Takeda (Italy)

Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments. Methods We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)-stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS). Results Of 1,950 randomly assigned patients, 1,925 received an ePET-361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. Conclusion In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.

INTRODUCTION: The incidence and mortality of lung cancer are highest in Asia compared with Europe and USA, with the incidence and mortality rates being 34.4 and 28.1 per 100,000 respectively in East Asia. Diagnosing lung cancer at early stages makes the disease amenable to curative treatment and reduces mortality. In some areas in Asia, limited availability of robust diagnostic tools and treatment modalities, along with variations in specific health care investment and policies, make it necessary to have a more specific approach for screening, early detection, diagnosis, and treatment of patients with lung cancer in Asia compared with the West. METHOD: A group of 19 advisors across different specialties from 11 Asian countries, met on a virtual Steering Committee meeting, to discuss and recommend the most affordable and accessible lung cancer screening modalities and their implementation, for the Asian population. RESULTS: Significant risk factors identified for lung cancer in smokers in Asia include age 50 to 75 years and smoking history of more than or equal to 20 pack-years. Family history is the most common risk factor for nonsmokers. Low-dose computed tomography screening is recommended once a year for patients with screening-detected abnormality and persistent exposure to risk factors. However, for high-risk heavy smokers and nonsmokers with risk factors, reassessment scans are recommended at an initial interval of 6 to 12 months with subsequent lengthening of reassessment intervals, and it should be stopped in patients more than 80 years of age or are unable or unwilling to undergo curative treatment. CONCLUSIONS: Asian countries face several challenges in implementing low-dose computed tomography screening, such as economic limitations, lack of efforts for early detection, and lack of specific government programs. Various strategies are suggested to overcome these challenges in Asia.

8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10 -5 ) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (<18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]

OBJECTIVE: Circulating adhesion molecules may have a prognostic significance as markers of endothelial damage. Drugs which inhibit the renin-angiotensin system may be effective in reducing circulating or tissue adhesion molecules, albeit data available are scarce. The aim of the study was to investigate the effects of an angiotensin-converting enzyme (ACE) inhibitor, enalapril and a highly selective angiotensin receptor blocker, candesartan cilexetil, on circulating adhesion molecules in a large sample of patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was comparative, multicenter, randomized and double blind, with two parallel groups. PATIENTS AND METHODS: NIDDM patients with a diagnosis of mild (grade 1) essential hypertension were included in the study, at the end of a 2-week placebo run-in period. The primary end-point of the study was to evaluate changes of intercellular adhesion molecule-1 (ICAM-1) plasma levels during treatment. The secondary end-points were: changes in vascular cells adhesion molecule-1 (VCAM-1), von Willebrand factor (vWF), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) circulating levels and of urinary albumin excretion rate (AER) as well; 129 patients were randomized: 66 in the candesartan group and 63 in the enalapril group, 118 of them completed the scheduled 24-week treatment period. RESULTS: Candesartan and enalapril equally reduced circulating level of ICAM-1 and exerted comparable effects on changes of other adhesion molecules and coagulation factors. A similar blood pressure-lowering effect was observed with the two drugs (candesartan: from 148/90 +/- 11/8 to 132/82 +/- 12/7 mmHg, P < 0.01, enalapril: from 148/91 +/- 12/8 to 131/85 +/- 14/6 mmHg, P < 0.01). Candesartan was more effective than enalapril in the reduction of albuminuria (P < 0.05 between treatments), although urinary protein excretion can be considered normal in the majority of patients. The two drugs were comparable in terms of adverse events reported. CONCLUSION: Candesartan and enalapril showed similar effects on blood pressure and on circulating adhesion molecules. In this study urinary protein excretion was reduced more by candesartan.

