Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry.

BACKGROUND: Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. METHODS: Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIMSM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2-124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. RESULTS: Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. CONCLUSIONS: Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. TRIAL REGISTRATION: PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Talimogene laherparepvec (T-VEC) as cancer immunotherapy.

Talimogene laherparepvec (T-VEC) is the first-in-class oncolytic virus immunotherapy for the treatment of cancer and was generated from an attenuated, recombinant herpes simplex virus. T-VEC has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents. This review will discuss the current landscape of melanoma, the construction and application of T-VEC for melanoma along with other indications for T-VEC, as well as highlight some of the novel challenges with oncolytic virus immunotherapy as it enters into clinical practice.

Periodontal cytokines profile under orthodontic force and extracorporeal shock wave stimuli in a rat model.

BACKGROUND AND OBJECTIVE: Extracorporeal shock wave therapy has been used in various clinical conditions as a result of its ability to stimulate healing processes in acute and chronic inflammatory states. Orthodontic force application triggers an inflammatory reaction in the periodontal tissue surrounding the involved teeth, resulting in tooth movement. Preliminary work revealed that extracorporeal shock wave therapy increased the expression of the inflammatory cytokines involved. Our aim was to investigate the expression of inflammatory cytokines in the periodontal tissues following orthodontic force induction, with and without shock wave therapy, in experimental rats. MATERIAL AND METHODS: An orthodontic appliance was fabricated and applied between the molars and the incisors of adult Wistar rats. In conjunction with orthodontic force commencement, the rats were treated with a single episode of 1000 shock waves. Every day, during the 3 d of the study, rats were killed and the immunolocalization of RANKL, interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha was evaluated. RESULTS: The percentage of the area staining positively for all inflammatory cytokines during the first 2 d decreased statistically significantly more in the shock wave-treated group compared with the nontreated control group. On the first day, the percentage of the area staining positively for IL-1ß and RANKL on the compression side peaked in both groups, with a sequential rise in the number of TRAP-positive cells. CONCLUSION: The induction of shock wave therapy during orthodontic tooth movement influences the expression of different inflammatory cytokines in the tissue and might alter the expected periodontal remodeling rate.

Importance of Fungicide Seed Treatment and Environment on Seedling Diseases of Cotton.

The importance of fungicide seed treatments on cotton was examined using a series of standardized fungicide trials from 1993 to 2004. Fungicide seed treatments increased stands over those from seed not treated with fungicides in 119 of 211 trials. Metalaxyl increased stands compared to nontreated seed in 40 of 119 trials having significant fungicide responses, demonstrating the importance of Pythium spp. on stand establishment. Similarly, PCNB seed treatment increased stands compared to nontreated seed for 44 of 119 trials with a significant response, indicating the importance of Rhizoctonia solani in stand losses. Benefits from the use of newer seed treatment chemistries, azoxystrobin and triazoles, were demonstrated by comparison with a historic standard seed treatment, carboxin + PCNB + metalaxyl. Little to no stand improvement was found when minimal soil temperatures averaged 25°C the first 3 days after planting. Stand losses due to seedling pathogens increased dramatically as minimal soil temperatures decreased to 12°C and rainfall increased. The importance of Pythium increased dramatically as minimal soil temperature decreased and rainfall increased, while the importance of R. solani was not affected greatly by planting environment. These multi-year data support the widespread use of seed treatment fungicides for the control of the seedling disease complex on cotton.

[Orthodontic tooth movement under extracorporeal shock wave therapy: the characteristics of the inflammatory reaction--a preliminary study].

