Comprehensive analysis of the clinical immuno-oncology landscape.

Advances from immuno-oncology (IO) are changing the standard of care of many types of cancer, and the paradigm of cancer treatments and drug development is being rewritten on a regular basis. Moreover, an unprecedented number of new investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape. To help the key stake holders in the field understand the latest IO landscape, we sought to present an unbiased, neutral, scientifically curated, and timely updated analysis of all the current IO agents in clinical development and the clinical trials testing these agents. We based our analyses on information collected from numerous trusted and publicly available sources. We have developed two databases. One database tracks 2004 IO agents (940 in clinical stage and 1064 in preclinical stage) against 303 targets, from 864 companies; the other tracks 3042 active clinical trials of these agents with a target enrollment of 577 076 patients. This report provides key analyses of these data. Furthermore, we will discuss a number of important and actionable trends in the current IO landscape: a large number of companies developing agents against the same IO targets; a rapid increase in the number of anti-PD-1/L1 combination studies, many of which are testing the same combinations and following inefficient patterns; and a significant increase in the number of small, investigator-initiated studies. For each of the findings, we speculate the causes and discuss a few initiatives that aim to address some of these challenges. Finally, by making these landscape analyses available, we aspire to inform the cancer community as they seek to strive for efficiencies and innovation while avoiding duplication.

Design and conduct of early clinical studies of immunotherapy agent combinations: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies task force considered aspects of the design and conduct of early studies of combinations of immunotherapy agents during their 2018 meeting. The task force defined the relevant data to justify combination clinical trials, which includes a robust hypothesis for the combination, pre-clinical data with evidence of efficacy and an understanding of the pharmacodynamics effects of each agent, and ideally evidence of single agent activity. Evaluation of pharmacodynamic biomarkers is critical in early phase combination trials, and should be incorporated into trial objectives and go/no-go decisions. The task force also identified the need to develop assessment tools and end points that capture the unique patterns of tumour responses to immunotherapy, including pseudoprogression and hyperprogression. At least one additional tumour measurement before baseline and an early CT scan (at 4 weeks for example) would help define the incidence of hyperprogression, although a common definition is needed. Finally, the task force highlighted substantial redundancy and inefficiency in the combination immunotherapy space, and recommended the adoption of innovative trial designs.

A comparative theoretical study of metal functionalized carbon nanocones and carbon nanocone sheets as potential hydrogen storage materials.

The hydrogen storage of Ti functionalized carbon nanocones and carbon nanocone sheets is investigated by using the state-of-the-art density functional theory calculations. The Ti atom prefers to bind at the hollow site of the hexagonal ring. The average adsorption energies corrected for dispersion forces are -0.54 and -0.39 eV per hydrogen molecule. With no metal clustering, the system gravimetric capacities are expected to be as large as 9.31 and 11.01 wt%. The hydrogen storage reactions are characterized in terms of simulated infrared spectra, projected densities of states, kinetics, and statistical thermodynamics. The free energies and enthalpies of the Ti functionalized carbon nanocone meet the ultimate targets of the Department of Energy for all temperatures and pressures. The closest reactions to zero free energy occur at 378.15 K/2.961 atm for carbon nanocones and 233.15 K/2.961 atm for carbon nanocone sheets. The translational component is found to exert a dominant effect on the total entropy change with temperature. More promising thermodynamics are assigned to the hydrogenation of Ti functionalized carbon nanocone sheets at 233.15 K. As the temperature is increased, the lifetimes of the hydrogen molecules adsorbed at the surface drop and the rate constants increase. At fixed pressure, the rate constants of hydrogenation of Ti functionalized carbon nanocones are smaller than those of Ti functionalized carbon nanocone sheets, while the lifetimes are greater.

Single-and double transition metal atoms anchored C2N as a high-activity catalyst for CO oxidation: A first-principles study.

