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]

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.

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.

-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%

Internet has become a central part of our everyday lives. Digital media are integrated in our daily routines and play a critical role in the dissemination of public health information and disease prevention guidelines. For this reason, digital activities are becoming more and more impacting in pharma company activities and this is an increasing trend after the pandemic period. Managing digital activities from pharmacovigilance (PV) perspective may have challenges linked to correct assessment of the activities and application of PV rules: this was underlined in recent publications, where the need to have more specific guidelines linked to digital activities management was evidenced. Considering this scenario and the continuous evolution of the digital activities, the SIMEF PV working group decided to work on a proposal guideline to provide support to PV departments in pharma companies, suggesting a framework to manage sponsored digital activities (i.e., website, web apps, social media webpage, chatbots) impacting potential collection of adverse events (AEs). The purpose of this guideline is to provide useful instructions on how to manage PV requirements for digital activities, suggesting potential solutions for assessing initiatives, creating governance framework, conducting a correct vendor management, and suggesting practical approaches for AEs reporting and follow-up. The aim of this document is also to trigger a broader discussion among relevant stakeholders on which PV guidelines may be useful and appropriate considering this continuous evolving scenario.

Background: The aim of this economic evaluation was to compare the cost per responder between vedolizumab and ustekinumab in patients with Crohn’s disease (CD) after failure of tumor necrosis factor-α inhibitors in Italy. Methods: Clinical efficacy was assessed using the results of an Italian large multicentre observational retrospective cohort study. The aim of the study was to compare the effectiveness of ustekinumab and vedolizumab as second line therapy in Crohn’s disease patients in which tumour necrosis factor-α inhibitors failed. Clinical efficacy of vedolizumab and ustekinumab was measured by clinical response and clinical remission. Treatment costs were based on the number of administrations at 26 or 52 weeks. Cost per responder, based on clinical efficacy and clinical response, was used as a cost-effectiveness indicator. Results: Regardless of the clinical efficacy measure used and the treatment duration considered, the cost per responder was consistently lower for vedolizumab compared with ustekinumab on all clinical measures. Considering the clinical response, the cost per responder at 26 weeks was € 15,640 for vedolizumab and € 23,667 for ustekinumab and at 52 weeks was € 23,927 for vedolizumab and € 30,820 for ustekinumab. Considering the clinical remission, the cost per responder at 26 weeks was € 22,832 for vedolizumab and € 33,786 for ustekinumab and at 52 weeks was € 29,488 for vedolizumab and € 46,847 for ustekinumab. Sensitivity analysis confirmed the validity of results. Conclusion: These results suggest that vedolizumab is a cost-effective option compared with ustekinumab from the perspective of the Italian health service in patients with CD after failure of TNF-α inhibitors.

Background: Primary (PID) or secondary (SID) immunodeficiencies are diseases caused by quantitative and/or functional alterations of the different mechanisms involved in the innate and adaptive immune response. This economic evaluation was conducted to compare the cost of treatment of HYQVIA® (hyaluronidase-facilitated subcutaneous infusion of immunoglobulin, fSCIG) compared to intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), currently reimbursed in Italy, in the treatment of PIDs or SIDs. Methods: A cost-minimisation analysis was carried out, considering the hospital’s perspective. The direct medical costs (cost of immunoglobulins and cost of administration) were assessed. The analysis was conducted considering one year (52 weeks) time horizon. The reference population included adult patients with PID with impaired antibody production or adult patients with SID with severe or recurrent infections, ineffective antimicrobial treatment and documented specific antibody defect (PSAF) or serum IgG level &lt; 4 g/L. Results: In the maintenance treatment of PID, HYQVIA® (€ 20,020.00) was the therapeutic alternative with the lowest mean annual cost compared to HIZENTRA® (€ 22,165.19) and VENITAL® (€ 24,967.68). Moreover, in the maintenance treatment of SIDs, HYQVIA® (€ 17,160.00) was the cost-saving therapeutic alternative compared to VENITAL® (€ 22,107.68). A sensitivity analysis confirmed the base case results. Conclusion: Due to lower costs of administration and different scheme of administration, HYQVIA® was a cost-saving alternative to SCIG e IVIG in the treatment of PID and to IVIG in the treatment of SID