Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity.

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor ECOG performance status with relapsed or refractory large B-cell lymphoma after 2 or more lines of prior therapy.

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance.

OBJECTIVE: The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection. DESIGN: We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice. RESULTS: The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment. CONCLUSIONS: Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.

Prognostic value and predictive biomarkers of phenotypes of tumour-associated macrophages in colorectal cancer.

BACKGROUND: The roles of different subtypes of tumour-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remain controversial. In this study, different subtypes of TAMs were investigated as prognostic and predictive biomarkers for CRC. METHODS: Expressions of CD68, CD86 and CD163 were investigated by immunohistochemistry (IHC) and immunofluorescence (IF), and the correlation between the expression of CD86 and CD163 was calculated in colorectal cancer tissues from 64 CRC patients. RESULTS: The results showed that high expressions of CD86+ and CD68+ CD86+ TAMs as well as low expression of CD163+ and CD68+ CD163+ TAMs were significantly associated with favourable overall survival (OS). The level of CD86 protein expression showed a negative correlation with CD163 protein expression. In addition, CD86 protein expression remarkably negatively correlated with tumour differentiation and tumour node metastasis (TNM) stage, while CD163 protein expression significantly positively correlated with tumour differentiation and tumour size. As an independent risk factor, high expression of CD86 TAMs had prominently favourable prognostic efficacy, while high expression of CD68+ CD163+ TAMs had significantly poor prognostic efficacy. CONCLUSIONS: These results indicate that CD86+ and CD68+ CD163+ TAMs as prognostic and predictive biomarkers for CRC.

Does Adding Femoral Lengthening at the Time of Rotation Hip Transposition After Periacetabular Tumor Resection Allow for Restoration of Limb Length and Function? Interim Results of a Modified Hip Transposition Procedure.

BACKGROUND: Reconstruction after pelvic tumor resection of the acetabulum is challenging. Previous methods of hip transposition after acetabular resection have the advantages of reducing wound complications and infections of the allograft or metal endoprosthesis but were associated with substantial limb length discrepancy. We therefore developed a modification of this procedure, rotation hip transposition after femur lengthening, to address limb length, and we wished to evaluate its effectiveness in terms of complications and functional outcomes. QUESTIONS/PURPOSES: In this study, we asked: (1) What were the Musculoskeletal Tumor Society scores after this reconstruction method was used? (2) What complications occurred after this reconstruction method was used? (3) What proportion of patients achieved solid arthrodesis (as opposed to pseudarthrosis) with the sacrum and solid union of the femur? (4) What were the results with respect to limb length after a minimum follow-up of 2 years? METHODS: From 2011 to 2017, 83 patients with an aggressive benign or primary malignant tumor involving the acetabulum were treated in our institution. Of those, 23% (19 of 83) were treated with rotation hip transposition after femur lengthening and were considered for this retrospective study; 15 were available at a minimum follow-up of 2 years (median [range], 49 months [24 to 97 months]), and four died of lung metastases before 2 years. No patients were lost to follow-up before 2 years. During the period in question, the general indications for this approach were primary nonmetastatic malignant bone tumor or a locally aggressive benign bone tumor that could not be treated adequately with curettage. There were seven men and 12 women with a median age of 43 years. Nine patients underwent Zones I + II resection, eight patients had Zones I + II + III resection, and two received Zones II + III resection. After tumor resection, rotation hip transposition after femur lengthening reconstruction was performed, which included two steps. The first step was to lengthen the femur with the insertion of an allograft. Two methods were used to achieve limb lengthening: a "Z" osteotomy and a transverse osteotomy. The second step was to take the hip transposition and rotate the femoral head posteriorly 10° to 20°. The median (range) operative time was 510 minutes (330 to 925 minutes). The median intraoperative blood loss was 4000 mL (1800 to 7000 mL). We performed a chart review on the 15 available patients for clinical and radiographic assessment of functional outcomes and complications. Arthrodesis and leg length discrepancy were evaluated radiographically. RESULTS: The median (range) Musculoskeletal Tumor Society score was 21 points (17 to 30). Eleven of 19 patients developed procedure-related complications, including six patients with allograft nonunion, two with deep infection, two with delayed skin healing, and one with a hematoma. Two patients had minor additional surgical interventions without the removal of any implants. Local recurrences developed in four patients, and all four died of disease. All seven patients treated with a Z osteotomy had bone union. Among the eight patients with transverse osteotomy, bone union did not occur in six patients. After hip transposition, stable iliofemoral arthrodesis was achieved in seven patients. Pseudarthrosis developed in the remaining eight patients. The median (range) lower limb length discrepancy at the last follow-up visit or death was 8 mm (1 to 42 mm). CONCLUSION: Although complex and challenging, rotation hip transposition after femur lengthening reconstruction with a Z osteotomy provides acceptable functional outcomes with complications that are within expectations for resection of pelvic tumors involving the acetabulum. Because of the magnitude and complexity of this technique, we believe it should be used primarily for patients with a favorable prognosis, both locally and systemically. This innovative procedure may be useful to other surgeons if larger numbers of patients and longer-term follow-up confirm our results. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Simultaneous Preparation of Abundant Flavonol Triglycosides from Tea Leaves.

