Overall survival from tebentafusp versus nivolumab plus ipilimumab in first-line metastatic uveal melanoma: a propensity score-weighted analysis.

BACKGROUND: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.

Two Novel Avian Influenza Virus Subtypes Isolated from Domestic Ducks in North of Iran.

Avian Influenza Viruses (AIV) are the causative agents of Avian Influenza (AI), which is a contagious and zoonotic disease in birds. Among birds, wild waterfowls and ducks are the primary and natural reservoirs of low pathogenic avian influenza viruses (LPAI). This study aimed to identify and differentiate between two AIV subtypes (i.e., hemagglutinin and neuraminidase from domestic ducks by hemagglutinin inhibition (HI) and neuraminidase inhibition (NI) assays. To this end, 962 cloacal swabs were collected from domestic ducks being sold at different Iranian Live Bird Markets in Gilan, Mazandaran, and Golestan provinces, located at the southern coast of the Caspian Sea. The samples were inoculated in 10-day-old embryonated specific pathogen-free chicken eggs, and subsequently, harvested allantoic fluids were subjected to agar gel immunodiffusion, HI, and NI assays. In total, five positive samples, including two H4N2 and three H3N2 AIV subtypes were identified. Isolation of H4N2 and H3N2 viruses has never been reported from Iranian domestic ducks previously. This finding further suggests the diversity of LPAI viruses in Iranian ducks and also shows that the HI and NI assays are highly efficient in determining AIV subtypes.

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Deciphering radiological stable disease to immune checkpoint inhibitors.

BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

Report of a new meq gene size: The first study on genetic characterisation of Marek's disease viruses circulating in Iranian commercial layer and backyard chicken.

1. In recent months, several outbreaks with clinical signs of MDV-1 were reported in Iranian parent and laying hen farms, in addition to backyard chickens. Several meq gene sequences from these outbreaks were amplified and molecularly characterised.2. The meq protein sequences revealed three different sizes, namely the standard 339 aa, a shorter form of 338 aa lacking a proline residue at position 191, and a very short (vs) size of 265 aa. Based on sequence and size, the 265 aa meq has never been reported from international research groups before. The protein has only one PPPP repeat motif suggesting it belongs to a highly virulent strain.3. The standard meq sequences showed 100% BLAST identity to the vv+ isolate Polen5. However, the 338 aa form clustered to the clade usually reported from North America.4. This is the first report on genetic analysis of MDV-1 from Iran, but further study is required to obtain a better picture of the diversity and prevalence of different MDV-1 strains circulating in the country's farms, backyard poultry and other bird species.

Outbreak Investigation of Officially Reported and Highly Pathogenic Avian Influenza (H5N8 Subtype) in Iran During 2016.

On 14 November 2016, an outbreak of highly pathogenic avian influenza (HPA) was reported from a commercial layer farm located in Malard, Tehran Province, Iran. This study aimed to investigate the HPAI H5N8 outbreaks in Iran. The questionnaire was prepared and completed through interviews with farm owners or field observations at the time of disease onset from November 2016 to February 2017. The HPAI H5N8 infection was confirmed in 30 different locations including 10 villages (33.3%), nine-layer farms (33%), two broiler breeder farms (6.67%), one layer breeder farm (3.3%), one turkey farm (3.3%), one partridge farm (3.3%), five national parks (16.7%), and one wetland (3.3%) in 12 provinces of Iran. The cumulative incidence rates of disease in villages, layer farms, broiler breeder farms, layer breeder farms, partridge farms, and turkey farms were 0.02%, 0.87%, 0.55%, 6.25%, 7.14%, and 0.69%, respectively. The findings reflect that among the investigated variables at infected locations, new birds entering the home in villages, live bird markets, inappropriate biosecurity conditions, transporting manure during the breeding period, close proximity of a common road to infected farms, and poultry movement inside (pullet) and outside were the most frequently observed possible risk factors for these outbreaks. In conclusion, attention should be focused on the study of the dynamics and movements of domestic poultry, investigation and modification of the structure of industrial poultry farms, training for all related people, enhancement of passive surveillance, an increase in biosecurity, raising the awareness of the authorities on the importance of the infection, and provision of the required credits and facilities.

In the soft grip of nature.

Biological grippers can inspire the development of a new class of versatile soft grippers in agrorobotics and beyond.

Investigation of Avian Influenza Viruses (H9N2-H5nx) in Pigeons during Highly Pathogenic Avian Influenza Outbreaks in Iran, in 2016.

