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UNLABELLED: Cyclooxygenase-2 (COX-2) is associated with tumour promotion, inhibition of apoptosis, angiogenesis and metastasis. Celecoxib, a selective COX-2 inhibitor was investigated, in patients with clinically localized prostate cancer using immunohistochemistry. PATIENTS AND METHODS: Patients with cT1-2 prostate cancer (n=45) were randomized to celecoxib 400mg b.d. or no treatment for four weeks prior to radical prostatectomy. Histological sections of preoperative biopsy and matched radical prostatectomy specimens were stained for markers of cell proliferation (MIB-1/Ki-67), microvessel density (CD-31 with Weidner scoring), COX-2, apoptosis (TUNEL analysis), angiogenic factors (VEGF and KDR) and HIF-1. RESULTS: Celecoxib decreased tumour cell proliferation, microvessel density, angiogenesis and HIF-1 whilst enhancing apoptosis. These effects approached statistical significance in a multivariate model and the cell proliferation index approached statistical significance on univariate analysis. CONCLUSION: In this pilot study a 4 week regimen of celecoxib resulted in measurable biological effects in prostate cancer tissue. These findings warrant further investigation.

The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered “adrenolytic,” is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one critical clinical issue—the risk of peritoneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peritoneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dissemination, a complication of laparoscopy that is uniformly fatal. Clin Cancer Res; 22(20); 4989–5000. ©2016 AACR. See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”

Purpose Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. Patients and Methods A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. Results CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. Conclusion Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI.

Purpose: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma. Responding patients generally do not have significant changes in noncutaneous RECIST targets before 30 to 60 days following TIL infusion, and complete responses are often not confirmed for 1 to 2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of circulating tumor DNA (ctDNA) in separating responding from nonresponding patients. Experimental Design: We studied BRAF V600E ctDNA levels by a sensitive allele-specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the NCI and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes. Results: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1 to 2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception. Conclusions: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in metastatic melanoma can be used to rapidly identify responding from nonresponding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy. Clin Cancer Res; 22(22); 5480–6. ©2016 AACR.

OBJETIVO: O pós-operatório da tonsilectomia é, em geral, bastante doloroso e os pacientes necessitam de analgésicos. Este estudo visou avaliar a eficácia da aplicação do laser terapêutico no controle da dor no pós-operatório de tonsilectomia. MÉTODOS: 18 crianças de cinco a 15 anos de idade foram submetidas à adenotonsilectomia, no período de junho de 2005 a outubro de 2006, sendo randomizadas para receber aplicações de laser terapêutico na área cirúrgica imediatamente após o procedimento e 24 horas após a cirurgia (n=9) ou seguir a rotina, com analgesia farmacológica, se necessário. A avaliação da dor foi realizada por escala analógica de dor, pela necessidade de analgésicos e pela aceitação da dieta no pós-operatório. RESULTADOS: Os pacientes submetidos à aplicação do laser apresentaram medianas das notas da escala de avaliação da dor menores e utilizaram menos analgésicos no pós-operatório em comparação aos pacientes controles. A aceitação da dieta nos dois grupos não foi diferente. CONCLUSÕES: Os resultados preliminares mostraram que o laser terapêutico foi eficaz na diminuição da dor e na redução de uso de analgésicos no pós-operatório de tonsilectomias em crianças e adolescentes.OBJECTIVE: The postoperative period of a tonsillectomy is usually very painful, requiring the use of pain-relieving drugs. The aim of this study was to evaluate the efficacy of low-level laser therapy in post-tonsillectomy pain control. METHODS: 18 children aged 5 to 15 years undergoing adenotonsillectomy between June 2005 and October 2006 were randomized to receive either local application of therapeutic laser immediately after surgery and 24 hours postoperatively (n=9) or routine analgesic drug therapy, if necessary. Pain was assessed by visual analog scale scores, need for analgesics, and acceptance of diet during the postoperative period. RESULTS: Patients undergoing laser applications had lower median pain scores and required less analgesic medication postoperatively than the control group. Acceptance of diet was similar in both groups. CONCLUSIONS: Preliminary results showed that low-level laser therapy is effective in the reduction of post-tonsillectomy pain, minimizing the need of analgesic medication in children and adolescents.