Extracorporeal generated shock waves were introduced in medical therapy approximately 20 years ago in order to disintegrate kidney stones. Over the last 10 years, extracorporeal generated shock waves have been used to stimulate healing processes. No report to date has examined its influence on different inflammation mediators and growth factors in the periodontium. Orthodontic tooth movement is a model including the induction of an aseptic inflammation and its resolution. We conducted a preliminary study to investigate the periodontium cytokine concentration fluctuations after induction of orthodontic force with and without extracorporeal shock wave therapy (ESWT) in a rat model. An orthodontic appliance was fabricated and applied between the molars and the incisors of rats. The rats were treated by a single episode of 1000 shock waves and gingival crevicular fluid was collected for 3 days. The concentration of typical acute phase cytokines was evaluated by ELISA assay. Of the three tested cytokines, IL-1beta was the only detected cytokine along the study timeframe. IL-1beta concentration rose in both the treated and non treated shockwave groups on the first day, however it was statistically significantly higher in the treated group on day 2. On day 3, IL-1beta concentrations in both groups decreased and reached a lower level in the treated group, revealing a statistically significant difference than its level on the previous day. The application of ESWT during orthodontic force induction enhances IL-1beta production as part of mechanical forces transduction triggering a biologic response, which may contribute to accelerated periodontal remodeling and therefore foreshortening the orthodontic tooth movement period.

Three-dimensional endoanal ultrasonography of external anal sphincter defects in patients with faecal incontinence: correlation with symptoms and manometry.

AIM: Anal sphincter anatomy on two-dimensional endoanal -ultrasonography (EUS) does not always correlate with the clinical data. The purpose of this study was to determine whether three-dimensional (3D) measurements yield a better correlation. METHOD: The study group included consecutive patients who underwent 3D EUS for faecal incontinence over a 2-year period. The medical charts were reviewed for Cleveland Clinic Foundation Fecal Incontinence (CCF-FI) score and manometric pressures. Endoanal ultrasonographic images were reviewed for the presence of an external anal sphincter (EAS) defect and its extent, as determined by the radial angle, length in the sagittal plane and percentage volume deficit. Correlational analyses were performed between the clinical and imaging data. RESULTS: Sixty-one patients of median age 53 years (range 15-82) were evaluated. Thirty-two patients had either a complete (17) or partial (15) EAS defect, and 29 patients had an intact sphincter. The CCF-FI scores were similar in patients with and without an EAS defect (12.5 ± 5.6 and 11.4 ± 5.5, respectively). The intact-sphincter group had a significantly greater EAS length (3 ± 0.4 vs 2 ± 0.62 cm, P = 0.02) and higher mean maximal squeeze pressure (MMSP; 99.7 ± 52.6 vs 66.9 ± 52.9 mmHg, P = 0.009). There were no statistically significant correlations between MMSP, CCF-FI score and EAS status on 3D EUS. Mean percentage volume of the defect was similar in patients with complete and partial tears (14.5 ± 5.5 and 17.5 ± 7.2%, P = 0.25) and showed no correlation with physiological tests or symptom scores. CONCLUSION: Improvements in external anal sphincter imaging have not yielded a better association with the clinical findings. The lack of clinical differences between patients with different EAS tears may reflect their similar volumetric defects.

The biological basis of the bone-muscle inter-relationship in the algorithm of fracture healing.

The biological cascade of fracture healing is intimately linked to the muscle envelope. It further depends on the preservation of stable, perpetual axial micromovements. The current study was designed to demonstrate that high molecular weight bioactive substances diffuse from the muscle envelope to initiate osteoinductive activity at experimental fracture sites. Forty-eight rats underwent an experimental fracture of the left tibia and stabilization with an intramedullary 20-gauge needle. The animals were divided into 4 groups (A-D) of 12 rats each according to the post-fracture treatment. In group A (control) no additional treatment was applied following fracture and intramedullary fixation. In groups B, C, and D, a nitrocellulose membrane of various sizes was wrapped around the fracture, separating the periosteum from the muscle envelope. The groups differed by the membrane pore size, allowing passage of the following molecular sizes: 50 kilodaltons (kDa), 12 to 14 kDa, and 3.5 kDa in groups B, C, and D, respectively. Four animals in each group were sacrificed 2, 5, and 10 weeks after the procedure for radiographic and histological evaluation of fracture healing. Radiographic evaluation revealed a decreased rate of bone synthesis that correlated with the nitrocellulose pore size. Morphological and functional analysis of the bone explants indicated poorly healed fractures in groups B, C, and D. Direct contact between fractured bone and its muscle envelope is essential for the biological sequence of new bone formation. The extent of obstruction between the fracture and its muscle envelope correlates with the delay in fracture healing.