The oxidation of CO has attracted great interest in recent years due to its important role in enhancing the catalyst durability in fuel cells and solving the growing environmental problems caused by CO emissions. Consequently, the catalytic oxidation of CO at double non-noble metal atoms anchored C2N is investigated using density functional theory (DFT) computations. All the screened Ti@C2N and Ti2@C2N are thermodynamically stable based on their binding energy calculations. The electronic characteristics, the natural bond orbital analyses (NBO), Frontier orbital, statistical thermodynamics, projected densities of states (PDOS) characteristics, non-covalent interactions (NCI), and quantum theory of atoms in molecules (QTAIM) descriptors of these systems have been examined to analyze the interaction process. Our comparative study suggested that the newly predicted double-atom catalyst (Ti2@C2N) is highly active for CO oxidation, which is a useful guideline for further development. The calculated static first-order hyperpolarizability (ßo) illustrated that the double-atom catalyst under investigation can be considered a potential candidate for non-linear optical behavior and could be used for NLO applications. CO oxidation on Ti2@C2N along the Eley-Rideal (ER) mechanism with a low energy barrier of 0.16 eV, which is smaller than the maximum energy barrier (0.73 eV) of CO oxidation along the Langmuir-Hinshelwood (LH) mechanism. Consequently, the ER mechanism is more favorable both thermodynamically and dynamically. This work can provide useful insights and guidelines for future theoretical and experimental investigations to promote the design and development of highly effective and low-cost non-precious-metal Ti2@C2N nanocatalysts towards CO oxidation at ambient temperature.

DFT study of adsorbing SO2, NO2, and NH3 gases based on pristine and carbon-doped Al24N24 nanocages.

The adsorption of SO2, NO2, and NH3 toxic gases on Al24N24 and Al24N23C nanocages was investigated by using density functional theory (DFT) calculations. The adsorption energies, frontier orbitals, charge transfer using natural bonding orbital (NBO) analysis, dipole moment, the partial density of states (PDOS), thermodynamic relationships, non-covalent interaction (NCI), and quantum theory of atoms in molecules (QTAIM) were considered. The results reveal that carbon-doped Al24N24 nanocage increases the adsorption energies for SO2 and NO2 gases while decreasing the adsorption energy of NH3 gas. The ΔG for all configurations were negative except the configurations A1 and G2 confirming the weak adsorption of these two complexes. In conclusion, Al24N24 and Al24N23C nanocages are in general promising adsorbents for the removal of SO2, NO2, and NH3 toxic gases. The Al24N24 and Al24N23C nanocages are ideal electronic materials.

B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells.

Dendritic cells (DCs), unique antigen-presenting cells (APCs) with potent T cell stimulatory capacity, direct the activation and differentiation of T cells by providing costimulatory signals. As such, they are critical regulators of both natural and vaccine-induced immune responses. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified among a library of genes differentially expressed between DCs and activated macrophages. B7-DC fails to bind the B7.1/2 receptors CD28 and cytotoxic T lymphocyte-associated antigen (CTLA)-4, but does bind PD-1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than B7.1 and induces a distinct pattern of lymphokine secretion. In particular, B7-DC strongly costimulates interferon gamma but not interleukin (IL)-4 or IL-10 production from isolated naive T cells. These properties of B7-DC may account for some of the unique activity of DCs, such as their ability to initiate potent T helper cell type 1 responses.