BACKGROUND: Lung cancer is the leading cause of cancer related deaths and Malignant Pleural Effusion (MPE) is a frequent complication. Current therapies suffer from lack of efficacy in a great percentage of cases, especially when cancer is diagnosed at a late stage. Moreover patients' responses vary and the outcome is unpredictable. Therefore, the identification of patients who will benefit most of chemotherapy treatment is important for accurate prognostication and better outcome. In this study, using malignant pleural effusions (MPE) from non-small cell lung cancer (NSCLC) patients, we established a collection of patient-derived Adenocarcinoma cultures which were characterized for their sensitivity to chemotherapeutic drugs used in the clinical practice. METHODS: Tumor cells present in MPEs of patients with NSCLC were isolated by density gradient centrifugation, placed in culture and genotyped by next generation sequencing. In a subset of cases patient derived xenografts (PDX) were obtained upon tumor cell inoculation in rag2/IL2 knock-out mice. Isolated primary cultures were characterized and tested for drug sensitivity by in vitro proliferation assays. Additivity, antagonism or synergy for combinatorial treatments were determined by analysis with the Calcusyn software. RESULTS: We have optimized isolation procedures and culture conditions to expand in vitro primary cultures from Malignant Pleural Effusions (MPEs) of patients affected by lung adenocarcinomas, the most frequent form of non small cell lung cancer. Using this approach we have been able to establish 16 primary cultures from MPEs. Cells were banked at low passages and were characterized for their mutational pattern by next generation sequencing for most common driver mutations in lung cancer. Moreover, amplified cultures were shown to engraft with high efficiency when injected in immunocompromised mice. Cancer cell sensitivity to drugs used in standard chemotherapy regimens was assessed either individually or in combination. Differential chemosensitivity and different mutation profiles were observed which suggests that this isolation method could provide a platform for predicting the efficacy of chemotherapy in the clinical setting. Most importantly for six patients it was possible to establish a correlation between drug response in vitro and response to therapy in the clinic. CONCLUSIONS: Results obtained using primary cultured cells from MPEs underscore the heterogeneity of NSCLC in advanced stage as indicated by drug response and mutation profile. Comparison of data obtained from in vitro assays with patients' responses to therapy leads to the conclusion that this strategy may provide a potentially useful approach for evaluating individual chemosensitivity profile and tailor the therapy accordingly. Furthermore, combining MPE-derived primary cultures with their genomic testing allows to identify patients eligible to trials with novel targeted agents.

AIM: Right ventricular hypertrophy (RVH) has been reported to be a component of cardiac damage in systemic hypertension; this evidence, however, is based on small studies and major determinants of biventricular hypertrophy are still undefined. Thus, the prevalence and clinical correlates of RVH have been investigated in essential hypertension. METHODS: A total of 330 untreated and treated uncomplicated essential hypertensives consecutively attending a hospital out-patient hypertension clinic were considered for the analysis. All individuals underwent a quantitative echocardiographic examination as well as extensive clinical and laboratory investigations. RVH was defined by an anterior RV wall thickness equal or higher than 3.1/3.0 mm/m2 in men and women, respectively, and left ventricular hypertrophy (LVH) by LV mass index equal or higher than 51/47g/m2.7 in men and women, respectively. RESULTS: Overall, 114 (34.5%) patients fulfilled the criteria for LVH and 111 (33.6%) for RVH; normal cardiac morphology was observed in 164 patients (49.6%), isolated RVH in 52 (15.7%), isolated LVH in 55 (16.6%) and bi-ventricular hypertrophy in 59 (17.8%). In a logistic regression analysis, modifiable risk factors such as abdominal obesity (OR 3.41, CI 1.73-6.74, P = 0.0004), LV mid-wall fractional shortening (OR 2.48, CI 1.26-4.85, P = 0.008), fasting blood glucose (OR 2.47, CI 1.25-4.89, P = 0.009) and systolic blood pressure (OR 2.39, CI 1.19-4.82, P = 0.014) were the major independent correlates of biventricular hypertrophy. CONCLUSION: RVH is commonly found in systemic hypertension and is associated with LVH (i.e., biventricular hypertrophy) in approximately one-fifth of the patients seen in a specialist setting. The clinical correlates of biventricular hypertrophy suggest that this phenotype is associated with a profile of very high cardiovascular risk.

AIMS: To compare long-term (1 year) efficacy and safety of pioglitazone and gliclazide in patients with Type 2 diabetes. METHODS: This was a double-blind, multicentre, comparative, parallel group trial in 283 patients with Type 2 diabetes, who were randomized to receive 1-year treatment with pioglitazone 30-45 mg/day or gliclazide 80-320 mg/day. Drug dose was titrated on the basis of self-monitored blood glucose (SMBG) measurements and HbA1c values. The 1-year changes in HbA1c, fasting blood glucose (FBG), insulin, HOMA-S (HOmeostatic Model Assessment) and SMBG were compared. In a subgroup of patients (n = 10), systemic glucose production and utilization were determined by a combination of isotopic (deuterated glucose) and clamp techniques. RESULTS: In both groups, there were similar decreases in HbA1c (pioglitazone: -0.79%; gliclazide: -0.79%) and FBG (pioglitazone: -1.0 mmol/l; gliclazide: -0.7 mmol/l), whereas the slope of the reduction of fasting blood glucose was different between groups (P = 0.004). Insulin levels as well as insulin resistance assessed using HOMA-S decreased significantly only after pioglitazone treatment (-11.94 pmol/l and -1.03, respectively, both P = 0.002 vs. baseline). A significantly greater reduction in systemic glucose production was observed in the pioglitazone group (-2.48 micromol/kg/min, P = 0.042) than in the gliclazide group (-1.02 micromol/kg/min). A few, mild adverse events occurred in both groups. CONCLUSIONS: A comparable decrease in HbA1c and FBG was observed with pioglitazone and gliclazide. However, with pioglitazone there was a continuous decrease in FBG over 1 year, whereas gliclazide failed to maintain a similar trend. This favourable effect of pioglitazone was due to its insulin-sensitizing effect and ability to decrease systemic glucose production.

