An integrated analysis of herpes virus infections from eight randomized clinical studies of baricitinib in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus. OBJECTIVES: This study examined treatment-emergent (TE) herpes simplex infection including eczema herpeticum (EH), and herpes zoster (HZ), in adult patients with AD receiving ≥1 dose of baricitinib (BARI), an oral selective inhibitor of Janus kinase 1/2. METHODS: We evaluated data from six double-blinded, randomized, placebo-controlled (PC) trials and two long-term extension studies, within three analysis sets: PC, 2-4-mg BARI extended and All-BARI-AD. Frequency, incidence rate (IR)/100 person-years (PYs) and clinical characteristics of TE-herpes simplex, EH and HZ were reported. RESULTS: In the All-BARI-AD dataset (n = 2531; 2247 PYs), herpes simplex was reported in 8.9% of patients (n = 224; IR = 10.3). Most herpes simplex events were rated as mild or moderate (93.3%), rarely led to permanent discontinuation (2.2%) and presented mostly as oral/perioral herpes simplex (51.3%). TE-EH occurred at a low frequency (All-BARI-AD 1.7% n = 43; IR = 2.0) and were reported in 0.5%, 0.2% and 1.4% of patients receiving placebo, 2-mg or 4-mg BARI respectively. In the All-BARI-AD dataset, most events were investigator-rated as mild/moderate (79.1%), affected ≤2% of the body surface area (74.2%) and occurred as single events (88.4%). Serious TE-EH (n = 11) occurred exclusively in patients with poor disease control (vIGA-AD™ score ≥3) at infection onset. TE-HZ was reported in 2.1% of BARI patients (n = 53; IR = 2.3), without a dose relationship during the PC period (IR = 2.7 and IR = 0.0) or the extended dataset (IR = 3.7 and IR = 1.7) for 2- or 4-mg BARI respectively. CONCLUSIONS: TE-herpes simplex was common, while occurrence of EH was uncommon. Most events of EH were localized with involvement of a small BSA and were linked to poor disease control. Events of HZ were rare in the PC dataset and without a dose dependent increase in frequency.

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

BACKGROUND: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. OBJECTIVE: To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. METHODS: This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. RESULTS: Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. CONCLUSION: This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

Ductal adenocarcinoma of the prostate diagnosed on needle biopsy: correlation with clinical and radical prostatectomy findings and progression.

Ductal adenocarcinoma of the prostate, previously referred to as endometrioid cancer, is typically diagnosed on transurethral resection. When treated by radical prostatectomy (RP), it pursues a more aggressive clinical course than usual acinar prostate cancer does. The significance of prostate cancer with ductal features found on needle biopsies from the peripheral zone is unknown. We reviewed 58 prostate needle biopsy cases with ductal adenocarcinoma for which we were able to obtain clinical information. Patients had a mean age of 69 years (range, 50-89 years) and had a wide range of levels of serum prostate-specific antigen (median, 7.9 ng/mL) and clinical stages. Six (10%) had metastases at the time of diagnosis. Cribriform or papillary structures or a mixture of the two patterns were seen in 86% of cases, whereas in the remaining cases, discrete glands composed of tall columnar cells were present. Stromal fibrosis accompanied the ductal carcinoma in 67% of the cases. A coexisting acinar carcinoma component was identified in 48% of the biopsy specimens. On biopsy, the ductal component composed a mean of 82% of the tumor. Of the 20 tumors treated by RP, 63% had extraprostatic spread of tumor and 20% had positive margins. Two (10%) cases showed seminal vesicle invasion, but none had lymph node metastases. The number of positive needle cores correlated with RP margin status (p<0.004) and with likelihood of clinical progression (p<0.02), but not with organ-confined status. Tumor volume calculated on the 11 extensively sampled RPs ranged from 0.15 cm3 to 20.3 mL (mean, 2.8 cm3). Two years after therapy, the actuarial risk of progression was between 34% (RP patients) and 42% (all patients). A shortened average time to progression was observed relative to a previous study group of men with acinar carcinoma. Serum prostate-specific antigen levels correlated with neither RP organ-confined status nor tumor volume. We conclude that prostatic ductal adenocarcinoma seen on needle biopsy implies more advanced cancer with a shortened time to progression.

Extensively necrotic cystic renal cell carcinoma: a clinicopathologic study with comparison to other cystic and necrotic renal cancers.

Renal cell carcinomas often show varying degrees of necrosis and cystic change. The prognostic importance of necrosis so extensive that only a few tumor cells can be identified is not clear. We gathered clinicopathologic and follow-up data on a group of eight such cases ("type I"). These patients were compared with two other groups of renal cell carcinomas: those with extensive necrosis (>50%), yet with readily identifiable tumor ("type II"), and cancers with extensive cystic change not resulting from necrosis, usually multiloculated ("type III"). The groups showed similar demographic characteristics, and within each group there was great variation in tumor size. Conventional (clear cell) histology was more common than papillary morphology in all groups. The type II neoplasms tended to be of higher nuclear grade and pathologic stage than the other groups. While one of six type I patients with follow up progressed 131 months after diagnosis, eight of 20 type II patients showed progression. None of the six type III patients with follow up progressed. We conclude that renal cell carcinomas showing extensive necrosis are capable of aggressive behavior, and patients with these lesions cannot be assured of cure following surgery. Pathologists must be aware of this entity and extensively sample any renal lesion showing extensive necrosis. The tumors showing a greater amount of viable neoplastic cells yet at least 50% necrosis had a higher rate of progression than did the type I patients. The lack of progression of any of the type III cases supports the idea that type III multiloculated cystic renal cell carcinomas may carry a distinctly better prognosis than other forms of renal cell carcinoma.