Flavonol glycosides are important components of tea leaves, contributing to the bioactivities as well as bitterness and astringency of tea. However, the standards of many flavonol triglycosides are still not available, which restricts both sensory and bioactivity studies on flavonol glycosides. In the present study, we established a simultaneous preparation method of seven flavonol triglycoside individuals from tea leaves, which consisted of two steps: polyamide column enrichment and preparative HPLC isolation. The structures of seven flavonol triglycoside isolates were identified by mass and UV absorption spectra, four of which were further characterized by nuclear magnetic resonance spectra, namely, quercetin-3-O-glucosyl-rhamnosyl-glucoside, quercetin-3-O-rhamnosyl-rhamnosyl-glucoside, kaempferol-3-O-glucosyl-rhamnosyl-glucoside and kaempferol-O-rhamnosyl-rhamnosyl-glucoside. The purities of all isolated flavonol triglycosides were above 95% based on HPLC, and the production yield of total flavonol glycosides from dry tea was 0.487%. Our study provides a preparation method of flavonol triglycosides from tea leaves, with relatively low cost of time and solvent but high production yield.

Effect and mechanisms of sacral nerve stimulation on visceral hypersensitivity mediated by nerve growth factor.

To investigate the efficacy of sacral nerve stimulation (SNS) on nerve growth factor (NGF) mediated visceral sensitivity in normal rat and visceral hypersensitivity model rats. 120 male newborn rats were randomly divided into 6 groups: group A was normal model group; group B ~ F were all sensitized with acetic acid enema and grouped again. Group c2 was given NGF antagonist, d2 group was given NGF agonist, e2 group was given PI3K inhibitor, and f2 group was given PLC-γ inhibitor. After treatment, the expression of NGF, TrKA, PI3K, AKT, PLC-γ, NF-κB, TRPV1, pTRPV1 and intracellular Ca2+ content were detected. The expression of protein TRPV1 and pTRPV1 was increased, and Ca2+ was increased in the visceral hypersensitive group. NGF, TrKA in NGF antagonist group, PI3K, AKT, NF-κB in PI3K inhibitor group, PLC-γ in PLC-γ inhibitor group were all almost not expressed. The relative expression of NGF, TrKA, PI3K, AKT, PLC-γ and NF-κB in NGF antagonist group was lower than that in visceral hypersensitivity group and NGF activator group (P < .01). The relative expression of NGF, TrKA, PI3K and AKT mRNA in NGF antagonist group was lower than that in the normal model group (P < .01). There was no significant difference in the relative expression of PLC-γ and NF-κB mRNA (P > .05). The expression level of MAPK, ERK1 and ERK2 in visceral hypersensitivity group was higher than that in PI3K inhibitor group and PLC-γ inhibitor group. The normal group Ca2+ curve was flat, and the NGF agonist group had the highest Ca2+ curve peak. Calcium concentration in visceral hypersensitivity group was higher than that in PI3K inhibitor group and that in PLC-γ inhibitor group was higher than that in NGF antagonist group. The binding of TrkA receptor to NGF activates the MAPK/ERK pathway, the PI3K/Akt pathway and the PLC-γ pathway, causing changes in the fluidity of intracellular and extracellular Ca2+ , resulting in increased sensitivity of visceral tissues and organs.