Hepatic steatosis is highly prevalent across the paediatric age spectrum, including in pre-school age children.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children is 8% in the general population, and 34% in the context of obesity. There is a paucity of data on the prevalence of hepatic steatosis in healthy children in Ontario. AIMS: To determine the prevalence of hepatic steatosis using abdominal computed tomography (CT) scans in a cohort of previously healthy children across the paediatric age spectrum in Ontario, Canada, and to determine any association between measures of abdominal adiposity and hepatic steatosis. METHODS: Retrospective review of the SickKids Trauma Database from 2004-2015. Previously healthy children ages 1-17 years having undergone an abdominal CT scan as a part of routine trauma assessment were included, and those with an intra-abdominal injury excluded. Steatosis was defined as a difference between liver and spleen attenuation ≤-25HU. The percentage of the total area occupied by abdominal subcutaneous adipose and visceral adipose tissue was measured. Anthropometrics and baseline demographics were collected. RESULTS: A total of 503 (51% male) children with mean (±SD) age 9.5 ± 4.5 years and weight z-score of 0.37 ± 1.05 were studied. Seventy-seven (15%, 95% CI [12%-18%]) had hepatic steatosis; no differences found between sexes or across age quartiles. The abdominal subcutaneous adipose tissue area was greater in those with hepatic steatosis compared to those without (32% [22-42] vs 24% [17-36], P = 0.003). The visceral adipose tissue area was significantly greater in older children ≥9.8 years with hepatic steatosis (7.7% [5.1-10] vs 6.6% (4.9-8.5), P = 0.04). CONCLUSION: Hepatic steatosis was highly prevalent in previously healthy children in Ontario, including children of pre-school age. We found an association between hepatic steatosis and abdominal subcutaneous adipose tissue, and in older children with visceral adipose tissue.

Measurement of mycophenolate mofetil effect in transplant recipients.

BACKGROUND: Immunosuppression involves the nature of the immunosuppressive agents and individual differences in patient factors. We investigated whether the effect of mycophenolate mofetil (MMF) is measurable using an in vitro measure of immunocompetence and related its effects to cyclosporine (CsA) in vitro. METHODS: Liver or kidney transplant recipients receiving prednisone; CsA or tacrolimus; and MMF, azathioprine (AZA), or neither, were studied. Immunocompetence was assessed by one-way mixed lymphocyte culture using patients' peripheral blood leukocytes (PBL) and three validated stimulators. The effect of immunosuppressive agents added in vitro on normal PBL stimulation by Staphylococcus enterotoxin B was determined by the carboxyfluorescein diacetate succinimidyl ester measurement of division. RESULTS: Patients receiving MMF had an average immunocompetence level of 12+/-23, compared with 39.7+/-65 and 25.5+/-42 for those receiving AZA or neither AZA nor MMF, respectively. Thus, there was an approximately 80% suppression of the response in the MMF group. Assessment of normal cell division revealed that CsA allowed multiple cell generations but suppressed the numbers of cells in each, whereas MMF blocked proliferation into subsequent generations. Addition of clinically relevant levels of mycophenolic acid, the active agent for MMF, added to more moderate levels of CsA, was required to achieve greater than 80% suppression, consistent with the degree of immunocompetence depression measured in patients. CONCLUSIONS: These data provide the novel finding that the effect of MMF treatment on patients is measurable in their PBL as decreased immunocompetence in vitro. The effect of MMF on normal PBL approximates the 80% inhibition that we found in patients. Moreover, the effect of MMF on cell division provides a rationale for the superior effectiveness of regimens including MMF.

An outbreak of Crimean-Congo hemorrhagic fever in the United Arab Emirates, 1994-1995.

A multi-faceted investigation was conducted in the United Arab Emirates to characterize the epidemiologic and ecologic factors underlying an outbreak of Crimean-Congo hemorrhagic fever (CCHF) noted in November 1994 among abattoir workers. A chart review was conducted among hospitalized suspected cases of viral hemorrhagic fever with onset between January 1994 and March 1995 coupled with serologic testing of available specimens for the presence of virus antigen and IgG and IgM antibodies by ELISA. Livestock handlers and animal skin processors were interviewed and tested for the presence of IgG antibody. Sera from imported and domestic ruminants were examined for antibody for CCHF virus, and ticks collected from these animals were tested with an antigen-capture ELISA. Thirty-five suspected cases of CCHF were identified (case fatality = 62%). Livestock market employees, abattoir workers, and animal skin processors accounted for 16 (57%) of 28 cases with known occupational status. Serologic evidence of past asymptomatic infection was noted in 12 (4%) of 291 livestock and abattoir workers but in none of the controls. Nineteen (7%) of 268 animals were positive for CCHF virus antibodies by ELISA including 12 ruminants from Somalia and Iran and five indigenous camels. One Hyalomma impeltatum and two H. excavatum from Somali cattle and one H. anatolicum from a Somali goat were positive for CCHF virus antigen.