PURPOSE: The goal of this study was to assess the impact of an interdisciplinary remote patient monitoring (RPM) program on clinical outcomes and acute care utilization in cancer patients with COVID-19. METHODS: This is a cross-sectional analysis following a prospective observational study performed at Mayo Clinic Cancer Center. Adult patients receiving cancer-directed therapy or in recent remission on active surveillance with polymerase chain reaction–confirmed SARS-CoV-2 infection between March 18 and July 31, 2020, were included. RPM was composed of in-home technology to assess symptoms and physiologic data with centralized nursing and physician oversight. RESULTS: During the study timeframe, 224 patients with cancer were diagnosed with COVID-19. Of the 187 patients (83%) initially managed in the outpatient setting, those who did not receive RPM were significantly more likely to experience hospitalization than those receiving RPM. Following balancing of patient characteristics by inverse propensity score weighting, rates of hospitalization for RPM and non-RPM patients were 2.8% and 13%, respectively, implying that the use of RPM was associated with a 78% relative risk reduction in hospital admission rate (95% CI, 54 to 102; P = .002). Furthermore, when hospitalized, these patients experienced a shorter length of stay and fewer prolonged hospitalizations, intensive care unit admissions, and deaths, although these trends did not reach statistical significance. CONCLUSION: The use of RPM and a centralized virtual care team was associated with a reduction in hospital admission rate and lower overall acute care resource utilization among cancer patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease (COVID-19), emerged in China in December 2019. Investigators have made rapid efforts to design therapeutic strategies targeting this rapidly spreading pathogen. Although not as lethal as SARS-CoV or Middle East respiratory syndrome (MERS)-CoV, the virus is highly transmissible, often without symptoms, with an estimated reproductive number (R0) of 2.2.1Li Q. Guan X. Wu P. Wang X. Zhou L. Tong Y. Ren R. Leung K.S.M. Lau E.H.Y. Wong J.Y. et al.Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.N. Engl. J. Med. 2020; 382: 1199-1207Crossref PubMed Scopus (10808) Google Scholar On March 12, 2020, a mere 2 months since the outbreak was detected, World Health Organization (WHO) announced that COVID-19 had reached pandemic status. As a consequence, containment strategies have been implemented to slow viral transmission, but control of the infection will be challenging without a vaccine. The global scientific community and the vaccine industry, supported by international organizations such as Coalition for Epidemic Preparedness Innovations (CEPI) and the European Commission, have committed to developing a safe vaccine able to elicit a potent and long-lasting virus-specific immune response against SARS-CoV-2. The ideal target vaccine product profile should comprise some key elements. It should be consistently immunogenic with minimal side effects, such as undesired immunopotentiation in the form of increased infectivity.2Jiang S. Bottazzi M.E. Du L. Lustigman S. Tseng C.T. Curti E. Jones K. Zhan B. Hotez P.J. Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome.Expert Rev. Vaccines. 2012; 11: 1405-1413Crossref PubMed Scopus (113) Google Scholar Vaccine production should be implemented in a timely and efficient manner and be relatively inexpensive and suitable for large-scale good manufacturing practice (GMP) manufacturing. Moreover, as requested by regulatory agencies during the first regulatory workshop on COVID-19 held in March 2020 under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), vaccine design should include a careful assessment of possible immune complications, such as the possibility of antibody-dependent-enhancement (ADE) of infection, before being released to the public. To this aim, diverse platforms have been set up, but only a few can address these requirements. Conventional vaccines, such as inactivated, attenuated, or subunit vaccines, have been successful but have drawbacks, such as their strain specificity, and consequently are potentially associated with risks of viral interference and cross-immunity3Laurie K.L. Guarnaccia T.A. Carolan L.A. Yan A.W. Aban M. Petrie S. Cao P. Heffernan J.M. McVernon J. Mosse J. et al.Interval Between Infections and Viral Hierarchy Are Determinants of Viral Interference Following Influenza Virus Infection in a Ferret Model.J. Infect. Dis. 2015; 212: 1701-1710Crossref PubMed Scopus (78) Google Scholar and can be allergenic in some patient groups. Furthermore, vaccines based on viral proteins tend to elicit immune responses that are limited to the CD4+ T cell response or antibody-dependent mechanisms and lack a CD8+ T cell response. Besides this, the production of conventional vaccines can be expensive and time-consuming. Safety concerns, commonly associated with the use of whole virus as a vaccine platform, have been overcome by the development of replication-defective recombinant adenoviruses, which have proven safe for administration in humans and effective in inducing robust innate and adaptive immune responses. Third-generation adenoviral vectors have been employed to prevent or treat life-threatening infectious diseases such as Ebola, Zika, malaria, hepatitis C virus (HCV), and HIV4Kennedy S.B. Bolay F. Kieh M. Grandits G. Badio M. Ballou R. Eckes R. Feinberg M. Follmann D. Grund B. et al.PREVAIL I Study GroupPhase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia.N. Engl. J. Med. 2017; 377: 1438-1447Crossref PubMed Scopus (177) Google Scholar,5López-Camacho C. Abbink P. Larocca R.A. Dejnirattisai W. Boyd M. Badamchi-Zadeh A. Wallace Z.R. Doig J. Velazquez R.S. Neto R.D.L. et al.Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors.Nat. Commun. 2018; 9: 2441Crossref PubMed Scopus (64) Google Scholar and tested in clinical trials for anticancer immunotherapy.6Zhang W.W. Li L. Li D. Liu J. Li X. Li W. Xu X. Zhang M.J. Chandler L.A. Lin H. et al.The first approved gene therapy product for cancer Ad-p53 (gendicine): 12 years in the clinic.Hum. Gene Ther. 2018; 29: 160-179Crossref PubMed Scopus (210) Google Scholar However, this vaccination strategy is hampered by issues such as pre-existing immunity in humans and challenges in construction. Therefore, newer vaccination approaches, such as genetic vaccines based on naked DNA or RNA, have emerged as promising alternatives owing to several beneficial features. First, they have a highly satisfactory safety profile without potential risk of integration or pathogenicity, and for this reason they are considered an ideal therapeutic strategy in cancer immunotherapy or for vaccinating immunocompromised people. Second, genetic vaccination can elicit both T cell activation and antibody production in response to even small amounts of expressed protein and, unlike whole virus vectors, can be more easily administered in multi-dose regimens without generating pre-existing immunity. Finally, the manufacturing process confers some advantages: both DNA and RNA are inexpensively and easily constructed directly from the genetic sequence of the desired antigen. Once established, the production process can be easily adjusted according to the histocompatibility leukocyte antigen (HLA) diversity in the field in order to include the most immunogenic antigens and modulators for a specific population. Hence, the use of nucleic acids in vaccine development programs is growing in a wide range of traditional pharmaceutical markets, such as cancers and allergies, as well as infectious diseases, and it is increasingly demonstrating its safety and efficacy in early and mid-stage human clinical trials.7Lee J. Arun Kumar S. Jhan Y.Y. Bishop C.J. Engineering DNA vaccines against infectious diseases.Acta Biomater. 2018; 80: 31-47Crossref PubMed Scopus (128) Google Scholar,8Liu M.A. A Comparison of Plasmid DNA and mRNA as Vaccine Technologies.Vaccines (Basel). 2019; 7: 37Crossref PubMed Scopus (280) Google Scholar Nevertheless, these vaccination strategies still present some drawbacks, and differences between DNA and RNA must be taken into account. As for immunogenicity, a number of factors can increase DNA potency, such as the use of immunostimulants (cytokines and immunostimulatory molecules), tailored delivery routes and devices (with intramuscular injection followed by electroporation having been found to be the most effective in inducing strong immune responses), and different combination strategies (e.g., DNA prime followed by viral vector, peptide, or recombinant protein heterologous boosts). Conversely, over the past decade, vaccine developers have striven to increase RNA stability, improve its cellular delivery through encapsulation into nanoparticles, and reduce its constitutive reactogenicity by using modified nucleosides and controlling the onset of eventual toxicities. Challenges remain for RNA-based strategies, such as further improving stability, reducing toxicity (due to intrinsic inflammatory activity), and increasing protein translation, necessitating additional clinical studies. Additionally, in order to avoid the use of any animal or cellular materials, researchers are exploring alternative manufacturing strategies, such as the use of PCR-generated linear DNA fragments.9Allen A. Wang C. Caproni L.J. Sugiyarto G. Harden E. Douglas L.R. Duriez P.J. Karbowniczek K. Extance J. Rothwell P.J. et al.Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model.Cancer Immunol. Immunother. 2018; 67: 627-638Crossref PubMed Scopus (26) Google Scholar As shown in Table 1, genetic vaccines, DNA-based ones in particular, are an ideal vaccination platform for infectious diseases: both DNA and RNA can be developed and manufactured rapidly, ensuring a reproducible and standard production process, whatever the target disease or gene insert, but still with some intrinsic limitations to overcome, such as lower immunogenicity, in comparison to protein- and viral-based conventional vaccines.10Lurie N. Saville M. Hatchett R. Halton J. Developing Covid-19 Vaccines at Pandemic Speed.N. Engl. J. Med. 2020; 382: 1969-1973Crossref PubMed Scopus (1071) Google ScholarTable 1Some Candidate Viral-Based and Genetic Vaccines against COVID-19 in Clinical/Preclinical EvaluationPlatformType of Candidate VaccineDeveloperCurrent Stage of Clinical Evaluation/Regulatory StatusDNADNA electroporationInovio Pharmaceuticalsphase 1 (NCT04336410)RNALNP-encapsulated mRNAModerna/NIAIDphase 2 (IND submission)phase 1 (NCT04283461)RNA3 LNP-mRNAsBioNTech/Fosun Pharma/Pfizerphase 1/2 (2020-001038-36)Non-replicating viral vectoradenovirus type5 vectorCanSino Biological/Beijing Institute of Biotechnologyphase 2 (ChiCTR2000031781)phase 1 (ChiCTR2000030906)Non-replicating viral vectorChAdOx1University of Oxfordphase 1/2 (NCT04324606)DNADNA/PCR electroporationTakis/Applied DNA Sciences/Evvivaxpreclinical evaluationDNADNA electroporationKarolinska Institute/Cobra Biologics (OPENCORONA Project)preclinical evaluationRNAmRNACurevacpreclinical evaluationNon-replicating viral vectorAd26Janssen Pharmaceutical Companiespreclinical evaluationNon-replicating viral vectorreplicationdefective simianadenovirusReiThera/LEUKOCARE/Univercellspreclinical evaluationNon-replicating viral vectororal vaccine platformVaxartpreclinical evaluationFrom WHO,11WHO DRAFT landscape of COVID-19 candidate vaccines – 20 April 2020.https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf?ua=Date: 2020Google Scholar updated on May 5, 2020. Open table in a new tab From WHO,11WHO DRAFT landscape of COVID-19 candidate vaccines – 20 April 2020.https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf?ua=Date: 2020Google Scholar updated on May 5, 2020. The last decade has witnessed the outbreak of several new human pathogens, including Ebola, Chikungunya, Zika, SARS-CoV, MERS-CoV, and more recently the novel coronavirus (SARS-CoV-2). The continuous spread of such diseases at regular intervals poses a significant threat to human health and the economy, and there is an urgent need for a vaccine technology that is able to protect against rapidly arising or mutating pathogens. Genetic vaccination represents an ideal vaccine target product profile to be developed in response to an unexpected pandemic outbreak, so, in the future, every effort must be addressed to develop a vaccine platform that can be designed and produced in large scale in a timely fashion to be ready for a “disease X.” A.C., E.M., G.R., F.P., and L.A. have an interest in developing vaccines and therapeutics to treat SARS-CoV-2. A patent has been filed at Takis for a genetic vaccine under development. G.C. declares no conflict of interest.