T Cell-Derived Lymphotoxin Is Essential for the Anti-Herpes Simplex Virus 1 Humoral Immune Response.

B cell-derived lymphotoxin (LT) is required for the development of follicular dendritic cell clusters for the formation of primary and secondary lymphoid follicles, but the role of T cell-derived LT in antibody response has not been well demonstrated. We observed that lymphotoxin ß-receptor (LTßR) signaling is essential for optimal humoral immune response and protection against an acute herpes simplex virus 1 (HSV-1) infection. Blocking the LTßR pathway caused poor maintenance of germinal center B (GC-B) cells and follicular helper T (Tfh) cells. Using bone marrow chimeric mice and adoptive transplantation, we determined that T cell-derived LT played an indispensable role in the humoral immune response to HSV-1. Upregulation of gamma interferon by the LTßR-Ig blockade impairs the sustainability of Tfh-like cells, leading to an impaired humoral immune response. Our findings have identified a novel role of T cell-derived LT in the humoral immune response against HSV-1 infection.IMPORTANCE Immunocompromised people are susceptible to HSV-1 infection and lethal recurrence, which could be inhibited by anti-HSV-1 humoral immune response in the host. This study sought to explore the role of T cell-derived LT in the anti-HSV-1 humoral immune response using LT-LTßR signaling-deficient mice and the LTßR-Ig blockade. The data indicate that the T cell-derived LT may play an essential role in sustaining Tfh-like cells and ensure Tfh-like cells' migration into primary or secondary follicles for further maturation. This study provides insights for vaccine development against infectious diseases.

Bursopentin (BP5) induces G1 phase cell cycle arrest and endoplasmic reticulum stress/mitochondria-mediated caspase-dependent apoptosis in human colon cancer HCT116 cells.

BACKGROUND: Bursopentin (BP5) is a multifunctional pentapeptide found in the chicken bursa of Fabricius. Recent study indicated that BP5 significantly stimulates expression of p53 protein in colon cancer HCT116 cells. However, the effects and underlying mechanisms of BP5 on HCT116 cell proliferation remain largely unclear. METHODS: Analyses of cell viability, cell cycle arrest as well as apoptosis were performed to study the actions of BP5 on HCT116 cells. Western blot analyse was assayed to measure the cell cycle-related and apoptosis-related proteins. Specific siRNAs targeting IRE1, ATF-6, and PERK were used for IRE1, ATF-6, and PERK knockdown, respectively. Cellular reactive oxygen species (ROS) were detected using a H2DCF-DA green fluorescence probe. Cytosolic free Ca2+ concentrations and mitochondrial membrane potential (ΔΨm) were measured using Fluo-3 AM and JC-1 stains, respectively. RESULTS: BP5 possessed strong inhibitory effects on the cell growth and induced apoptosis in HCT116 cells. Mechanistically, BP5 arrested the cell cycle at G1 phase by increasing p53 and p21 expression and decreasing cyclin E1-CDK2 complex expression. BP5 treatment dramatically activated the endoplasmic reticulum (ER) stress-mediated apoptotic pathway, as revealed by the significantly enhanced expression of unfolded protein response (UPR) sensors (IRE1α, ATF6, PERK) as well as downstream signaling molecules (XBP-1s, eIF2α, ATF4 and CHOP), and by the significantly altered the BP5-induced phenotypic changes in IRE1, ATF6, and PERK knockdown cells. Additionally, BP5-induced ER stress was accompanied by the accumulation of cytosolic free Ca2+ and intracellular ROS. Furthermore, BP5 treatment resulted in the increase of Bax expression, the decrease of Bcl-2 expression and the reduction of ΔΨm, subsequently causing a release of cytochrome c from the mitochondria into the cytoplasm and finally enhancing the activities of caspase-9 and -3. In addition, z-VAD-fmk, a pan-caspase inhibitor, markedly rescued BP5-induced cell viability reduction and reduced BP5-induced apoptosis. CONCLUSIONS: Our present results suggest that BP5 has an anticancer capacity to arrest cell cycle at G1 phase and to trigger ER stress/mitochondria-mediated caspase-dependent apoptosis in HCT116 cells. Therefore, our findings provide insight into further investigations of the anticancer activities of BP5.

Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project.

