Τετάρτη 31 Ιανουαρίου 2018
Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study
Abstract
Background
Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent anti-mitotic agent, monomethyl auristatin E (MMAE), which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug-conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients. Patients and Methods
Platinum-resistant OC patients were randomized to receive LIFA (2.4 mg/kg, intravenously, every 3 weeks [Q3W]), or pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary endpoint was progression-free survival (PFS) in intent to treat (ITT) and NaPi2b-high patients. Results
Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 (95% CI, 0.46–1.31; p=0.34) with a median PFS of 5.3 vs. 3.1 months (LIFA vs. PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40–1.26; p=0.24) with a median PFS of 5.3 vs. 3.4 months (LIFA vs. PLD arm, respectively) in NaPi2b-high patients. The objective response rate (ORR) was 34% (95% CI, 22–49%, LIFA) vs. 15% (95% CI, 7–28%, PLD) in the ITT population (p=0.03), and 36% (95% CI, 22–52%, LIFA) vs.14% (95% CI, 6–27%, PLD) in NaPi2b-high patients (p=0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA vs. 2 (4%) PLD patients had grade ≥ 2 neuropathy. Conclusion
Lifastuzumab vedotin Q3W was well-tolerated and improved ORR with a modest, non-statistically significant improvement of PFS compared to PLD in platinum-resistant OC. While the response rate for the MMAE-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADC's in OC. Clinical trials.gov
NCT01991210Results of a multi-institutional, randomized, non-inferiority, phase 3 trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group study (JCOG0701)
Background
We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and Methods
In this multi-institutional, randomized, phase 3 trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1 − 2N0M0, age 20 − 80, Eastern Cooperative Oncology Group (ECOG) performance status of 0 − 1, and adequate organ function. Patients were randomly assigned to receive either SF of 66 − 70 Gy (33 − 35 fractions), or AF of 60 − 64.8 Gy (25 − 27 fractions). The primary endpoint was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results
Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4 − 85.4) for SF and 81.7% (95% CI 75.4 − 87.0) for AF (difference 1.8%, 91% CI 5.1%−8.8%; one-sidedP = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year OS between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1(0.5%)) in the SF/AF arms. Conclusion
Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared to SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. UMIN000000819Real world data on the efficacy and safety of apremilast in patients with moderate to severe plaque psoriasis
Abstract
Background
Psoriasis is a chronic inflammatory skin disease, which requires long term, safe and effective treatment. Apremilast, a small-molecule PDE4 inhibitor, has been introduced as psoriasis (and psoriatic arthritis) treatment in Europe in 2015.
Objective
We analysed and report the efficacy and safety of apremilast in the first 51 patients with psoriasis that have undergone treatment with this novel small molecule in our outpatient clinic.
Method
Our primary endpoint was the evaluation of clinical response to apremilast according to the percentage of PASI reduction (ΔPASI) at 16 weeks after treatment initiation. Secondary endpoints were the evaluation at week 16 of: (i) Psoriasis Area Severity Index (PASI); (ii) Dermatology Life Quality Index (DLQI); (iii) Physician Global Assessment (PGA); (iv) Psoriasis Scalp Severity Index (PSSI); and (v) the percentage of patients who achieved ΔPASI50, ΔPASI75, ΔPASI90 and ΔPASI100; (vi) adverse events (AE); (vii) reasons for drug discontinuation; and (viii) drug survival.
Results
59.3% of the patients who remained on apremilast achieved at least ΔPASI75 at week 16, while 11.1% achieved combined 50%≤PASI<75% and DLQI≤5 (satisfactory response) adequate enough to maintain treatment. Five patients (18.5%) also achieved ΔPASI100. Patients discontinued apremilast (28%), mostly during the first four weeks due to adverse events (12%) with gastrointestinal symptoms being the most common, and later due to lack of efficacy (16%). A statistically significant improvement of PASI, DLQI, PGA and PSSI scores was observed after 4 and 16 weeks of treatment relative to pre-treatment measurements.
Conclusion
Apremilast is a safe and efficacious treatment for psoriasis patients as it produces ΔPASI75 and ΔPASI50 responses combined with DLQI≤5 in 16 weeks in 70.4% of the patients. These results, from a real-world setting, confirm the efficacy and safety of apremilast which has been demonstrated in large phase III clinical trials.
This article is protected by copyright. All rights reserved.
Inequalities in zoster disease burden: a population-based cohort study to identify social determinants using linked data from the UK Clinical Practice Research Datalink
Abstract
Background
Zoster vaccination was introduced in England in 2013, where tackling health inequalities is a statutory requirement. However, specific population groups with higher zoster burden remain largely unidentified.
Objective
To evaluate health inequalities in zoster disease burden prior to zoster vaccine introduction in England.