Introduction Thymic epithelial tumors are rare mediastinal malignancies that can be invasive and difficult to treat. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor implicated in the regulation of cell metabolism, growth, and survival. As higher levels of IGF-1R protein expression may be associated with relative sensitivity to anti-IGF-1R antibody treatment, we investigated IGF-1R expression in thymic malignancies. Methods Sixty-three thymic tumors (56 thymomas and seven thymic carcinomas) were analyzed for total IGF-1R expression using immunohistochemistry with a specific antibody (clone G11, Roche-Ventana, Tucson, AZ). Expression levels were correlated with relevant clinical and pathologic variables, including epidermal growth factor receptor and KIT expression, and patient outcome. Results IGF-1R staining was negative in 13 (21%) cases, low (1+) in 20 (32%) cases, moderate (2+) in 20 (32%) cases, and high (3+) in 10 (16%) cases. Moderate to high IGF-1R staining was observed in 6 of 7 (86%) thymic carcinomas and in 24 of 56 (43%) thymomas ( p = 0.039). Moderate to high IGF-1R staining was associated with high epidermal growth factor receptor staining ( p = 0.015). By multivariate analysis, only tumor stage and histologic type were significant prognostic factors on time to progression (hazard ratio [HR] = 4.12, 95% confidence interval [CI]: 1.98–14.23; p = 0.010 and HR=2.79, 95% CI: 1.62–12.50; p = 0.018, respectively). There was no association between IGF-1R expression and time to progression (HR = 3.07, 95% CI: 0.38–24.59; p = 0.291). Conclusion A majority of thymic malignancies display moderate to high expression of IGF-1R. The lack of preclinical models prevented us to further study the functional consequences of anti-IGF-1R therapy in this setting. However, given correlations in other cancers, these data support the evaluation of anti-IGF-1R inhibitors in thymic tumors.

The wind power input to near-inertial (NI) motions is studied using a global eddy-permitting ocean general circulation model. The model is forced by high- (1-hourly, at 0.35° resolution) and low-resolution (6-hourly, at 1.875° resolution) wind data. A change from low- to high-resolution forcing results in an increase in NI kinetic energy by a factor three and raises the wind-generated power input to NI motions from 0.3 TW to 1.1 TW. Time and space filtering of the wind fields yield less kinetic energy, with a larger drop from time filtering. This strong sensitivity to wind forcing points to a possible underestimation of the wind-generated energy available for deep ocean mixing in previous studies based on low-resolution winds.

Background There can be considerable overlap in the clinical presentation and laboratory features of dengue, malaria, and enteric fever, three important causes of fever in returned travelers. Routine laboratory tests including full blood examination (FBE), liver function tests (LFTs), and C-reactive protein (CRP) are frequently ordered on febrile patients, and may help differentiate between these possible diagnoses. Methods Adult travelers returning to Australia who presented to the Royal Melbourne Hospital with confirmed diagnosis of dengue, malaria, or enteric fever between January 1, 2000 and March 1, 2013 were included in this retrospective study. Laboratory results for routine initial investigations performed within the first 2 days were extracted and analyzed. Results There were 304 presentations including 58 with dengue fever, 187 with malaria, and 59 with enteric fever, comprising 56% of all returned travelers with a febrile systemic illness during the study period. Significant findings included 9-fold and 21-fold odds of a normal CRP in dengue compared with malaria and enteric fever, respectively. The odds of an abnormally low white cell count (WCC) were also significantly greater in dengue versus malaria or enteric fever. Approximately one third of dengue presentations and almost half of the malaria presentations had platelet counts