BACKGROUND: Small-scale studies suggest that hyperkalaemia is a less threatening condition in chronic kidney disease (CKD), arguing adaptation/tolerance to potassium (K+) retention. This study formally evaluates this hypothesis by estimating the distribution of plasma K+ and its association with mortality across CKD stages. METHODS: This observational study included all patients undergoing plasma K+ testing in Stockholm during 2006-11. We randomly selected one K+ measurement per patient and constructed a cross-sectional cohort with mortality follow-up. Covariates included demographics, comorbidities, medications and estimated glomerular filtration rate (eGFR). We estimated K+ distribution and defined K+ ranges associated with 90-, 180- and 365-day mortality. RESULTS: Included were 831 760 participants, of which 70 403 (8.5%) had CKD G3 (eGFR <60-30 mL/min) and 8594 (1.1%) had CKD G4-G5 (eGFR <30 mL/min). About 66 317 deaths occurred within a year. Adjusted plasma K+ increased across worse CKD stages: from median 3.98 (95% confidence interval 3.49-4.59) for eGFR >90 to 4.43 (3.22-5.65) mmol/L for eGFR ≤15 mL/min/1.73 m2. The association between K+ and mortality was U-shaped, but it flattened at lower eGFR strata and shifted upwards. For instance, the range where the 90-day mortality risk increased by no more than 100% was 3.45-4.94 mmol/L in eGFR >60 mL/min, but was 3.36-5.18 in G3 and 3.26-5.53 mmol/L in G4-G5. In conclusion, CKD stage modifies K+ distribution and the ranges that predict mortality in the community. CONCLUSION: Although this study supports the view that hyperkalaemia is better tolerated with worse CKD, it challenges the current use of a single optimal K+ range for all patients.

Overexpression of MTHFD1 in hepatocellular carcinoma predicts poorer survival and recurrence.

Aim: MTHFD1 was the enzyme providing one-carbon derivatives of tetrahydrofolate. We sought to investigate the impact of MTHFD1 on hepatocellular carcinoma (HCC). Methods: Bioinformatic analysis, western blot and immunohistochemistry were conducted to detect MTHFD1 expression in HCC. The relationships between MTHFD1 and prognosis of 172 HCCs were analyzed by Kaplan-Meier method and Cox proportional hazards model. Results: High MTHFD1 expression in HCC represented poor prognosis (overall survival p = 0.025; time to recurrence p = 0.044). Combining MTHFD1 with serum AFP, survival analysis demonstrated the prognosis of the MTHFD1 low expression and AFP ≤20 ng/ml group was better than that of the MTHFD1 high expression or AFP >20 ng/ml group and the MTHFD1 high expression and AFP >20 ng/ml group (overall survival p < 0.0001; time to recurrence p < 0.0001). Conclusion: High MTHFD1 expression in HCC indicated poorer prognosis. Combining MTHFD1 with serum AFP improved the accuracy of prognostic prediction.

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

DOPPS data suggest a possible survival benefit of renin angiotensin-aldosterone system inhibitors and other antihypertensive medications for hemodialysis patients.

The benefits of renin angiotensin-aldosterone system inhibitors (RAASi) are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, conflicting evidence from trials and concerns about hyperkalemia limit RAASi use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers. Therefore, we investigated prescription patterns and associations with mortality for RAASi and other antihypertensive agents using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Cox regression was used to estimate the effect of the prescription of RAASi and other antihypertensive agents at study entry on mortality in 11,421 incident (120 days or less) hemodialysis and 37,124 prevalent (over 120 days) hemodialysis patients from DOPPS phases 2-5 (2002-2015). Over 95% of RAASi were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RAASi prevalence was 39% and varied minimally by CHF and CAD. The adjusted hazard ratio for RAASi (vs. no RAASi) was 0.89 (95% confidence interval 0.80-0.99) among incident and 0.94 (0.90-0.99) among prevalent hemodialysis patients, with no convincing evidence of interaction with diabetes, CAD or CHF. Inverse associations with mortality were also observed for beta blockers and calcium channel blockers, and were stronger for angiotensin receptor blockers than angiotensin-converting enzyme inhibitors, but this latter finding requires further study. Thus, our observations suggest a relatively small survival benefit of RAASi and other antihypertensive agents in hemodialysis patients, though randomized prospective studies are needed to potentially change prescribing criteria.