Avian influenza (AI) virus (H9N2 and H5 subtypes) infections in birds cause major concerns around the world. The majority of the avian species, such as domestic, pet, and wild birds, are natural and experimental hosts of avian influenza viruses. There are global concerns about members of the Columbidae family, namely pigeons or doves, for their role as the potential interspecies bridge in influenza A viruses ecology. The acquired scientific data in this regard is still not clear since there are doubts about whether or not they transmit viruses between susceptible populations, and spread viruses among farms during outbreaks. To monitor H5 and H9 influenza virus infection status in the rural, backyard, and domestic birds, an annual active surveillance program was performed from September to October 2016. In December 2016, an outbreak of highly pathogenic avian influenza (HPAI) virus subtype H5N8 was detected in a layer farm in Tehran province, Iran. The present research was conducted to study H9N2 or H5 infections in pigeons within HPAI H5N8 2016 outbreaks and annual national AI surveillance in Iran. For this purpose, cloacal swabs and tissue samples (trachea, lung, brain, liver, heart, pancreas, and cecal tonsil) were collected and examined by real-time reverse transcription-polymerase chain reaction (RT-PCR) method and virus isolation. Results of the tests performed on the swab and tissue samples were negative for H5 nor H9N2 viruses. The samples in real-time RT-PCR that after three passages still showed negative results in HA and molecular tests were considered negative. Moreover, the Newcastle disease virus was isolated in most of the samples taken from dead pigeons, after inoculation in embryonated chicken eggs.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Effectiveness of Thermostable Vaccine for Newcastle Disease Produced by the Razi Institute on Backyard Poultry in Iran during 2015.

Newcastle disease causes many economic losses to the poultry industry in most countries. This disease is endemic in Iran. Backyard poultry is considered the reservoir of Newcastle virus; however, there is either no vaccination program against Newcastle, or it is performed in a restricted manner. Commercial live vaccines are inactive and sensitive to temperature; moreover, vaccine delivery to villages and remote areas requires special equipment and high cost to maintain the cold chain. This study evaluated the effectiveness of a thermostable Newcastle vaccine produced by the Razi Institute (ND.TR.IR) on the backyard poultry. In four provinces, at least 4 villages were selected as the treatment group, and the same number was selected as the control group. At least, 30 birds were sampled in each village. In each group, blood samples were collected before vaccination and 2 weeks later, and the serum titer of the samples was examined with the haemagglutination inhibition test. The arithmetic mean and standard deviation of the sample titers at the rural level were compared using paired t-test before and after vaccination in each group. Moreover, Repeated Measures ANOVA was utilized to compare the vaccinated and control groups in terms of the titer changes before and after vaccination. In this study, 584 and 389 samples were taken from the treatment (53 households in 20 villages) and control groups (33 households in 14 villages). The mean serum titer values of Newcastle were 4.51&plusmn;3.03 and 6.64&plusmn;2.48 in the treatment group before and after vaccination, respectively (P&lt;0.001). The increase in mean titer of the treatment group (2.31 log) was statistically higher than that in the control group (0.66 log) (P&lt;0.001). Out of 584 birds, 517 (88.5%) ones had titer above 3 in the second turn in the treatment group. The thermostable vaccine (ND.TR.IR) produced by the Razi institute is suitable for backyard poultry, which immunizes them against Newcastle disease. Appropriate vaccination programs for backyard poultry should be made; moreover, vaccination of backyard poultry can be effective in preventing the circulation of the field viruses.

Trend of Changes in the Titer of Antibody against Avian Influenza Virus H9n2 during Raising Period in Vaccinated and Unvaccinated Broiler Farms in Qazvin Province, Iran: A Cohort Study.

