Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. Conclusions: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab

Strategies for Retaining Employees for Call Centers

Voluntary employee turnover has several adverse consequences for call center managers, including lowered productivity and decreased profitability. The purpose of this descriptive multiple case study was to explore strategies used to reduced voluntary employee turnover among 2 call center managers in the southern United States. These managers had been recommended by the human resource directors of the organizations because of their implementation of strategies to reduce voluntary employee turnover. The conceptual framework for this study was Herzberg\u27s motivation-hygiene theory. Data were collected from semistructured face-to-face interviews and employee handbooks. The data analysis consisted of compiling the data, disassembling the data into common codes, reassembling the data into themes, interpreting the meaning, and reporting the themes. The use of member checking and methodological triangulation increased the trustworthiness of the study. Themes that emerged were job satisfaction, employee compensation, opportunity and advancement, reward and recognition, and employee engagement. Recommendations for action include selecting strategies for reducing voluntary employee turnover and using the strategies to improve the commitment of the workers. The findings from this study may contribute to social change by providing strategies that call center managers can use to reduce voluntary employee turnover, thereby positively improving the standard of living for families, and strengthening community wealth and well-being

New insights on metal allergy in total joint arthroplasty

Metal allergy is an uncommon and not completely understood cause of failure in total joint arthroplasty (TJA). However, either immunopathology neither histologic studies clarified the mechanisms through which the metal ions could lead to the complications related to them. The lack of evidence around this topic also reflects the difficulties to diagnose the MRP in TJA. In fact, the diagnosis is generally based on the exclusion of other causes. Currently, skin-patch testing and lymphocyte transformation test (LTT) are being commonly used to investigate about metal hypersensitivity and a delayed type-IV hypersensitivity is the immuno-histologic response to metals involved in TJA loosening. A review of the recent publications about this topic has been made focusing on immunology, histopathology, and clinics to better understand a still debated topic in orthopedic practice

Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer

Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1(Bright) CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b(+)/Gr1(+)/Ly6G(−)/Ly6C(hi)) significantly increase the frequency of ALDH1(Bright) CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14(+) peripheral blood monocytes into Mo-MDSC (CD14(+)/HLA-DR(low/−)) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1(Bright) CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1(Bright) CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1(Bright) CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00262-014-1527-x) contains supplementary material, which is available to authorized users

Age over 50 does not predict results in anterior cruciate ligament reconstruction

Introduction Grown in the worldwide population of over 50 of age individuals who remain in good health and continue to engage in sports has led to an increase of anterior cruciate ligament (ACL) tears in this aged population. ACL reconstruction was reserved for young and active athletes, but seems to produce good outcomes also in over 50s. Purpose To compare the patient-reported functional scores, arthrometric outcomes, and complications of primary ACL reconstruction between older (>50 years) and younger (<50 years) patients. Methods A systematic review was performed on Pubmed, Scopus, Google Scholar and Cochrane library regarding studies that compared the clinical outcomes of ACLR between patients aged > 50 years and those aged < 50 years. The outcomes evaluated were knee functional outcomes, antero-posterior laxity and complications rate. Results This study included 5 retrospective cohort studies with a total of 645 patients (357 in the older 50 group and 288 in the younger group). All included studies reported significant improvements in clinical outcomes in both groups after ACL reconstruction. No significant differences were noted in terms of International Knee Documentation Committee (IKDC), Lysholm, Tegner scores and anteroposterior instability between the two groups (p = n.s.). Over 50 cohort seem to have an increased risk for complication rate when compared with the younger cohort (p= 0.0005). Conclusion ACL reconstruction in patients older than 50 years is a safe procedure with good results that are comparable to those of younger patients

Long-term results of chemoradiation plus pulsed-dose-rate brachytherapy boost in anal canal carcinoma: A mono-institutional retrospective analysis