Pulsatility Index as a Novel Parameter for Perfusion in Mouse Model of Hindlimb Ischemia.

BACKGROUND/AIMS: In clinical settings, the pulsatility index (PI) has become a widely used tool for monitoring obstetrics or other vascular diseases. It is based on the maximum Doppler shift waveform derived from ultrasonography. However, it remains unclear whether the PI levels are correctly predicted from the perfusion in mouse model of hindlimb ischemia. METHODS: To explore the relationship between PI and perfusion, we generated a unilateral hindlimb ischemia model in 8-week-old C57BL/6 male mice by ligation of the right common iliac artery and femoral artery. These mice were monitored with laser Doppler perfusion imaging (LDPI) and an ultrasound system (Vevo2100). Vessel densities in ischemic skeletal muscles were measured with vWF staining, which functions as a marker for endothelial cells. In order to further verify PI evaluation in other conditions, we performed therapeutic experiments using hindlimb ischemic mouse with PBS or FGF2 treatment. RESULTS: In the mouse model of hindlimb ischemia, the PI levels were continuously elevated and were accompanied by an increased ratio of perfusion to blood flow. 1 and 4 weeks after ischemia, the densities of vWF staining were correlated with PI values. Moreover, the PI index exactly reflected the perfusion in hindlimb ischemic mice after FGF2 treatment, while it indicated the condition of angiogenesis after therapeutic treatment based on the association between PI values and the number of vWF-positive stained cells in muscles. CONCLUSION: This study confirms the utility of a noninvasive and reproducible ultrasound index for a rapid evaluation of perfusion and blood recovery after hindlimb ischemia in vivo. PI, as one stable and comparable parameter, is correlated with angiogenesis in hindlimb ischemic mouse. Moreover, PI can exactly reflect perfusion and angiogenesis in therapeutic hindlimb ischemic mouse models. This study suggested that PI can serve as a novel index for relatively reproducible and repeatable blood flow recovery in the evaluation of emerging ischemic therapies and disease development in mouse models of hindlimb ischemia.

Computer Navigation in Orthopaedic Tumour Surgery.

In orthopaedic bone tumour surgery, surgeons perform malignant bone tumour resections with tumour-free margin. The bone defects following the resections have to be reconstructed to restore limb function. An inaccurate resection with positive surgical margin increased the risk of local recurrence and compromised patients' survival. Conventionally, orthopaedic tumour surgeons analyse two-dimensional (2D) imaging information and mentally integrate to formulate a three-dimensional (3D) surgical plan. It is difficult to translate the surgical plan to the operating room in complex cases.Computer-assisted tumour surgery (CATS) has been developed in orthopaedic oncology for the last decade. The technique may enable surgeons' 3D surgical planning and image-guided bone resection as planned. The technique may apply to difficult surgery in pelvic or sacral tumours, limited resection in joint-preserving tumour surgery or bone defect reconstruction using CAD prostheses or allograft.Early results suggested that the technique may help in safe tumour resection and improve surgical accuracy by replicating the preoperative planning. The improved surgical accuracy may offer clinical benefits.Surgeons have to be aware of the potential errors of the technique that may result in inaccurate bone resections with possible adverse clinical outcomes. Given that bone sarcoma is rare, the published reports from different tumour centres could only analyse relatively small patient population with the heterogeneous histological diagnosis. Multicentre comparative studies with long-term follow-up are necessary to confirm its clinical efficacy.This chapter provides an overview of computer navigation in orthopaedic tumour surgery over the past decade. It (1) describes the current workflow, (2) reports the clinical indications and results and (3) discusses its limitations and future development.

How does iliosacral bone tumor resection without reconstruction affect the ipsilateral hip joint?