Evaluation of a face-to-face psychosocial screening intervention for cancer patients: acceptance and effects on quality of life.

OBJECTIVE: This study evaluated a psychosocial screening intervention that offers cancer patients counselling. The assumption underlying the intervention was that barriers are often present that hamper patients' awareness of and active request for psychosocial care. An active yet unobtrusive approach was hypothesized to improve accessibility to psychosocial services. METHODS: In a sequential cohort design, patients newly admitted to the oncology department of an academic hospital were assigned to a usual care group (n=50) or a screening group (n=79). A retrospective, medical records group (n=89) was also included. At baseline and 4 weeks following discharge, the usual care and screening groups completed mental health and quality of life questionnaires. RESULTS: Half the screening group actually wanted and received counselling. At follow-up, the screening group reported significantly less pain, better mental health and better physical and role functioning than the usual care group. CONCLUSION: The face-to-face screening intervention appears an effective means of identifying patients interested in obtaining formal psychosocial counselling, and may result in improvements in physical and mental health outcomes. PRACTICE IMPLICATIONS: This screening intervention may be particularly useful for hospitals that prefer a personal approach to psychosocial screening, but do not have sufficient resources to interview every new patient.

A phase I trial of pox PSA vaccines (PROSTVAC-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM) in patients with prostate cancer.

PURPOSE: Based on previous studies that demonstrated the safety profile and preliminary clinical activity of prostate specific antigen (PSA) targeted therapeutic vaccines, as well as recent laboratory data supporting the value of the addition of co-stimulatory molecules B7-1, ICAM-1, and LFA-3 (designated TRICOM) to these vaccines, we conducted a Phase I study to evaluate the safety and immunogenicity of a novel vaccinia and fowlpox vaccine incorporating the PSA gene sequence and TRICOM. METHODS: In this study, ten patients with androgen independent prostate cancer with or without metastatic disease were enrolled. Patients were treated with 2 x l0(8) pfu of a recombinant vaccinia virus vaccine (PROSTVAC-V) followed by 1 x 10(9) pfu of the booster recombinant fowlpox virus (PROSTVAC-F) both with gene sequences for PSA and TRICOM. The mean age of patients enrolled in the study was 70 (range 63 to 79). The mean PSA at baseline was 434 (range 9-1424). RESULTS: There were no deaths, and no Grade 3 or 4 adverse events. The most commonly reported adverse events, regardless of causality, were injection site reactions and fatigue. One serious adverse event (SAE) occurred that was unrelated to vaccine; this patient developed progressive disease with a new sphenoid metastasis. PSA was measured at week 4 and week 8. Four patients had stable disease (with less than 25% increase in PSA) through the week 8 study period. Anti-PSA antibodies were not induced with therapy: however, anti-vaccinia titers increased in all patients. CONCLUSION: This study demonstrated that vaccination with PROSTVAC-V and PROSTVAC-F combined with TRICOM is well-tolerated and generated an immune response to vaccinia. Therefore, PROSTVAC-VF/TRICOM represents a feasible therapeutic approach for further phase II and III study in patients with prostate cancer.

Complications encountered while using thin-wire-hybrid-external fixation modular frames for fracture fixation. A retrospective clinical analysis and possible support for "Damage Control Orthopaedic Surgery".