Status of imported malaria in a control zone of the United Arab Emirates bordering an area of unstable malaria.

A concerted malaria eradication programme in the United Arab Emirates has reduced local transmission to only a very few small foci in the country. The Al Ain district is now a consolidation zone. However, transmission across the undemarcated border with Oman continues. Malaria imported by the large immigrant work force from major disease endemic areas remains a large burden. An added threat is the appearance of chloroquine-resistant Plasmodium falciparum principally from Sudan and Pakistan but increasingly amongst Omani cases seen in the hospitals and clinics in Al Ain. The implications of re-introduction of malaria and the establishment of chloroquine resistance, particularly for non-immune residents and visitors, are emphasized.

PIP: In Al Ain District located in the Abu Dhabi Emirate of the United Arab Emirates (UAE), clinicians at the Al Ain General Hospital outpatient clinic conduct a medical examination of and take blood samples from all new immigrants applying for resident or work permits. All persons with malaria receive 600 mg chloroquine phosphate at the clinic (day 0) and a prescription for another 600 mg for day 1 and 300 mg on day 2. The malaria cases are to return to the clinic on day 3. Entomologists record mosquito larval counts at all field sides and conduct susceptibility tests in the laboratory. The malaria control program applies a larvicide on breeding sites and uses pyrethroids to eliminate adult flying insects. In 1981, local transmission of malaria ceased. During 1988-1991, 4.7-9.1% of the population was slide-positive for malaria. This incidence rate is high enough to introduce imported malaria into the local anopheline mosquito population, should malaria control activities be reduced. Pakistanis, UAE nationals, and Omanis comprise most malaria cases (36.3-56.6%, 12.8-21.9%, and 15.7-25.3%, respectively). The immigrants tend to visit their home countries, where they acquire malaria. All UAE nationals acquire it while on holiday in or traveling to endemic areas, especially Oman. In 1991, out of 1150 cases, the leading sources of malaria were clearly Pakistan (576) and Oman (526). Most slide-positive children are either Omanis or part of UAE families with relatives across the border in Oman. Plasmodium falciparum, mostly from Pakistan and Oman, is responsible for 69.5% of malaria cases. The Indian subcontinent is the source of most P. vivax cases. Beginning in 1987, the number of chloroquine-resistant P. falciparum cases increased from 9 to 302. The leading sources of resistant cases originate from Oman (160), Pakistan (100), and Sudan (26). All chloroquine-resistant cases except one responded to Fansidar. Factors that may disturb effective malaria control efforts in this new agriculture area are rapid development of water resources and the undemarcated border with Oman.

Tendon injury and repair after core biopsies in chronic Achilles tendinosis evaluated by serial magnetic resonance imaging.

OBJECTIVE: To evaluate the morphological response and healing process after transverse ultrasound guided core biopsies in chronic Achilles tendinosis using serial magnetic resonance imaging (MRI) over a period of one year. METHODS: The study included 10 patients. Six had five transverse core biopsies and were longitudinally evaluated by MRI before the biopsies and then after one week, three months, seven months, and one year. These patients started a three month eccentric training programme one to two weeks after the biopsy. Four "non-biopsied" and untreated patients were used for comparison. The clinical outcome was categorised according to the level of pain and performance. RESULTS: The MRI one week after the biopsies showed an increase in tendon volume (T1-WI) and mean signal intensity (PD-WI) of 29% and 30% (p = 0.04). During follow up, tendon volume and mean signal intensity gradually decreased. One year after the biopsy, the tendon volume had decreased by 20% and the intratendinous signal by 28% compared with the index MRI (p = 0.04). The untreated patients showed an increase in both tendon volume (39%, p = 0.06) and intratendinous signal (37%, p = 0.14) at the one year follow up. After one year, pain and performance had improved in the treated patients but not the untreated patients. CONCLUSION: Five transverse ultrasound guided core biopsies induced a lesion in the diseased Achilles tendon. Alterations during healing such as tendon size and intratendinous signal intensity could be evaluated by MRI. The tendon alterations had decreased one year after the core biopsies.