BACKGROUND: Whether reconstruction is more beneficial after iliosacral bone tumor resection remains controversial. Because of high rates of complications and recurrence, few patients benefit from reconstruction. The aim of this study is to assess functional outcomes and to reveal changes in the ipsilateral hip joint after partial iliosacral resection. METHODS: From 1998 to 2016, 21 patients aged 20-66 years underwent iliosacral resection, 18 without reconstruction (group 1) and 3 with reconstruction (group 2). Function was evaluated using the Musculoskeletal Tumor Society 1993 rating scale (MSTS 1993), and disability was measured using the Toronto Extremity Salvage Score (TESS). I-A distance was defined as the distance from the iliosacral joint to the upper line of the acetabulum along the curved line. Group 1 were subdivided into two groups: group 1A included the patients with a defect less than one-third of the I-A distance and group 1B the remainder. Acetabulum-head index (AHI) and center-edge angle (CE angle) were measured. The relationship between defect length and femoral head coverage was analyzed. RESULTS: The mean follow-up was 67.3 months. Eighteen patients were included in group 1 and three in group 2. Preoperative data of the 3 groups were statistically equivalent. In addition, no difference of postoperative functional outcome has been highlighted. The final average MSTS 1993 score was 93.6% in group 1 and 93.3% in group 2. The mean TESS was 98 in group 1 and 98.5 in group 2. AHI and CE angle between groups 1 and 2 were not different. The AHI was 80 ± 5.4% in group 1A and 67 ± 9.0% in group 1B (t = - 3.740, P = 0.002), while the CE angle was 29 ± 5.9° in group 1A and 20 ± 6.3° in group 1B (t = - 3.172, P = 0.006) at the last follow-up. Regarding the limb-length discrepancy, group 1 and 2 were similar whereas group 1A and 1B were statistically different (group 1A: 0.7 ± 0.7 cm; group 2: 2.6 ± 1.0 cm; t = - 4.324, P = 0.001). CONCLUSIONS: Ilio-sacral resection without reconstruction removing more than one- third of the I-A distance leads to an impairement of the limb-length discrepancy and an increase of the defect of the acetabular coverage without altering the functional outcome. Nevertheless, iliosacral resection without reconstruction could serve as a viable treatment option for pelvic type I-IV tumors.

Renal Resistive Index as a Novel Indicator for Renal Complications in High-Fat Diet-Fed Mice.

BACKGROUND/AIMS: The renal resistive index (RI) is a novel candidate as a renal injury prognostic indicator, but it remains unclear how renal RI levels correspond to renal injury in diabetic nephropathy. METHODS: To examine this issue, we compared 8-week-old male C57BL/6 mice fed with high-fat diet (HFD) versus chow diet (CHD) for 16 weeks. At 8 and 12 weeks, the glomerular filtration rate (GFR), urinary albumin-to-creatinine ratio (UACR), and inflammatory factors (IL-1ß, IL-6, TNFα, and MCP-1) were measured, along with the increase in renal RI. RESULTS: Our study suggests RI values positively correlate with GFR for the first 12 weeks of HFD feeding. In contrast, the GFR of 16-week HFD feeding is lower than that of 12-week HFD feeding, whereas RI levels are significantly increased. Additionally, our study suggests RI values accurately indicate the renal fibrosis and renal injury in HFD-fed mice treated with lovastatin. CONCLUSION: This study seems to confirm the utility of a noninvasive and repeatable ultrasound parameter to rapidly evaluate renal fibrosis in a HFD-induced type 2 diabetic mouse model in vivo. This highly sensitive and comparable renal RI measurement could monitor the whole procedure of disease development in real-time. RI measurement of the renal artery is capable of differentiating responses to standard therapy with lovastatin in HFD-fed mice from the CHD group.

Risk of infection among patients with non-metastatic solid tumors or non-Hodgkin's lymphoma receiving myelosuppressive chemotherapy and antimicrobial prophylaxis in US clinical practice.

