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

The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: The Δ-Meet-URO analysis

Background: Treatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors. Methods: By a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs. Results: The analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction <0.001), higher baseline IR values (NLR: p = 0.012, SII: p = 0.003, PLR: p = 0.003), increasing NLR and systemic immune-inflammatory index (SII) (i.e., NLR x platelets) Δ (p for interaction time-group = 0.0053 and 0.0435, respectively) were associated with disease progression. OS and PFS were significantly shorter in patients with baseline lower lymphocytes (p < 0.001 for both) and higher platelets (p = 0.004 and p < 0.001, respectively) alongside early neutrophils Δ (p = 0.046 and p = 0.033, respectively). Early neutrophils and NLR Δ were independent prognostic factors for both OS (p = 0.014 and p = 0.011, respectively) and PFS (p = 0.023 and p = 0.001, respectively), alongside baseline NLR (p < 0.001 for both) and other known prognostic variables. Conclusions: Early neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions

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

Reliability of forced internal rotation and active internal rotation to assess lateral instability of the biceps pulley

PURPOSE: the aim of this study was to investigate the relationship between positive painful forced internal rotation (FIR) and lateral pulley instability in the presence of a pre-diagnosed posterosuperior cuff tear. The same investigation was conducted for painful active internal rotation (AIR). METHODS: a multicenter prospective study was conducted in a series of patients scheduled to undergo arthroscopic posterosuperior cuff repair. Pain was assessed using a visual analog scale (VAS) and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH) was administered. The VAS score at rest, DASH score, and presence/absence of pain on FIR and AIR were recorded and their relationships with lesions of the lateral pulley, cuff tear patterns and shape of lesions were analyzed. RESULTS: the study population consisted of 115 patients (mean age: 55.1 years) recruited from 12 centers. The dominant arm was affected in 72 cases (62.6%). The average anteroposterior extension of the lesion was 1.61 cm. The mean preoperative VAS and DASH scores were 6.1 and 41.8, respectively. FIR and AIR were positive in 94 (81.7%) and 85 (73.9%) cases, respectively. The lateral pulley was compromised in 50 cases (43.4%). Cuff tears were partial articular in 35 patients (30.4%), complete in 61 (53%), and partial bursal in 19 (16.5%). No statistical correlation between positive FIR or AIR and lateral pulley lesions was detected. Positive FIR and AIR were statistically associated with complete lesions. Negative FIR was associated with the presence of partial articular tears. CONCLUSIONS: painful FIR in the presence of a postero-superior cuff tear does not indicate lateral pulley instability. When a cuff tear is suspected, positive FIR and AIR are suggestive of full-thickness tear patterns while a negative FIR suggests a partial articular lesion. LEVEL OF EVIDENCE: level I, validating cohort study with good reference standards

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

Bayesian Modeling of the Yeast SH3 Domain Interactome Predicts Spatiotemporal Dynamics of Endocytosis Proteins

A genome-scale specificity and interaction map for yeast SH3 domain-containing proteins reveal how family members show selective binding to target proteins and predicts the dynamic localization of new candidate endocytosis proteins