Avian influenza virus (AIV) H9N2 is endemic in Iran and its large-scale circulation in the poultry industry of the country is devastating. This virus was first reported in the industrial poultry populations of Iran in July 1998. Some of the published studies showed that inactivated avian influenza (AI) vaccines are capable of inducing an immune response and providing protection against morbidity and mortality in different countries (Vasfi et al., 2002; Tavakkoli et al., 2011). Low pathogenicity avian influenza subtype H9N2 virus has been reported to have a zoonotic potential and widespread distribution in Iran. Therefore, water-in-oil emulsion vaccines are employed to control the disease in chickens (Nili and Asasi, 2003). This cohort study was conducted during July 2016-November 2017 in broiler chicken farms of Qazvin province, Iran to investigate the serological change trends in broiler chickens in this region. Level of immunity against the H9N2 virus was evaluated by hemagglutination inhibition assay. Fifteen farms out of thirty enrolled units used AI H9N2 killed vaccines. The minimum of mean antibody titers (MATs) was 4.54-2.42 and the maximum of MATs was 4.54+2.42 on day 3. In addition, the minimum and maximum MATs on day 50 were 0.4-0.64 and 0.4+0.064, respectively. The transfer rate of H9N2 AIV antibodies from the serum of breeders to the serum of chickens was calculated as 60.35% in our study. A significant difference was revealed between the maternal mean antibody titers (MMATs) and the MATs on day 3 (P&lt;0.001). In addition, the difference between the MATs on day 3 and the MATs on day 10 was found to be significant (P&lt;0.01). Moreover, MATs were significantly different between the vaccinated and unvaccinated herds on day 40 (P&lt;0.05), while no significant difference was observed on days 3, 10, 20, and 30 (P&gt;0.05). According to the results of this study, antibody titers in the vaccinated farms did not reach the protective level until the end of the rearing period. Most of the unvaccinated herds experienced a spurt in antibody titers due to exposure to the virus. Consequently, biosecurity measures must be implemented more seriously and strictly in broiler farms.

Development and Evaluation of Real-Time Reverse Transcription Polymerase Chain Reaction Test for Quantitative and Qualitative Recognition of H5 Subtype of Avian Influenza Viruses.

Avian influenza viruses (AIV) affect a wide range of birds and mammals, cause severe economic damage to the poultry industry, and pose a serious threat to humans. Highly pathogenic avian influenza viruses (HPAI) H5N1 were first identified in Southeast Asia in 1996 and spread to four continents over the following years. The viruses have caused high mortality in chickens and various bird species and deadly infections in humans. Multiple conventional methods have been so far introduced for the detection and identification of avian influenza viruses. Traditional virus isolation methods are gold standard protocol in AI detection; nonetheless, virus isolation in embryonating chicken eggs (ECE) is not a rapid method for the detection of influenza viruses since it is time-consuming and labor-intensive. Furthermore, the isolation of highly pathogenic viruses, such as H5, needs BSL3 laboratories. Real-Time Reverse Transcription-Polymerase Chain Reaction (RRT-PCR) is a sensitive and specific method for the detection of influenza viruses. The application of these nucleic acid-based techniques has increased our ability to identify and perform influenza virus care programs, especially in surveillance programs. The current study aimed to detect H5 subtype of avian influenza (AI) virus using fast, specific, and sensitive TaqMan RRT-PCR. Notably, single step RRT-PCR was used to prevent possible laboratory contamination. The specificity of this test was evaluated using nucleic acid extracted from several poultry pathogenic microorganisms and negative clinical specimens from AI-uninfected birds. The sensitivity analysis of the RRT-PCR assay was performed using in vitro-transcribed RNA copy and 10-fold serial dilution of standard AI virus with specific titer. The results indicated the high sensitivity of this method and the lowest detectable dilution of this method based on RNA copies and 1:10 serial dilutions of the standard virus was 10 1.9 EID50 /100.

Seroprevalence Investigation of Newcastle Disease in Rural Poultries of the Northern Provinces (Golestan, Gilan, and Mazandaran) of Iran.

Rural poultry farming is common in the Northern provinces. Similar to commercial poultry, rural poultry is susceptible to most infectious diseases. In addition, by increasing the density of poultry farming, the probability of disease incidences has been increased. Newcastle disease is the most highly infectious disease which is endemic in Iran and causes outbreaks among commercial and rural poultry every year. The present study aimed to investigate the prevalence and virus circulation of Newcastle disease among rural poultry in Northern provinces of Iran. In the current study, 70 villages in 3 provinces (20, 30, and 20 villages in Mazandaran, Golestan, and Gilan, respectively) and a total of 1,374 birds (600, 400, and 374 birds in Mazandaran, Golestan, and Gilan, respectively) were sampled. Each village was regarded as an epidemiological unit. In the present study, birds of 67 (96%) villages were positive (presence of antibodies against Newcastle disease virus), including 28 (93.3%), 19 (95%), and 20 (100%) villages in Golestan, Mazandaran, and Gilan, respectively. Moreover, out of 1,374 birds, 616 (45%) of them were seropositive against Newcastle disease virus with 242 (41%), 159 (39.8%), and 211 (56%) samples in Mazandaran, Golestan, and Gilan, respectively. According to the results of the current study, the seroprevalence rate was reported to be high in both villages and birds. Such a high seroprevalence rate was indicative of the continuous exposure of the rural poultry to Newcastle virus and high virus circulation rate in the mentioned provinces which could result in the dissemination of the disease to commercial farms. Consequently, the implementation of proper control and care programs (e.g., vaccination of native poultry) can facilitate the reduction of Newcastle disease prevalence.

