG-US and Gordon's classification are valid tools to differentiate between NEC and other ANID including SIP. Although an effect of these proposed diagnostic tools on treatment regimen and operative management has yet to be verified, the improvement in diagnosing ANID is certainly valuable.

Biliary atresia: lessons learned from the voluntary German registry.

INTRODUCTION: Aim of the study was to carry out a 5-year survey of German patients with biliary atresia (BA) and to launch a discussion regarding the feasibility of voluntary registries in unregulated healthcare systems. METHODS: A retrospective analysis of German BA patients born between 2001 and 2005, based on data collected from the voluntary European Biliary Atresia Registry (EBAR), was carried out and supplemented by data from all BA patients who underwent liver transplantation at the only 4 pediatric transplantation centers (pLTx) in Germany which are so far not registered at EBAR. Survival rates were calculated using Kaplan-Meier analysis and compared by Cox regression to determine the predictive value of age at surgery and the influence of the center size (fewer or more than 5 patients/study period) on overall survival and survival with native liver. RESULTS: A critical review of the 148 German EBAR charts revealed that 11 patients (7.4%) had no biliary atresia. The remaining 137 patients from EBAR together with 46 BA patients who underwent LTx without prior registration at EBAR were evaluated with a median follow-up of 39 months (range: 25-85 months). 29 hospitals performed a total of 159 Kasai procedures, but only 7 centers treated 5 or more patients (116 patients, range: 5-68), and 22 hospitals performed less than 5 KP (43 patients, range: 1-4). Primary LTx was performed in 21 patients (11.5%) and 3 patients died without surgical intervention. 16 patients were lost to follow-up (8.7%). Overall survival after 2 years was 83.3% (139 patients), including 105 patients (63%) who had undergone LTx and 34 patients (20.3%) with native liver. 28 patients died (16.7%), 8 after LTx (5.8%). The experience of the center was the only factor with a significant predictive value for jaundice-free survival with native liver (p=0.001). CONCLUSION: 25% of all German BA patients were not registered at EBAR, and 29 clinics were involved in the surgical management of BA patients. Therefore a new approach consisting of an internet-based decentralized registry for rare neonatal liver diseases is outlined which could improve the future management of patients with BA. The centralization of such patients at experienced centers with higher caseloads is necessary in Germany and would improve the outcome of patients with biliary atresia.

Clinical comparison of patients with osteonecrosis of the jaws, with and without a history of bisphosphonates administration.

This retrospective study aimed to evaluate the role of bisphosphonates in jaw osteomyelitis. 29 patients were included: 18 had been treated with bisphosphonates (12 with multiple myelomas, 3 with breast carcinomas, 2 with prostate carcinomas, and 1 with osteoporosis). Of 11 control patients, 2 had breast carcinomas, 2 had bronchial carcinomas, and 7 had no cancer. Descriptive and statistical evaluations were conducted to investigate the influence of chemotherapy, corticosteroids, stem cell transplantation, and bisphosphonates on the development and clinical picture of osteomyelitis. Both groups had similar disease histories, clinical pictures, treatment methods, and outcome. Wound dehiscence frequencies were also similar (Mann-Whitney rank sum test 1.66±1.5 vs. 1.45±2.0 p=0.393). Chemotherapy, steroid therapy, stem cell transplantation, or bisphosphonate administration did not correlate with the clinical picture. Neither the duration of therapy nor the type of bisphosphonate influenced the clinical picture (negative Fisher's tests). The bisphosphonate group showed a characteristic settlement of Actinomyces in the exposed bone (positive Fisher's test, p=0.021). These results suggested that osteomyelitis developed as a consequence of the simultaneous, cumulative action of many factors. Bisphosphonates played a role comparable to other predisposing features. Coating the jaws with bisphosphonates could promote the settlement of Actinomyces.

CO2 modulates the inflammatory cytokine release of primary human pleural macrophages.

BACKGROUND: It is well known that CO (2) used during laparoscopy affects the peritoneal surface and local inflammatory response, including the inflammatory reactivity of peritoneal macrophages. However, little is known about the local effects of CO (2) during thoracoscopy. In a previous study we have shown that in healthy adolescents, macrophages are the dominant cell population on the pleural surface. Therefore, we examined the effects of CO (2) on the inflammatory response of primary human pleural macrophages. METHODS: Human primary macrophages were harvested lavage from healthy adolescents undergoing elective surgery for pectus bar correction (n=8). After purification and 24 h resting, cells were incubated for 2 h in 100% CO (2), 5% CO (2) or 95% inert helium with 5% CO (2) as hypoxic control. After incubation cells were stimulated with LPS for 4 h and 24 h. The release of TNF-alpha, IL-8, IL-6, IL-10 and IL-1 beta were determined by ELISA. RESULTS: CO (2), but not hypoxia, induced a significant reduction in the release of TNF-alpha and IL-8 as well as a significant increase in the release of IL-10 and IL-1 beta within the first 4 h after incubation. The levels of IL-6 and the release of cytokines at 24 h after incubation were not significantly affected. CONCLUSIONS: CO (2) directly modulates the immediate inflammatory response of pleural macrophages. Therefore, CO (2) insufflation during thoracoscopy could lower the local stress response, but does not appear to have a lasting effect.

Preconceptional oral vaccination prevents experimental biliary atresia in newborn mice.

INTRODUCTION: Biliary atresia (BA) in humans resembles BA induced in Balb/c-mice by Rhesus Rotavirus (RRV). In mice, susceptibility to BA is ascribed to the lack of maternally derived immune protection. This study investigated whether vaccination of dams against RRV protected their offspring from developing BA. MATERIALS AND METHODS: Before mating, female mice were vaccinated orally with RotaTeq or Rotarix. Pups (n=243) from both test groups and a control group were intraperitoneally infected with RRV. Sacrifice of the animals was scheduled for days 7, 14 and 21 after infection. Then, gross and mircoscopia findings of the liver and the hepatoduodenal ligament gave evidence of BA, and hepatic viral load was tested by virus-specific real-time PCR, as well as plaque forming units. RESULTS: Two weeks after infection, the incidence of cholestasis was 100% in controls, 77% in pups of RotaTeq-vaccinated dams, and 56% in pups of Rotarix-vaccinated dams. However, in contrast to controls (incidence of BA: 82%) most pups in the test groups recovered (incidence of BA in pups of RotaTeq-vaccinated dams 11%; incidence of BA in pups of Rotarix-vaccinated dams 3%). Hepatic viral load was identical at various time-points in all pups, suggesting that differences in RRV clearance did not underlie this effect. CONCLUSION: In this mouse model, oral vaccination with RotaTeq and Rotarix prevented most RRV-induced BA. This provides a new approach to a better understanding of both the pathomechanism of BA development and the capabilities of the innate immune system. It also suggests a first approach for prophylaxis against BA.