An open-label randomized pilot study was conducted to evaluate the efficacy and acceptability of 6 months treatment with leuprolide in a 3-monthly versus a monthly i.m. depot injection for the relief of chronic pelvic pain in women with endometriosis. A total of 30 women aged 18-38 years were allocated to the 3-monthly depot arm (n = 15) or to the monthly depot arm (n = 15) after laparoscopic diagnosis of pelvic endometriosis. Mean (SD) deep dyspareunia scores according to a 0-3 point verbal rating scale decreased from 1.8 (0.9) at baseline to 1.3 (0.7) at the end of treatment in the 3-monthly depot group and from 2.1 (1.2) to 1.3 (0.7) in the monthly depot group. Corresponding values in non-menstrual pain scores fell from 2.1 (0.6) to 1.1 (0.3), and from 2.1 (0.8) to 1.2 (0.4) respectively, without statistically significant differences between the groups. Serum luteinizing hormone (LH) and 17 beta-oestradiol concentrations were significantly suppressed at 12 and 24 weeks compared with baseline values, without differences between the groups. The monthly depot caused a slightly more marked inhibition of serum follicle stimulating hormone (FSH) levels with respect to the 3-monthly preparation. Mean (SD) endometriosis scores at baseline and at 6-month follow-up laparoscopy were respectively 32.8 (25.1) and 12.2 (9.3) in the 3-monthly depot group and 29.0 (22.7) and 13.1 (15.3) in the monthly depot group (paired t-test, P < 0.05). Mean percentage decrease in lumbar spine bone mineral density was 5.2% in the former and 4.9% in the latter subjects. In the 3-monthly depot group, 13 women graded the tolerability of their treatment schedule as "good' compared with seven in the monthly depot group (chi 2 = 5.40, P = 0.02).