Development and Evaluation of Real-Time RT-PCR Test for Quantitative and Qualitative Recognition of Current H9N2 Subtype Avian Influenza Viruses in Iran.

Avian influenza H9N2 subtype viruses have had a great impact on Iranian industrial poultry production economy since introduction in the country. To approach Rapid and precise identification of this viruses as control measures in poultry industry, a real time probe base assay was developed to directly detect a specific influenza virus of H9N2 subtype -instead of general detection of Influenza A viruses- which has been endemic over two last decades in the country. An Iranian avian influenza virus strain of A/Iran/chicken/772/1998 H9N2 subtype were selected as reference strain for of primers and probe designing. The high agreement value of 99% indicated that the devolved real time assay for detection of H9 subtype viruses could easily replace the conventional method of virus isolation particularly in investigation of viruses like national surveillance plan. The limit of detection was almost one EID50 which was the least real infectious unit could be detected. So it can be said that this sensitive assay provided a powerful tool to not to miss any significant viral biological activity neither in the host body nor in the environment. A high level of correlation coefficient (R2 = 0.998) also indicated a good correlation between Ct values and viral concentrations. , it can be conclude that the real time RT-PCR could be easily replace virus isolation in detection of H9N2 influenza viruses especially in large monitoring program. The ability in quantifying of the virus concentration extends usage of test in more accurate studies.

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results: Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

The Characteristics of an Ovine Lymphoid Cell-Line sensitive to Vaccinal Infectious Bursal Disease Virus Strain.

Infectious bursal disease (IBD), also known as Gumboro disease, is a globally well-known disease with a significant socio-economic effect. For control of IBD, several commercial egg- and cell-based vaccines are prepared. The cell-based IBD vaccines are significantly cost-effective; however, it is essential to confirm their safety and efficacy. The main cell line used to product the cell-based IBD vaccines, is a primary chicken embryo fibroblast (CEF). Nevertheless, manipulation of CEF is extremely challenging and time-consuming. This study aimed to characterize a sensitive suspension cell culture from ovine lymphoid, according to WHO technical report series; No. 978, Annex III. This authentication covered the growth curves, sensitivity, stability, karyotyping and identifying the adventitious agents. This cell line passed all defined tests and was considered as a suitable one for IBD vaccine preparation in a large scale.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Overall Survival and Response to Systemic Therapy in Metastatic Extrauterine Leiomyosarcoma.

Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy. Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1. Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) in N = 113 was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26-0.79, p = 0.005). Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites.

Histology and ultrastructure of the developing superficial digital flexor tendon in rabbits.

This study was designed to investigate the developmental changes in the superficial digital flexor tendon (SDFT) of the white New Zealand rabbit, from 5 to 7 days pre-natal to 112 days post-natal (PN), at histological and ultrastructural levels. The tendons changed from being highly cellular with 13079 +/- 2538 cell/mm(2) and little directional organization to a longitudinally oriented, predominantly connective tissue structure with relatively few, mature tenocytes (2384 +/- 365 cell/mm(2)). Fibrillogenesis was seen in isolated vacuoles of fibroblast cytoplasm during fetal life as well as after birth, but less frequently with increasing age. At the ultrastructural level, there was a progressive increase in the mean diameter of collagen fibrils with age throughout the population, until PN day 28. A bimodal distribution of collagen fibril size was first observed on PN day 56 while at day 112, the fibrils were fully differentiated and showed a multimodal size distribution. The development of elastic fibres preceded that of collagen fibres and accompanied progressively more marked sinusoidal crimping in collagen fibres on PN days 7 and 14. The tendons of older animals became less tightly crimped. The cells of the epi- and endotenon were less mature and relatively undifferentiated compared with the cells in the body of the tendon of the same age, which might explain their ability to initiate healing of tendon injuries in older animals. In conclusion, extensive changes were observed in tendons during growth and maturation, with diameters of collagen fibrils, tissue orientation and cellularity being the parameters affected, probably due largely to increased physical activity.