Semitendinosus muscle in anterior cruciate ligament surgery: Morphology and function.

PURPOSE: To evaluate the fate of the hamstring muscles in general and the semitendinosus muscle in particular, after anterior cruciate ligament (ACL) reconstruction with an autologous semitendinosus tendon graft from the ipsilateral side. TYPE OF STUDY: Prospective consecutive case series investigation. METHODS: Included were 16 consecutive patients, 14 male and 2 female, with a mean age of 26 years. The inclusion criterion was chronic unilateral ACL insufficiency with no concomitant knee ligament injuries. ACL reconstruction was performed with a quadruple semitendinosus tendon graft using the EndoButton technique (Acufex, Mansfield, MA). Intraoperatively, muscle specimens were taken from the semitendinosus muscle on the harvested side. Follow-up at a minimum of 6 months included clinical examination, isokinetic strength performance, magnetic resonance imaging (MRI) of the thigh and knee, and ultrasound-guided muscle biopsy procurement from the semitendinosus muscle for histochemical and enzymatic analyses. RESULTS: Of the patients, 75% showed regeneration of their semitendinosus tendons. The neotendons all inserted below the knee joint where they had fused with the gracilis tendon to a conjoined tendon inserting in the pes anserinus. The semitendinosus muscle had a smaller cross-sectional area on the operated side but none showed total atrophy. Less atrophy was present in the patients with a regenerated semitendinosus neotendon compared with those without regeneration (P =.029). In the latter group the semimembranosus muscle seemed to compensate for this with hypertrophy (P =.019). Cross-sectional muscle fiber areas, the relative number of each fiber type and oxidative potential as estimated by citrate synthase activity, showed no significant differences between the operated and nonoperated legs. The isokinetic strength of the hamstrings and quadriceps was significantly lower in the operated leg than in the nonoperated leg. CONCLUSIONS: With this surgical technique, the semitendinosus muscle can recover and the tendon has, according to the MRI images, a great potential to regenerate after its removal.

Intratendinous alterations as imaged by ultrasound and contrast medium-enhanced magnetic resonance in chronic achillodynia.

OBJECTIVES: We performed a comparative study of ultrasonography and gadolinium imaging contrast-enhanced T1-weighted magnetic resonance to evaluate tendon pathology in chronic Achilles tendon disorder. Another main issue was to evaluate the structural basis as defined by histopathology from hypoechoic compared with normoechoic areas within the same tendon. MATERIALS AND METHODS: Twenty patients (16 male, 4 females, median age 40 years) with chronic achillodynia participated in the study. Clinical examination revealed swelling and tenderness localized to the midportion of the Achilles tendon. Contrast medium-enhanced magnetic resonance imaging (CME-MRI) was performed in all patients. Ultrasonography-guided core biopsies were taken from regions with a clear widening of the tendon and a pathologic low-echo signal as well as from normoechoic areas. The specimens were analyzed with a standardized protocol giving a total tendon score (0-24), and a stereologic method for quantification of glycosaminoglycan (GAG)-rich areas. RESULTS: The volume of the intratendinous abnormality was larger in 13 of 20 when imaged by CME-MR (P < 0.05), whereas the shape and enlargement of the tendon per se were similarly imaged by ultrasound (US) and CME-MR. Tendon pathology as imaged by US was graded as severe from hypoechoic regions and moderate from normoechoic regions. The corresponding quantification of GAGs was 0.36 compared with 0.17, respectively (P < 0.001). CONCLUSION: CME-MR imaging revealed greater sensitivity in demonstrating intratendinous pathology than the ultrasound; this was documented by the larger size of the corresponding lesion and the fact that the pathology was occurring in areas that were considered normal by ultrasonography. US hypoechoic areas showed a markedly abnormal tendon structure including an increased amount of GAG-rich areas. However, moderate pathology was also found in the neighboring normoechogenous areas within the same tendon, indicating a more generalized disorder than depicted by echogenic properties.