PURPOSE: To develop a public-private partnership to study the feasibility of a new approach in collecting and analyzing clinically annotated imaging data from landmark phase III trials in advanced solid tumors. PATIENTS AND METHODS: The collection of clinical trials fulfilled the following inclusion criteria: completed randomized trials of > 300 patients, highly measurable solid tumors (non-small-cell lung cancer, colorectal cancer, renal cell cancer, and melanoma), and required sponsor and institutional review board sign-offs. The new approach in analyzing computed tomography scans was to transfer to an academic image analysis laboratory, draw contours semi-automatically by using in-house-developed algorithms integrated into the open source imaging platform Weasis, and perform serial volumetric measurement. RESULTS: The median duration of contracting with five sponsors was 12 months. Ten trials in 7,085 patients that covered 12 treatment regimens across 20 trial arms were collected. To date, four trials in 3,954 patients were analyzed. Source imaging data were transferred to the academic core from 97% of trial patients (n = 3,837). Tumor imaging measurements were extracted from 82% of transferred computed tomography scans (n = 3,162). Causes of extraction failure were nonmeasurable disease (n = 392), single imaging time point (n = 224), and secondary captured images (n = 59). Overall, clinically annotated imaging data were extracted in 79% of patients (n = 3,055), and the primary trial end point analysis in each trial remained representative of each original trial end point. CONCLUSION: The sharing and analysis of source imaging data from large randomized trials is feasible and offer a rich and reusable, but largely untapped, resource for future research on novel trial-level response and progression imaging metrics.