Purpose: Concurrent chemoradiation (CCRT) is the standard curative treatment of anal canal cancer (ACC). The role of a brachytherapy (BRT) boost in this setting is still debated. Therefore, the aim of this analysis was to retrospectively evaluate the clinical outcomes in a large cohort of ACC patients treated with CCRT plus BRT boost or external beam radiotherapy (EBRT) boost.Material and methods: Patients with non-metastatic ACC, treated in our department between January 2003 and December 2014 were included in this analysis. The initial treatment was based on EBRT to the pelvis (prescribed dose, 45 Gy/1.8 Gy) plus concurrent chemotherapy (5-fluorouracil and mitomycin-C). Patients received a pulsed-dose-rate BRT boost on the primary tumor (median dose, 20 Gy; range, 13-25 Gy) 2-3 weeks after the end of CCRT. In patients with contraindications to BRT, an EBRT boost (prescribed dose, 16 Gy, 2 Gy/fraction) was delivered immediately after CCRT.Results: One-hundred-twenty-three patients were included in this analysis (median age, 61 years; range, 36-93 years; squamous-cell carcinoma, 78%; HIV+, 6%; median follow-up, 71 months; range, 2-158 months). The actuarial 5-year local control (LC), distant metastasis-free survival, colostomy-free survival, and overall survival (OS) rates were 81.7%, 92.3%, 62.3%, and 74.0%, respectively. At univariate analysis, patients aged <= 65 years (p < 0.010), cT1-2 stage (p = 0.004), and receiving a BRT boost (p = 0.015) showed significantly improved OS. At multivariate analysis, advanced tumor stage cT3-cT4 (HR, 2.12; 95% CI: 1.09-4.14; p = 0.027), and age > 65 years (HR, 3.03; 95% CI: 1.54-5.95; p = 0.001) significantly predicted increased risk of mortality. The crude rate of toxicity-related colostomies was 4.9%.Conclusions: The role of BRT boost in ACC remains unclear since the outcomes were not clearly different compared to CCRT alone. However, further improvement of clinical results in ACC treatment is needed, and therefore prospective trials based on advanced (image-guided/adapted) BRT techniques are warranted

Teaching NeuroImage: Spontaneously Resolving Ring-Enhancing Lesions Due to Immunodeficiency-Associated CNS Lymphoma

A 57-year-old woman with systemic lupus erythematosus on mycophenolate mofetil (MMF) presented after a tonic-clonic seizure. Brain MRI revealed 7 gadolinium-enhancing lesions (Figure 1A). CSF protein, glucose, and cell count were normal, and microbiological tests for opportunist agents were negative, raising our suspicion for lymphoma. Prebiopsy MRI showed spontaneous improvement of most lesions, with increased size of the largest lesion (Figure 1B). Brain biopsy (Figure 2) was consistent with immunodeficiency-associated CNS lymphoma. MMF treatment cessation led to substantial improvement after 5 months (Figure 1C)

Osteointegration of soft tissue grafts within the bone tunnels in anterior cruciate ligament reconstruction can be enhanced

Anterior cruciate ligament reconstruction with a soft tissue autograft (hamstring autograft) has grown in popularity in the last 10 years. However, the issues of a relatively long healing time and an inferior histological healing result in terms of Sharpey-like fibers connection in soft tissue grafts are still unsolved. To obtain a promising outcome in the long run, prompt osteointegration of the tendon graft within the bone tunnel is essential. In recent decades, numerous methods have been reported to enhance osteointegration of soft tissue graft in the bone tunnel. In this article, we review the current literature in this research area, mainly focusing on strategies applied to the local bone tunnel environment. Biological strategies such as stem cell and gene transfer technology, as well as the local application of specific growth factors have been reported to yield exciting results. The use of biological bone substitute and physical stimulation also obtained promising results. Artificially engineered tissue has promise as a solution to the problem of donor site morbidity. Despite these encouraging results, the current available evidence is still experimental. Further clinical studies in terms of randomized control trial in the future should be conducted to extrapolate these basic science study findings into clinical practice. © 2009 Springer-Verlag.postprin

Controversies in ACL revision surgery: Italian expert group consensus and state of the art

Background: Revision ACL reconstruction is a complex topic with many controversies and not-easy-to-make decisions. The authors’ aim is to provide some feasible advice that can be applied in daily clinical practice with the goal of facilitating the decision-making process and improving the outcomes of patients subjected to revision ACL reconstruction. Methods: A national survey with seven questions about the most controversial topics in revision ACL reconstruction was emailed to members of two societies: SIOT and SIAGASCOT. The participants’ answers were collected, the most recent literature was analyzed, and a consensus was created by the authors, according to their long-term surgical experience. Conclusions: The decision-making process in revision ACL reconstruction starts with a standardized imaging protocol (weight-bearing radiographs, CT scan, and MRI). One-stage surgery is indicated in almost all cases (exceptions are severe tunnel enlargement and infection), while the choice of graft depends on the previously used graft and the dimensions of the tunnels, with better clinical outcomes obtained for autografts. Additional procedures such as lateral extra-articular tenodesis in high-grade pivot-shift knees, biplanar HTO in the case of severe coronal malalignment, and meniscal suture improve the clinical outcome and should be considered case by case. Level of evidence: V (Expert opinion)