This paper presents an estimate of the oceanic Lorenz energy cycle derived from a simulation forced by 6-hourly fluxes obtained from NCEP–NCAR reanalysis-1. The total rate of energy generation amounts to 6.6 TW, of which 1.9 TW is generated by the time-mean winds and 2.2 TW by the time-varying winds. The dissipation of kinetic energy amounts to 4.4 TW, of which 3 TW originate from the dissipation of eddy kinetic energy. The energy exchange between reservoirs is dominated by the baroclinic pathway and the pathway that distributes the energy generated by the time-mean winds. The former converts 0.7 to 0.8 TW mean available potential energy to eddy available potential energy and finally to eddy kinetic energy, whereas the latter converts 0.5 TW mean kinetic energy to mean available potential energy.This energy cycle differs from the atmospheric one in two aspects. First, the generation of the mean kinetic and mean available potential energy is each, to a first approximation, balanced by the dissipation. The interaction of the oceanic general circulation with mesoscale eddies is hence less crucial than the corresponding interaction in the atmosphere. Second, the baroclinic pathway in the ocean is facilitated not only by the surface buoyancy flux but also by the winds through a conversion of 0.5 TW mean kinetic energy to mean available potential energy. In the atmosphere, the respective conversion is almost absent and the baroclinic energy pathway is driven solely by the differential heating.

OBJETIVO: O pós-operatório da tonsilectomia é, em geral, bastante doloroso e os pacientes necessitam de analgésicos. Este estudo visou avaliar a eficácia da aplicação do laser terapêutico no controle da dor no pós-operatório de tonsilectomia. MÉTODOS: 18 crianças de cinco a 15 anos de idade foram submetidas à adenotonsilectomia, no período de junho de 2005 a outubro de 2006, sendo randomizadas para receber aplicações de laser terapêutico na área cirúrgica imediatamente após o procedimento e 24 horas após a cirurgia (n=9) ou seguir a rotina, com analgesia farmacológica, se necessário. A avaliação da dor foi realizada por escala analógica de dor, pela necessidade de analgésicos e pela aceitação da dieta no pós-operatório. RESULTADOS: Os pacientes submetidos à aplicação do laser apresentaram medianas das notas da escala de avaliação da dor menores e utilizaram menos analgésicos no pós-operatório em comparação aos pacientes controles. A aceitação da dieta nos dois grupos não foi diferente. CONCLUSÕES: Os resultados preliminares mostraram que o laser terapêutico foi eficaz na diminuição da dor e na redução de uso de analgésicos no pós-operatório de tonsilectomias em crianças e adolescentes. OBJECTIVE: The postoperative period of a tonsillectomy is usually very painful, requiring the use of pain-relieving drugs. The aim of this study was to evaluate the efficacy of low-level laser therapy in post-tonsillectomy pain control. METHODS: 18 children aged 5 to 15 years undergoing adenotonsillectomy between June 2005 and October 2006 were randomized to receive either local application of therapeutic laser immediately after surgery and 24 hours postoperatively (n=9) or routine analgesic drug therapy, if necessary. Pain was assessed by visual analog scale scores, need for analgesics, and acceptance of diet during the postoperative period. RESULTS: Patients undergoing laser applications had lower median pain scores and required less analgesic medication postoperatively than the control group. Acceptance of diet was similar in both groups. CONCLUSIONS: Preliminary results showed that low-level laser therapy is effective in the reduction of post-tonsillectomy pain, minimizing the need of analgesic medication in children and adolescents.

[1] The spatial and temporal distributions of tropical instability waves (TIWs) in the Atlantic Ocean are investigated using a combination of current observations with moored instruments deployed at the equator at 23 degrees W and a realistic eddy-resolving (1/12 degrees) general circulation model of the Atlantic Ocean. The meridional and vertical shears of the zonal current system contribute to the eddy production rates and thus to the generation of TIWs in the central tropical Atlantic Ocean. In the Southern Hemisphere, TIWs are forced only by baroclinic instability associated with the vertical shear of the central part of the South Equatorial Current (SEC). In the Northern Hemisphere, baroclinic instability due to the vertical shear of the northern SEC (nSEC) as well as barotropic instabilities due to horizontal shears of the Equatorial Undercurrent (EUC)/nSEC and nSEC/North Equatorial Countercurrent (NECC) contribute to the generation of the TIWs. Since seasonal changes of the instability production rates related to the EUC/nSEC are comparable low while the rates related to the nSEC/NECC are high, we suggest that the seasonality of the NECC dominates the seasonal modulation of the TIWs.