One hundred ninety eight adult patients who had sustained long bone fractures were treated by external fixation from admission to bone healing and consolidation. Of these, 135 had sustained high-energy injuries, 39 of them had suffered multi-system injuries. Superficial pin track infection was the most common complication, occurring predominantly in pins located in the femur, upper tibia and upper humerus. There were no cases of deep infection or osteomyelitis. One patient with a femoral shaft fracture developed a DVT although he was on preventive low molecular weight heparin, i.e. sc Clexane 40 mg daily. There were no cases of PE or ARDS. External fixation systems are a minimal invasive surgical modality, which allow three-dimensional fracture fixation after closed or minimal open reduction. They require a good command of surgical anatomy, but provide an optimal preservation of the fracture's soft tissue envelope, the critical biological factor for new bone formation and fracture healing. Recent publications have suggested that in the critically ill patient, minimally invasive fracture fixation surgery may prevent the perpetuation of a reactive, life threatening inflammatory reaction (the "second hit") which may induce the development of multiple organ dysfunction (MODS).

Evaluation of Several Approaches to Manage Meloidogyne incognita and Cotton Seedling Disease Complexes in the High Plains of Texas.

Field experiments were conducted for control of the southern root-knot nematode (Meloidogyne incognita) and cotton seedling disease fungi (primarily Thielaviopsis basicola) in one naturally infested field during 1999 and 2000 and in three additional fields in 2000. Treatments included: seed-applied fungicides (triadimenol + mefenoxam + thiram and carboxin + PCNB + mefenoxam), cultivars (Paymaster [PM] 2326 RR and PM 2200 RR), and a nematicide (aldicarb at 0.83 kg a.i/ha). Plant stands were higher (P = 0.02) in the presence of aldicarb (77% emergence) than in its absence (74% emergence). Hypocotyl disease symptom ratings were lower (P = 0.0001) following triadimenol + mefenoxam + thiram seed treatment (0.53) as compared with carboxin + PCNB + mefenoxam (0.93). Root necrosis was lower (P = 0.002) following triadimenol + mefenoxam + thiram seed treatment (27%) as compared with carboxin + PCNB + mefenoxam (34%). In one field, in both years, aldicarb was associated with more root necrosis (58%) than in its absence (46%) (P = 0.004). At three other sites aldicarb did not affect root necrosis. Population densities of Meloidogyne incognita eggs and juveniles at midseason were greater (P = 0.005, P = 0.003, respectively) on PM 2200 RR (less resistant) than on PM 2326 RR (more resistant). Yield was affected by the plant genotype by aldicarb interaction (P = 0.02) but not by seed treatments. Aldicarb effect on yield was dependent on cultivar, whereas affect of seed treatment on root health was consistent and independent of cultivar and aldicarb. No conditions were identified when use of triadimenol + mefenoxam was detrimental.

Use of an implantable marker for rapid intraoperative localization of nonpalpable tumors: a pilot study in a swine colorectal model.

BACKGROUND: This study aimed to establish the accuracy and reproducibility of localization of intraluminal markers by laparoscopic and open techniques in a swine colorectal model, using a prototype for a novel wireless system. METHODS: A prototype marker was placed into the colon of an adult pig. The surgeon was blinded to placement and localized the marker using a detection probe (3 surgeons/10 trials/2-D and 3-D systems). RESULTS: Each surgeon was able to accurately locate the marker within 28.7 +/- 20.6 (LAP) and 18.3 +/- 6.7 (OPEN) sec ( p = 0.013). There were no significant differences between surgeons in localization times, regardless of experience. A 3-D interface made no difference in accuracy or time (LAP = 35 vs 28 seconds; p = NS [not significant]). CONCLUSIONS: This study demonstrates the use of a novel system for intraoperative identification of nonpalpable lesions. This technology may have important implications in the surgical management of nonpalpable tumors and in applications of interventional radiology.

Focal levator ani eventrations: detection and characterization by magnetic resonance in patients with pelvic floor dysfunction.