Purpose Guidelines generally do not recommend oral antimicrobials for prophylaxis against chemotherapy-related infections in patients with solid tumors. Evidence on antimicrobial prophylaxis use, and associated chemotherapy-related infection risk, in US clinical practice is limited. Methods A retrospective cohort design and data from two US private healthcare claims repositories (2008-2011) were employed. Study population included adults who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for non-Hodgkin's lymphoma. For each subject, the first chemotherapy course was characterized, and within the first course, each chemotherapy cycle and chemotherapy-related infection episode was identified. Use of prophylaxis with oral antimicrobials and colony-stimulating factors in each cycle also was identified. Results A total of 7116 (22% of all) non-metastatic breast cancer, 1833 (15%) non-metastatic colorectal cancer, 1999 (15%) non-metastatic lung cancer, and 1949 (21%) non-Hodgkin's lymphoma patients received antimicrobial prophylaxis in ≥1 cycle. Mean number of antimicrobial prophylaxis cycles during the course among these patients was typically <2, with little difference across cancers and chemotherapy regimens. Fluoroquinolones were the most commonly received class of antimicrobials, accounting for 20%-50% all antimicrobials administered. Among subjects who received first-cycle antimicrobial prophylaxis, chemotherapy-related infection risk in that cycle ranged from 3% to 6% across cancer types. Among patients who received first-cycle antimicrobial prophylaxis and developed chemotherapy-related infections, 38%-67% required inpatient care. Chemotherapy-related infection risk in subsequent cycles with antimicrobial prophylaxis was comparable. Conclusion The results of this study suggest that use of antimicrobial prophylaxis during myelosuppressive chemotherapy is far from uncommon in clinical practice. The results also suggest that an important minority of cancer chemotherapy patients receiving antimicrobial prophylaxis still develop serious infection requiring hospitalization.

Recurrence and survival factors analysis of 171 cases of sacral chordoma in a single institute.

PURPOSE: To evaluate postoperative recurrence, survival and metastasis results and related factors of sacral chordoma. METHODS: Between 1978 and 2013, a total of 171 patients with sacral chordoma were diagnosed at our institution and 162 cases underwent operation. The clinical characteristics, treatment and outcomes of all these patients were reviewed. RESULTS: The 3-year recurrence free survival rate was 83.1%. The median recurrence free survival time was 73 ± 7.8 months. Tumor level in sacrum and surgical margin were significant factors influencing recurrence. Recurrence was significant factor influencing metastasis. One hundred and fifty-seven cases were followed up for an average of 55.6 months. 135 cases (86%) survived, 37 cases (23.6%) developed recurrence, and 17 cases (10.8%) developed metastasis. The overall 5- and 10-year survival rate was 88.3% and 59.6%, respectively. Age (p = 0.037) and metastasis (p = 0.001) were significant factors influencing survival. The 3-year recurrence free survival rate was 80.1%. The median recurrence free survival time was 69 ± 12.7 months. Tumor level in sacrum (p = 0.035) and surgical margin (p = 0.009) were significant factors influencing recurrence. Seventeen cases (10.8%) had metastasis. Recurrence (p = 0.016) was significant factors influencing metastasis. CONCLUSIONS: Sacral chordoma tended to occur in elderly male patients and locate below sacral 3 level. The recurrence rate was high, especially for tumor above sacral 3 level. Wide surgical margin is very important for good local control. The patients with metastasis had poor prognosis.

AMPKα1 deficiency promotes cellular proliferation and DNA damage via p21 reduction in mouse embryonic fibroblasts.

Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, controls the cell cycle and protects against DNA damage. However, the molecular mechanisms by which AMPKα isoform regulates DNA damage remain largely unknown. The aim of this study was to determine if AMPKα deletion contributes to cellular hyperproliferation by reducing p21(WAF1/Cip1) (p21) expression thereby leading to accumulated DNA damage. The markers for DNA damage, cell cycle proteins, and apoptosis were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKα1, or AMPKα2 homozygous deficient (AMPKα1(-/-), AMPKα2(-/-)) mice by Western blot, flow cytometry, and cellular immunofluorescence staining. Deletion of AMPKα1, the predominant AMPKα isoform, but not AMPKα2 in immortalized MEFs led to spontaneous DNA double-strand breaks (DSB) which corresponded to repair protein p53-binding protein 1 (53BP1) foci formation and subsequent apoptosis. Furthermore, AMPKα1 localizes to chromatin and AMPKα1 deletion down-regulates cyclin-dependent kinase inhibitor, p21, an important protein that plays a role in decreasing the incidence of spontaneous DSB via inhibition of cell proliferation. In addition, AMPKα1 null cells exhibited enhanced cell proliferation. Finally, p21 overexpression partially blocked the cellular hyperproliferation of AMPKα1-deleted MEFs via the inhibition of cyclin-dependent kinase 2 (CDK2). Taken together, our results suggest that AMPKα1 plays a fundamental role in controlling the cell cycle thereby affecting DNA damage and cellular apoptosis.