A morphometric comparative study of the lateral geniculate body in selected placental mammals: the common shrew, the bank vole, the rabbit, and the fox

The lateral geniculate body (LGN) was morphometrically examined and compared in representatives of four mammalian orders (Insectivora, Rodentia, Lagomorpha, and Carnivora). In each studied species, the lateral geniculate body was divided into two distinct parts: the dorsal nucleus (LGNd) and the ventral nucleus (LGNv). The lateral geniculate body of the common shrew and the bank vole are very similar in appearance and nuclear pattern. The dorsal and ventral nuclei of these two species also have the most similar statistical characteristics. The lateral geniculate body of the fox has the most complicated morphology and multilayered structure. A significant disproportion was observed between the sizes of both geniculate nuclei in the fox, where the dorsal nucleus definitely surpassed the ventral nucleus in terms of volume. With the exception of the fox, the neuronal density of the LGN nuclei was negatively correlated with the volumes of the LGN. The mean neuronal size of the LGNd and LGNv, which was the resultant of the length, width, area, and circumference of the soma, grew correlatively to the volumes of these nuclei. In all examined species, somas of the LGNd neurons are distinctly larger and have more similar shapes than the LGNv perikarya. In addition, the numerical density of neurons in the ventral nucleus is significantly higher than in the dorsal nucleus. All these morphometric parameters clearly differentiate the LGNd from the LGNv

The nerve cells of the neostriatum in the common shrew (Sorex araneus) and bank vole (Clethrionomys glareolus): a Golgi comparative study

The studies were carried out on 12 brains derived from adult representatives of two mammalian orders, Insectivora and Rodentia. The neostriatum was compared in the common shrew (Sorex araneus) and bank vole (Clethrionomys glareolus). Three main types of striatal neuron were distinguished in the common shrew and five types of neurons in the bank vole. The fifth type of bank vole neurons was additionally divided into two subtypes with respect to dendritic pattern

The neuronal structure of the dorsal nucleus of the lateral geniculate body in the common shrew (Sorex araneus) and the bank vole (Clethrionomys glareolus): Golgi and Nissl studies

The topography and neuronal structure of the dorsal nucleus of the lateral geniculate body (GLd) of the common shrew and the bank vole are similar. The lateral geniculate body of both the species examined has a homogeneous structure and no observable cytoarchitectonic lamination. On the basis of the shape of the dendritic arbours as well as the pattern of dendritic arborisations the following two types of neurons were distinguished. Type I “bushy” neurons that have multipolar or round perikarya (common shrew perikarya 9–12 µm, bank vole perikarya 10–13 µm), with 4–6 short thick dendritic trunks that subdivide into many bush-like branches. The dendritic trunks are smooth, in contrast to the distal branches, which are covered with numerous spine-like protrusions of different lengths and forms. An axon emerges from the soma, sometimes very close to one of the primary dendrites. The type I neurons are typically projection cells that send their axons to the primary visual cortex. These neurons predominate in the GLd of both species. Type II neurons, which have an elongated soma with primary dendrites arising from opposite poles of the perikaryon (common shrew perikarya 8–10 µm, bank vole perikarya 9–11 µm). The dendritic arbours of these cells are less extensive and their dendrites have fewer spines than those of the type I neurons. Axons were seldom observed. The type II neurons are presumably interneurons and are definitely less numerous than the type I neurons

The neuronal structure of the preoptic area in the mole and the rabbit: Golgi and Nissl studies

The present studies were carried out on the brains of the adult mole and rabbit. The preparations were made by means of the Golgi technique and the Nissl method. Two types of neurons were distinguished in the preoptic area (POA) of both species: bipolar and multipolar. The bipolar neurons have oval, fusiform or round perikarya and two dendritic trunks arising from the opposite poles of the cell body. The dendrites bifurcate once or twice. The dendritic branches have swellings, single spine-like and filiform processes. The multipolar neurons usually have triangular and quadrangular perikarya and from 3 to 5 dendritic trunks. The dendrites of the mole neurons branch sparsely, whereas the dendrites of the rabbit neurons display 2 or 3 divisions. On the dendritic branches varicosities and different protuberances were observed. The general morphology of the bipolar and multipolar neurons is similar in the mammals studied, although the neurons of the rabbit POA display a more complicated structure. Their dendritic branches show more divisions and possess more swellings and different processes than the dendrites of the neurons of the mole POA. Furthermore, of the multipolar neurons only the dendrites in POA of the rabbit were observed to have a rosary-like beaded appearance

A morphometric study of the preoptic area of the guinea pig

The aim of the study was to provide the topography and morphometric characteristics of the preoptic area (POA) of the guinea pig. The study was carried out on the brains of sexually mature guinea pigs of both sexes. A uniform procedure was followed in the study of the paraffin-embedded brain tissue blocks of males and females. The blocks were cut in the coronal plane into 50 mm sections and stained according to the Nissl method. The guinea pig POA consists of four parts: the medial preoptic area (MPA), lateral preoptic area (LPA), periventricular preoptic nucleus (PPN), and median preoptic nucleus (MPN). The topography and general structure of POA parts are similar in males and females. However, the PPNa cells of females are more intensely stained and are more densely packed than the PPNa cells of males. For morphometric analysis, the MPA and LPA as well as PPN and MPN were considered respectively as uniform structures, namely MPA-LPA and PPN-MPN. The statistical analysis showed that the volume of the PPN-MPN was larger in males than in females, whereas the MPA-LPA volume did not differ between the sexes. Moreover, the numerical density and the total number of neurons were statistically larger in males than in females in both the MPA-LPA and PPN-MPN. The parameters describing POA neurons were larger for MPA-LPA neurons in comparison with the PPN-MPN neurons. However, in this respect no sex differences were observed in both studied complexes. Folia Morphol 2010; 69, 1: 15-2

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

© 2019 by The American Society of Hematology Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n 5 195) and PCYC-1115/1116 (RESONATE-2, n 5 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n 5 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n 5 173, 52% any-grade; n 5 15, 5% grade 3) and fatigue (n 5 119, 36% any-grade; n 5 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n 5 60, 18%) and pneumonia (n 5 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade $3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n 5 4), anemia (n 5 3), and atrial fibrillation (n 5 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069

Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kδ inhibition

The majority of chronic lymphocytic leukemia (CLL) patients are diagnosed with early-stage disease but the currently used prognostic tools appear to be less informative in this group of patients.1 This is especially problematic for patients with mutated immunoglobulin genes (M-CLL) as they have a more diverse clinical course when compared with patients with unmutated immunoglobulin genes (U-CLL).1, 2, 3, 4 Given the emergence of promising targeted, less toxic, therapeutics in CLL,5, 6 there is an increased need to identify patients who might benefit from early treatment with these new agents

Outcomes with ibrutinib by line of therapy and post‐ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first‐line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher‐risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib‐treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single‐agent ibrutinib: RESONATE (PCYC‐1112) in patients with R/R CLL and RESONATE‐2 (PCYC‐1115) in patients with treatment‐naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib‐treated non‐del(17p) patients with CLL (136 TN and 135 R/R). Median progression‐free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow‐up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow‐up 18 months, n = 51) and was not reached in TN patients (median follow‐up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2.

Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], ≥75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade ≥3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346