INTRODUCTION: The advent of cancer immunotherapy is going to profoundly transform the therapy of cancer. In this context, therapeutic cancer vaccines will offer significant opportunities, provided an efficient and robust technology is developed. AREAS COVERED: Targeting tumor-associated antigens via immunization with homologous immunogens derived from other species, an approach called xeno vaccination, combined with gene delivery is believed to be a viable strategy. Xenogene vaccination has demonstrated to be more efficient than vaccination with 'self' antigens in rodent models in prophylactic and therapeutic settings against cancer. Depending upon the targeted antigen, the mechanism of action of xeno vaccines has been shown to depend upon the development of antibody and/or cytotoxic T-cell responses. More importantly, xenogene vaccination has been shown to reproducibly affect cancer growth and to improve survival in veterinary cancer patients, mainly in dogs affected by spontaneous disease. One of these vaccines against dog melanoma has been approved by regulatory authorities in USA. Finally, several xenogene vaccines have been advanced to early Phase I/II human clinical trials where they have shown to be safe, well tolerated and capable to induce detectable immune responses against human tumor antigens. EXPERT OPINION: Based on this compendium of results we believe that xenogene vaccination may soon become a well-established weapon in the fight against cancer.

BACKGROUND: This study was designed to compare the effectiveness of co-administration of pioglitazone with metformin or a sulfonylurea (SU), with a fixed-dose combination of metformin and glibenclamide on glycemic control and beta-cell function in patients with type 2 diabetes. METHODS: Patients (n = 250) treated with metformin (<or=3 g/day) or an SU as monotherapy for >3 months and with glycosylated hemoglobin (HbA(1c)) between 7.5% and 11% inclusive were randomized to receive either pioglitazone (15-30 mg/day) as add-on therapy to metformin or an SU or a fixed-dose combination of metformin (400 mg) and glibenclamide (2.5 mg) (up to three tablets per day) for 6 months. HbA(1c) and fasting plasma glucose (FPG) were measured at baseline and 2, 4, and 6 months. C-peptide levels were measured at baseline and 6 months, and post-challenge glucose and insulin responses were measured. RESULTS: After 6 months, pioglitazone-based and fixed-dose metformin + glibenclamide resulted in similar reductions in HbA(1c) (-1.11% vs. -1.29%, respectively; P = 0.192) and FPG (-2.13 vs. -1.81 mmol/L, respectively; P = 0.370). Patients treated with pioglitazone for 6 months had significantly reduced C-peptide levels compared with baseline (-0.09 nmol/L, P = 0.001), while patients receiving fixed-dose metformin + glibenclamide combination had slightly increased C-peptide levels (+0.04 nmol/L, P = 0.08). Pioglitazone treatment also improved post-challenge insulin responses. CONCLUSIONS: Co-administration of pioglitazone with metformin or an SU is an effective alternative to fixed-dose metformin + glibenclamide combination for patients with type 2 diabetes. The complementary effects of pioglitazone with either metformin or an SU may also have the potential to preserve beta-cell function and delay the progression of type 2 diabetes.