The aim of this study was to assess the frequency and imaging characteristics of focal levator eventrations in patients with pelvic floor dysfunction on magnetic resonance (MRI). A review of 81 dynamic MR pelvic examinations in patients with pelvic floor dysfunction was carried out to detect and characterize focal eventrations in the levator ani muscle. These were defined as muscle outpouchings which made an angle of >180 degrees with the remainder of the muscle and had a depth of >or=1 cm. Of 81 patients 11(13.5%) had focal eventrations in the levator muscle on MRI: bilateral in 2 cases, right in 5 and left in 4. There was protrusion of pelvic viscera into the eventration in 5 cases, fat in 7 and fluid in 1. Focal levator ani muscle abnormalities are not uncommon on MRI in patients with pelvic floor dysfunction. Characterization of levator muscle morphology can be useful as a research tool in this population.

Confocal microscopy of Aspergillus fumigatus keratitis.

AIM: To use a confocal microscope to characterise the treated and untreated courses of fungal keratitis. METHODS: In the first experiment, Aspergillus fumigatus stromal keratitis was produced in both eyes of seven New Zealand white rabbits. In the second experiment, keratitis was induced in right eyes of 20 rabbits. Group 1 rabbits were treated with topical fluconazole, group 2 rabbits received oral fluconazole, and group 3 rabbits were used as controls. The rabbits were examined with a slit lamp and confocal microscope 2, 6, 10, 14, and 20 days after inoculation. The corneal cultures were taken on days 2, 14, and 20 and biopsies were taken on days 2 and 22. RESULTS: On days 14 and 22 confocal microscopy was more sensitive than culture technique in both treated and untreated animals, since not all cases of fungal keratitis can be cultured. CONCLUSION: This study indicates that confocal microscopy is a rapid and sensitive diagnostic tool for both the early diagnosis and non-invasive follow up of fungal keratitis

Relationship of Aerial Broad Band Reflectance to Meloidogyne incognita Density in Cotton.

Aerial images were obtained on 22 July 1999 and 4 August 2000 from five cotton sites infested with Meloidogyne incognita. Images contained three broad bands representing the green (500-600 nm), red (600-700 nm), and near-infrared (700-900 nm) spectrum. Soil samples were collected and assayed for nematodes in the fall at these sites. Sampling locations were identified from images, by locating the coordinates of a wide range of light intensity (measured as a digital number) for each single band, and combinations of bands. There was no single band or band combination in which reflectance consistently predicted M. incognita density. In all 10 site-year combinations, the minimum number of samples necessary to estimate M. incognita density within 25% of the population mean was greater when sampling by reflectance-based classes (3 to 4 per site) than sampling based on the entire site as one unit. Two sites were sampled at multiple times during the growing season. At these sites, there was no single time during the growing season optimal to take images for nematode sampling. Aerial infrared photography conducted during the growing season could not be used to accurately determine fall population densities of M. incognita.

Carcinoembryonic antigen (CEA) presentation and specific T cell-priming by human dendritic cells transfected with CEA-mRNA.

The feasibility of dendritic cells (DC) for cancer immunotherapy after transfection by electroporation with mRNA encoding the human carcinoembryonic antigen (CEA) was investigated. Both, total RNA from the CEA(+) colon cancer cell line SW480 and mRNA transcribed in vitro from cDNA3.1-plasmids (pcDNA3.1+/-HisC) with a CEA-insert (ivt-CEA-mRNA, ivt-CEA/HisC-mRNA) were used. Labelled ivt-CEA-mRNA was detectable in DC by light and electron microscopy and by fluorescence-activated cell-sorting (FACS) even 15 min after electroporation. Four hours after transfection with ivt-CEA/HisC-mRNA, we detected specific expression of CEA and the histidine-tag by immunofluorescence microscopy and by FACS. CEA-specific T lymphocytes were successfully primed by transfected DC and were able to lyse CEA-expressing target cells, even from the CEA-expressing human colon adenocarcinoma cell line SW480. Thus, DC transfected by electroporation with CEA-mRNA are valuable tools for the immunotherapy of CEA(+) tumour entities.