Absorption characteristics of a new valproate formulation: divalproex sodium-coated particles in capsules (Depakote Sprinkle).

To determine the absorption characteristics of a new dosage form of divalproex sodium consisting of coated particles in a pull-apart capsule (Depakote Sprinkle, Abbott Laboratories, North Chicago, IL), two absorption studies were conducted in adult volunteers. Ten fasting men participated in a single-dose, crossover study comparing absorption from Sprinkle capsules versus enteric-coated tablets (study 1). Eleven men participated in a multidose study (study 2) in which Sprinkle capsules or enteric-coated tablets were given once every 24 hours for three doses under fasting and nonfasting conditions. In study 1, the extent of absorption from Sprinkle capsules equalled that from enteric-coated tablets. Compared to enteric-coated tablets, Sprinkle capsules had earlier absorption onset, 1 versus 2.6 hours (P less than .05), slightly slower absorption rate, time to reach peak (tmax) of 4.0 versus 3.4 hours (P less than .1), and lower maximum peak plasma drug concentration (Cmax), 20.7 versus 25.9 mcg/mL (P less than .05). In study 2, food intake did not affect onset or extent of absorption nor maximum concentration, but did slow rate of absorption. Time to reach peak concentration was 2.7 hours for tablet (fasting), 3.3 hours for capsule (fasting), and 4.8 hours for capsule (nonfasting) (P less than .05). Intrasubject absorption performance from the three doses was highly consistent, regardless of food intake. These data indicate that Sprinkle capsules possess desirable absorption characteristics in a form that makes ingestion easier for patients who have difficulty taking other valproate dosage forms.

Atypical extralobar sequestration: CT-pathological correlation.

Pulmonary sequestration is a malformation comprised of dysplastic lung tissue without normal communication with the tracheobronchial tree and with an anomalous systemic arterial supply. Pulmonary sequestration is classified into two types, intralobar and extralobar based on the location of the malformation and the venous drainage. Extralobar sequestration is less common than intralobar sequestration and usually has systemic venous drainage into the azygos system. Most patients with extralobar sequestration are diagnosed before the age of 10. We present an interesting and unusual case of extralobar sequestration which presented as a retroperitoneal mass in an asymptomatic adult.

Unit dose sampling and final product performance: an alternative approach.

This article documents a proposed plan for validation testing for the content uniformity for final blends and finished solid oral dosage forms (SODFs). The testing logic and statistical justification of the plan are presented. The plan provides good assurance that a passing lot will perforin well against the USP tablet content uniformity test. The operating characteristics of the test and the probability of needing to test for blend sampling bias are reported. A case study is presented.

Can ploidy of prostate carcinoma diagnosed on needle biopsy predict radical prostatectomy stage and grade?

PURPOSE: Deoxyribonucleic acid ploidy correlates with the biological behavior of prostate carcinoma. However, the usefulness of ploidy on needle biopsies that show prostate cancer has not been established to our knowledge. MATERIALS AND METHODS: We retrospectively determined ploidy on needle biopsies of 159 men with prostate carcinoma treated surgically at Johns Hopkins Hospital. Ploidy was determined by image analysis of Feulgen stained slides. Needle ploidy and Gleason score were compared as prognostic tools in the prediction of grade and stage of subsequent prostatectomy. RESULTS: Of the 159 cases 98 (62%) were diploid, 16 (10%) tetraploid and 45 (28%) aneuploid. Of the diploid, tetraploid and aneuploid tumors 69, 50 and 44%, respectively, proved to be organ confined. Tetraploid and aneuploid tumors were grouped for the remaining analysis. Needle ploidy correlated significantly with pathological stage (p = 0.003). However, needle Gleason score correlated even more strongly (p <0.001), and on multivariate analysis ploidy was not further predictive of pathological stage once Gleason score was considered. Needle ploidy and Gleason score were predictive of prostatectomy Gleason score (6 or less versus 7 or greater), and on multivariate analysis ploidy was an independently significant predictor of this parameter (p = 0.04). In 13 cases (8%) there was an important grading discrepancy, in which needle ploidy would have accurately predicted prostatectomy grade. However, in 33 cases (21%) needle and prostatectomy Gleason scores were congruent, and needle ploidy did not accurately predict prostatectomy Gleason score. CONCLUSIONS: With accurate needle Gleason grading, ploidy is not helpful in predicting prostatectomy findings. However, ploidy correlates with prostatectomy stage and grade, and may be useful if accurate Gleason grading is a concern.