BACKGROUND: Prosthesis rehabilitation after dysvascular transtibial amputation (TTA) is focused on optimizing functional capacity with limited emphasis on promoting health self-efficacy. Self-efficacy interventions decrease disability for people living with chronic disease, but the influence of self-efficacy on disability is unknown for people with dysvascular TTA. OBJECTIVES: To identify if self-efficacy mediates the relationship between self-reported functional capacity and disability after dysvascular TTA. DESIGN: Cross-sectional, secondary data analysis. SETTING: Outpatient rehabilitation facilities. PARTICIPANTS: Thirty-eight men (63.6 ± 9.1 years old) with dysvascular TTA. METHODS: Participants had been living with an amputation for less than 6 months and using walking as their primary form of locomotion using a prosthesis. The independent variable, functional capacity, was measured using the Prosthesis Evaluation Questionnaire-Mobility Scale (PEQ-MS). The proposed mediator, self-efficacy, was measured with the Self-Efficacy of Managing Chronic Disease questionnaire (SEMCD). MAIN OUTCOME MEASURE: Disability was measured using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire. RESULTS: The relationship between self-reported functional capacity and disability is partially mediated by self-efficacy. Relationships between WHODAS 2.0 and PEQ-MS (r = -0.61), WHODAS 2.0 and SEMCD (r = -0.51), and PEQ-MS and SEMCD (r = 0.44) were significant (P < .01). Controlling for SEMCD (P = .04), the relationship between PEQ-MS and WHODAS 2.0 remained significant (P < .01). Statistically significant mediation was determined by a bootstrap method for the product of coefficients (95% confidence interval: -2.23, -7.39). CONCLUSIONS: This study provides initial evidence that the relationship between self-reported functional capacity and disability is partially mediated by self-efficacy after dysvascular TTA. The longitudinal effect of self-efficacy should be further examined to identify causal pathways of disability after dysvascular amputation. Furthermore, additional factors contributing to the relationship between self-reported functional capacity and disability need to be identified. LEVEL OF EVIDENCE: III.

We have generated a xenogeneic vaccine against human carcinoembryonic antigen (hCEACAM-5 or commonly hCEA) using as immunogen rhesus CEA (rhCEA). RhCEA cDNA was codon-usage optimized (rhCEAopt) and delivered by sequential DNA electro-gene-transfer (DNA-EGT) and adenoviral (Ad) vector. RhCEAopt was capable to break tolerance to CEA in hCEA transgenic mice and immune responses were detected against epitopes distributed over the entire length of the protein. Xenovaccination with rhCEA resulted in the activation of CD4+ T-cell responses in addition to self-reactive CD8+ T-cells, the development of high-titer antibodies against hCEA, and significant antitumor effects upon challenge with hCEA+ tumor cells. The superior activity of rhCEAopt compared with hCEAopt was confirmed in hCEA/HHD double-transgenic mice, where potent CD8+ T-cell responses against specific human HLA A*0201 hCEA epitopes were detected. Our data show that xenogeneic gene-based vaccination with rhCEA is a viable approach to break tolerance against CEA, thus suggesting further development in the clinical setting.

The solid state of four novel S -(+)-Naproxen ( S-Nap ) diastereomeric salts with cis -1-amino-2-indanol ( SR-AI and RS-AI enantiomers) is reported. The anhydrous SR-AI_S-Nap_A is the only obtained phase in all the experimental conditions used, while the kinetically preferred diastereomeric salt RS-AI_S-Nap_A1 forms only in certain conditions and undergoes an irreversible phase transition to RS-AI_S-Nap_A2 after melting; this second phase was obtained even by dehydration of the monohydrate salt RS-AI_S-Nap_W . The preferred crystallization of SR-AI_S-Nap_A was observed when S-Nap was introduced in a solution containing equimolar quantity of the racemic cis -1-amino-2-indanol, in spite of the strict similarity of the crystal packings of SR-AI_S-Nap_A and RS-AI_S-Nap_A1 . With the aim of trying to explain the preference of S-Nap for the SR-AI enantiomer, an in-depth analysis and comparison of the diastereomeric salt crystal structures were carried out.