Methods
This population-based cohort study utilised anonymised UK primary care data linked to hospitalisation and deprivation data. Individuals aged ≥65 years without prior zoster history (N=862,470) were followed from 01/09/2003-31/08/2013. Poisson regression was used to obtain adjusted rate ratios (ARR) for the association of socio-demographic factors (ethnicity, immigration status, individuals' area-level deprivation, care home residence, living arrangements) with first zoster episode. Possible mediation by co-morbidities and immunosuppressive medications was also assessed.
Results
There were 37,014 first zoster episodes, with incidence of 8.79 (95% confidence interval (CI):8.70-8.88) per 1,000 person-years at risk. In multivariable analyses, factors associated with higher zoster rates included care home residence (10% higher versus those not in care homes), being female (16% higher versus males), non-immigrants (~30% higher than immigrants) and White ethnicity (for example, twice the rate compared to those of Black ethnicity). Zoster incidence decreased slightly with increasing deprivation (ARR most versus least deprived=0.96 (95%CI:0.92-0.99) and among those living alone (ARR 0.96 (95%CI:0.94-0.98). Mediating variables made little difference to the ARR of social factors but were themselves associated with increased zoster burden (ARR varied from 1.11-3.84).
Conclusions
The burden of zoster was higher in specific socio-demographic groups. Further study is needed to ascertain whether these individuals are attending for zoster vaccination.
This article is protected by copyright. All rights reserved.
The PARACELSUS score: A novel diagnostic tool for pyoderma gangrenosum
Abstract
Background
The lack of objective diagnostic criteria renders pyoderma gangrenosum (PG) a diagnosis of exclusion. The diagnostic approaches proposed to date have not been systematically evaluated. Thus, PG remains a challenging and frequently misdiagnosed disorder.
Objectives
To develop and assess a comprehensive yet clinically practicable as well as sensitive diagnostic scoring system for PG.
Methods
Clinical history and images of a total of 60 subjects with previously confirmed PG located on the lower extremity as well as a control cohort of 50 patients with venous leg ulcers were retrospectively evaluated by expert teams at two tertiary dermatological centres specializing in wound care using a newly developed diagnostic scoring system composed of ten criteria.
Results
The three major diagnostic criteria are rapidly progressing disease, assessment (absence) of relevant differential diagnoses and reddish-violaceous wound border (prevalent in 98.3% of PG patients, respectively). Minor criteria (evident in 61-95% of PG cases) include amelioration (alleviation) by immunosuppressant drugs, characteristically irregular shape of ulceration, extreme pain >4/10 on visual analogue scale, and localization of lesion at site of trauma. Three additional criteria (observed in up to 60% of PG subjects) encompass suppurative inflammation in histopathology, undermined wound margins as well as concomitant systemic disease. A total score value of ten points or higher indicates a high likelihood of PG and differentiates PG from venous leg ulcers. The initial letters of the above-listed criteria form the acronym PARACELSUS.
Conclusion
The PARACELSUS score represents a novel, easily implementable, effective and sensitive diagnostic tool for PG.
This article is protected by copyright. All rights reserved.
Sirolimus for treatment of Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon: A retrospective cohort study
Abstract
Kaposiform hemangioendothelima (KHE) is a locally aggressive vascular tumor that mainly occurs during childhood and invades adjacent tissue and organ. It is commonly complicated by Kasabach-Merritt phenomenon (KMP) in about 50%-70% of the cases. KMP is most often associated with a rapidly growing, large solitary tumor that may result in severe hemorrhage and directly responsible for high mortality and morbidity.
This article is protected by copyright. All rights reserved.
“Cleaved Lymphocytes” Could Be Induced by Pertussis Toxin Injection in Mice, and Are Actually Not Lymphocytes
To the Editor—With great interest we read the most recent contribution of Zhang et al reporting that a simple blood smear may provide a diagnostic clue for Bordetella pertussis infection [1]. Zhang et al described a case of pertussis with peripheral blood smear showing mature lymphocytes with cleaved nuclei, characteristic of B. pertussis lymphocytosis. As the authors state, this finding provides a possibly easy and new way to determine pertussis, because current laboratory tests, such as isolation of B. pertussis and detection of its bacterial DNA, are not widely available. Their results were also supported by other 2 previous reports published in Blood [2] and The Lancet Infectious Diseases [3]. However, there were several questions about these "cleaved lymphocytes." Can these cells occur in the blood after the pertussis toxin (PT) injection? PT is a specific toxin of B. pertussis and is the cause of lymphocytosis [4]. If true, cleaved lymphocytes could be a clue to suspect pertussis. In addition, do the cleaved lymphocytes belong to lymphocytes? After all, their morphologic characteristics are obviously different from normal lymphocytes.
Discharge Criteria for Patient With Lassa Fever Infection
To the Editor—We read with interest the report on 2 epidemiologically linked patients with Lassa fever (LF) secondarily acquired from the same index case in Togo and medically evacuated to Cologne, Germany (patient E) and to Atlanta, Georgia (patient F), respectively [1].