Spectral studies and molecular orbital PPP-calculations of some azo-dyes.

The UV, IR and 1H-NMR spectra of some 4-(R-phenyl azo) 1-hydroxy 2-naphthoic acid derivatives are studied. The effects of substituent groups and the solvent polarity on electronic spectral, IR bands and 1H-NMR proton chemical shifts are considered, the molecular orbital calculations obtained are rationalized quantitatively with that obtained practically using the PPP-model with configuration interaction (CI).

Effect of previous chloroquine intake on in vivo P. falciparum drug sensitivity.

Investigation of the in vivo response of P. falciparum malaria parasites to chloroquine was conducted during 1993/94 in Al-Ain District of Abu Dhabi Emirate, UAE. Sixty seven expatriates who developed falciparum malaria on their return from Pakistan, Oman and Sudan were recruited for the WHO in vivo tests. Of the 67 patients, eight were classified as having RII and RIII responses, while 59 remained aparasitaemic at the end of the seven-day WHO standard test. On continuation into the 28-day WHO extended test, a further 34 patients exhibited RI resistance. Resistance of parasites to chloroquine was confirmed by measurement of plasma chloroquine using High-Performance Liquid Chromatography. In all 67 patients, the level of chloroquine was well above the minimum therapeutic level. The outcome of the in vivo test in patients treated for the first time was significantly different from that in patients who were previously on chloroquine. Among patients treated for the first time, 36 out of 41 (88%) had a resistant response, whereas, among those previously on chloroquine only six out of 26 (23%) had a resistant response. The difference is probably due to the higher initial plasma level of chloroquine among patients who were previously on the drug. Curing more patients with higher plasma chloroquine implies that chloroquine shall continue to be useful, particularly if resistance is at the RI level. Appropriate higher therapeutic levels of chloroquine should be defined for such patients.

Prevalence of intestinal parasites among expatriated workers in Al-Ain, United Arab Emirates.

A retrospective study was conducted among expatriate workers in Al-Ain City, United Arab Emirates (UAE), to determine the prevalence of pathogenic parasitic infestation. The study was based largely on expatriates arriving from India, Pakistan, Bangladesh, Iran, Philippines, Sri Lanka, and other Arab countries and mainly employed as food handlers, housemaids, baby sitters, and private drivers. This group represents 45.7% of the total number of new arrivals of expatriates during the period between 1 January 1985-31 December 1988. Stool specimens were examined in 60,268 screened individuals, of which 14,010 were found to be positive with pathogenic intestinal parasitic disease. Overall parasitic prevalence was 23.1%. The most common parasites found included: Ancylostoma (2.4%), Ascaris lumbricoides (6.6%), Trichuris trichiura (6.2%), and Giardia lamblia (2.4%). The distribution of intestinal parasites among expatriates was different for all nationalities. The results showed that Giardia lamblia was more prevalent among Iranians (54.7%) and Pakistanis (42.2%). Ancylostome species was found to be more prevalent among Sri Lankans (33.3%) and Indians (39.6%). Ascaris lumbricoides was more prevalent among Bangladeshis (33.1%), and Trichuris trichiura was more prevalent among Filipinos (40.2%).

Role of cationic size in the optical properties of the LiCl crystal surface: theoretical study.

The size of the cations (either Ca(2+), Sr(2+), Ga(+), or Au(+)) at the F(A1)-type color centers on the (100) surface of LiCl crystal plays an important role in the optical properties of this surface. In this work, double-well potentials at this surface were investigated using ab initio quantum mechanical methods. Quantum clusters were embedded in simulated Coulomb fields that closely approximate the Madelung fields of the host surface, and the ions that were the nearest neighbors to the F(A1) site were allowed to relax to equilibrium. The calculated Stokes-shifted optical transition bands, optical-optical conversion efficiency, and relaxed excited states of the defect-containing surface, as well as the orientational destruction of the color centers, recording sensitivity, exciton (energy) transfer, and the Glasner-Tompkins empirical relation were all found to be sensitive to the size of the dopant cation.