Histologic transformation is one of the mechanisms of resistance to EGFR tyrosine kinase inhibitor in patients with NSCLC with EGFR mutation. The transformation from adenocarcinoma to squamous cell carcinoma (SCC) has been recently recognized as a mechanism of resistance to osimertinib. The prognosis after transformation to SCC is considered to be poor, and the therapeutic strategy for these patients is unclear. Herein, we report a case of long-term response to pembrolizumab monotherapy for an SCC-transformed lesion in a patient with EGFR -mutated adenocarcinoma after osimertinib treatment. A 68-year-old man underwent right upper lobectomy and was diagnosed with lung adenocarcinoma, pathologic stage IIA, with EGFR L858R . Five years after the surgery, he was diagnosed with recurrence and administered osimertinib. Ten months after, biopsy for an enlarged subpleural lesion revealed SCC with EGFR L858R , leading to a diagnosis of histologic transformation. Notably, the programmed death-ligand 1 expression level of the transformed lesion was higher than that of the adenocarcinoma (90% versus <1%). The size of the SCC lesion had reduced with pembrolizumab monotherapy, and the reduction was maintained for over 47 months since transformation. Nevertheless, the original adenocarcinoma lesion progressed after pembrolizumab therapy and was controlled by other cytotoxic drugs and readministration of osimertinib. Immune checkpoint inhibitor therapy is generally ineffective against EGFR -mutated adenocarcinoma. Nevertheless, it may be promising for achieving a good prognosis when EGFR -mutated adenocarcinoma transforms to SCC after developing EGFR tyrosine kinase inhibitor resistance—particularly if the transformed lesion has high programmed death-ligand 1 expression.

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions. Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers. Methods: (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk. Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18). Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk.

We encountered 6 cases of cervical mycobacterial lymphadenitis and a case of non-tuberculous mycobacterial infection of the parotid gland over a 19-month period. The incidence of mycobacterial infection is currently increasing among elderly persons and foreign workers who are socially vulnerable, and cervical mycobacterial lymphadenitis is no exception to that trend.Six of our 7 cases were over 60 years old and the mean patient age was 75.7 years, the remaining one case was a young foreign worker. In the latter case, multiple lymphadenopathies were noted on the first examination and 6-months of oral antibiotic administration resulted in only partial improvement.Cervical mycobacterial infection can present in many forms depending on the stage of the disease. Regarding diagnostic methods, although an accurate diagnosis was easily reached by tuberculous DNA polymerase chain reaction (PCR) in cases showing abscess formation, clinical diagnosis was delayed in atypical cases not presenting with neck abscess and excisional biopsies were needed. The clinical courses of these cases are presented along with a review of the literature.

8009 Background: Carf plus Len-Dex (KRd) or Cyclo-Dex (KCd) is effective in NDMM. Treatment of high-risk pts is an unmet medical need. Methods: NDMM pts ≤65 yrs were randomized (1:1:1; stratification ISS and age) to ARM A: 4 28-day induction cycles with KCd (Carf: 20/36 mg/m2 IV days 1,2,8,9,15,16; Cyclo: 300 mg/m2 days 1,8,15; Dex: 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and consolidation with 4 KCd; ARM B: 4 28-day cycles with KRd (Carf: 20/36 mg/m2 IV days 1,2,8,9,15,16; Len: 25 mg days 1-21; Dex: 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd; ARM C: 12 KRd cycles. Primary endpoint was VGPR rate with KRd vs KCd induction. For this analysis, the 2 KRd arms were pooled (2:1), as treatment was the same until that point. Enrollment was completed in March, 2017; data cut-off was November 30, 2017. Results: 474 pts were randomized (KRd, n = 315; KCd, n = 159). Pts characteristics were well balanced: 49% of KRd pts vs 49% of KCd pts had ISS Stage 2-3 at baseline, 31% vs 35% had high-risk chromosomal abnormalities [del17 and/or t(4;14) and/or t(14;16) by FISH], 68% vs 74% had Revised ISS Stage 2-3. Rates of sCR/CR (14% vs 3%; P = 0.0004), ≥nCR (33% vs 21%; P = 0.0106) and ≥VGPR (75% vs 60%; P = 0.0017) were significantly higher with KRd vs KCd. The advantage of KRd was consistent in all subgroups; ≥VGPR, ≥nCR in high-risk pts treated with KRd were comparable to the overall population. MRD evaluation (8 color second generation flow cytometry, sensitivity 10-5) was available in a subset of pts: 144 KRd and 56 KCd. Rate of MRD negativity in evaluable pts was 56% with KRd vs 29% with KCd (P = 0.008). MRD negativity in high-risk pts treated with KRd was comparable to the overall population (Table). Treatment was well tolerated, as previously shown (Gay F ASCO 2017). Conclusions: KRd induction significantly improved sCR/CR, ≥nCR, ≥VGPR rates and MRD negativity vs KCd with similar efficacy in high-risk pts. Clinical trial information: NCT02203643. All pts HIGH RISK by FISH ISS 2-3 Revised ISS 2-3 KCd KRd KCd KRd KCd KRd KCd KRd Response N = 159 N = 315 N = 43 N = 79 N = 69 N = 143 N = 91 N = 173 ≥nCR 21% 33% 12% 30% 16% 31% 13% 29% ≥VGPR 60% 75% 63% 71% 58% 78% 59% 76% MRD N = 56 N = 144 N = 14 N = 38 N = 36 N = 73 N = 39 N = 88 MRD negative 29% 56% 36% 61% 31% 58% 26% 56%