Reply to Nicastri et al
To The Editor— We appreciate the comments of Nicastri, Vairo, and Ippolito regarding the need to identify parameters for safe hospital discharge of Lassa fever patients in nonendemic settings.
Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial
Abstract
Background
Vaccination of human immunodeficiency virus (HIV)-infected infants with bacille Calmette-Guérin (BCG) is contraindicated. HIV-exposed newborns need a new tuberculosis vaccination strategy that protects against tuberculosis early in life and avoids the potential risk of BCG disease until after HIV infection has been excluded. Methods
This double-blind, randomized, controlled trial compared newborn MVA85A prime vaccination (1 × 108 PFU) vs Candin® control, followed by selective, deferred BCG vaccination at age 8 weeks for HIV-uninfected infants and 12 months follow-up for safety and immunogenicity. Results
A total of 248 HIV-exposed infants were enrolled. More frequent mild–moderate reactogenicity events were seen after newborn MVA85A vaccination. However, no significant difference was observed in the rate of severe or serious adverse events, HIV acquisition (n = 1 per arm), or incident tuberculosis disease (n = 5 MVA85A; n = 3 control) compared to the control arm. MVA85A vaccination induced modest but significantly higher Ag85A-specific interferon gamma (IFNγ)+ CD4+ T cells compared to control at weeks 4 and 8 (P < .0001). BCG did not further boost this response in MVA85A vaccinees. The BCG-induced Ag85A-specific IFNγ+ CD4+ T-cell response at weeks 16 and 52 was of similar magnitude in the control arm compared to the MVA85A arm at all time points. Proliferative capacity, functional profiles, and memory phenotype of BCG-specific CD4 responses were similar across study arms. Conclusions
MVA85A prime vaccination of HIV-exposed newborns was safe and induced an early modest antigen-specific immune response that did not interfere with, or enhance, immunogenicity of subsequent BCG vaccination. New protein-subunit and viral-vectored tuberculosis vaccine candidates should be tested in HIV-exposed newborns. Clinical Trials Registration
NCT01650389.Trichomonas vaginalis Brain Abscess in a Neonate
Abstract
We describe a case of cerebral trichomoniasis in a neonate in whom seizures and multiorgan failure developed during treatment for staphylococcal sepsis. Brain abscesses were identified with cranial sonography, and Trichomonas vaginalis was isolated from cerebrospinal fluid samples. The patient died despite metronidazole therapy.Dengvaxia Efficacy Dependency on Serostatus: A Closer Look at More Recent Data
To the Editor—We read with concern the recent article by Yang and colleagues, "Dependency of Vaccine Efficacy on Pre-Exposure and Age: A Closer Look at a Tetravalent Dengue Vaccine" [1]. We agree that Dengvaxia was efficacious among children who were dengue seropositive at baseline, but it is important to mention that it is not known how long vaccinated seropositive individuals will be protected. More studies are necessary as this vaccine could be giving only a temporary boost to their immunity.
Reply to Aguiar and Stollenwerk
To the Editor—Aguiar and Stollenwerk [1] analyzed the safety data provided in Martínez-Vega et al [2] for 2 phase 3 clinical trials of Dengvaxia during up to 6 years of follow-up. The authors reported negative vaccine efficacy (VE) against hospitalization, –76% among baseline seronegative individuals 2–8 years old and –40% among 2–16 years old and expressed their concerns, although neither estimate is statistically significant. Martínez-Vega et al presented similar results but challenged the concept of vaccine-induced antibody-dependent enhancement among seronegative young children [2]. Despite the safety concerns, Dengvaxia remains important in the current portfolio for controlling dengue [3]. The ongoing debate on the utility of Dengvaxia justifies our focus on a thorough quantification of the impact of preexposure and age on VE against general dengue disease during the 25-month active phase [4]. A deep understanding of major determinants of the VE against general clinical outcomes would greatly benefit the assessment of the overall public health impact of Dengvaxia in the long run, for example, using the approach of mathematical modeling [3, 5].
Reply to Gilchrist et al. and to Musher
To the Editor—We read with interest Gilchrist and colleagues' report of an adult case of recurrent bacterial meningitis, presenting with both an immunodeficiency and a local promoting factor. The patient first presented with a history of 2 episodes of pneumococcal meningitis in 3 years and then an episode of meningococcal meningitis 6 years later, despite antibiotic prophylaxis (the details of which were not provided) and protein-conjugate vaccination (probably against Streptococcus pneumoniae). After the first 2 episodes, immunological evaluation detected an IgG2 subclass deficiency and associated poor anti-pneumococcal antibody responses. Surprisingly, an initial computed tomography (CT) scan did not find any skull base abnormalities after the 2 episodes of pneumococcal meningitis. However, dehiscence of the right tegmen tympani was observed after the episode of meningococcal meningitis—suggesting a cerebrospinal fluid leak. When directly questioned in this respect, the patient reported watery rhinorrhea.
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