Bosutinib in Combination With the Aromatase Inhibitor Exemestane: A Phase II Trial in Postmenopausal Women With Previously Treated Locally Advanced or Metastatic Hormone Receptor‐Positive/HER2‐Negative Breast Cancer

Background.

Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC.

Methods.

This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned.

Results.

Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy’s law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0–15.6).

Conclusion.

The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.     

Cystic neoplasms of the pancreas with mucin-production.

AIM: To compare the clinico-pathological features of intraductal papillary mucinous cystic tumours (IPMT) and mucinous cystic tumours (MCT) of the pancreas. METHODS: Eighteen patients with IPMT and 18 with MCT who underwent surgical resection between 1990 and 2004 were retrospectively reviewed. Their clinico-pathological features were compared using univariate analysis. Statistical analyses of potential predictive factors of malignancy for each of these two groups were also conducted. RESULTS: Patients with IPMT were found to be older (64+/-10 vs 43+/-18 years, p<0.001) and were predominantly male (male:female ratio, 5:4 vs 1:17, p=0.003) as compared to patients with MCT. MCTs were found in the body-tail region (100%) whereas IPMTs were more evenly distributed (50% in the head) (p=0.001). Pathologically, IPMT was distinct from MCT in terms of size (3.8+/-3.2 vs 9.1+/-4.4 cm, p=0.001), association with secondary pancreatitis (50 vs 0%, p=0.011), communication with the pancreatic duct (94 vs 0%, p<0.001), presence of a dilated main pancreatic duct (61 vs 0%, p<0.001) and the presence of ovarian-type stroma (0 vs 44%, p=0.003). CONCLUSION: IPMT and MCT are distinct clinico-pathological entities. This distinction is important as management and outcome of these entities may differ.     

Human Parainfluenza Virus in Homeless Shelters before and during the COVID-19 Pandemic,Washington, USA

To determine the epidemiology of human parainfluenza virus in homeless shelters during the COVID-19 pandemic, we analyzed data and sequences from respiratory specimens collected in 23 shelters in Washington, USA, during 2019–2021. Two clusters in children were genetically similar by shelter of origin. Shelter-specific interventions are needed to reduce these infections.     

Small cell variant of Ki-1 lymphoma associated with myelofibrosis and a novel constitutional chromosomal translocation t(3;4) (q13;q12).

An unusual case of small cell variant of Ki-1 non-Hodgkin's lymphoma diagnosed one year after an original diagnosis of idiopathic myelofibrosis is reported. On the second occasion, the patient presented with fever, lymphadenopathy and hepatosplenomegaly. A lymph node biopsy specimen confirmed a diagnosis of small cell variant of Ki-1 lymphoma. A repeat bone marrow biopsy specimen showed myelofibrosis with no evidence of lymphomatous infiltration, but cytogenetic studies on blood, bone marrow and skin fibroblasts revealed a novel chromosomal translocation t(3,4)(q13;q12).     

H2‐M3‐restricted CD8+ T cells augment CD4+ T‐cell responses by promoting DC maturation

Infection with Listeria monocytogenes triggers the activation and expansion of nonconventional CD8⁺ T cells restricted by the MHC class Ib molecule, H2‐M3. H2‐M3‐restricted CD8⁺ T cells exhibit a memory phenotype, rapidly produce cytokines, and reach peak frequencies sooner than conventional MHC class Ia‐restricted CD8⁺ T cells. In this study, we found that simultaneous in vivo priming of H2‐M3‐restricted T cells and adoptively transferred OT‐II CD4⁺ T cells on the same DC enhances the survival of OT‐II cells. Stimulation of H2‐M3‐restricted T cells were found to induce DC maturation resulting in costimulatory molecule upregulation and production of T_H1‐type cytokines, which was dependent on both cell‐to‐cell contact and soluble factors, particularly TNF‐α, produced by activated H2‐M3‐restricted T cells. Interestingly, H2‐M3‐restricted T cells were more efficient than activated NK cells in inducing DC maturation. Furthermore, we found that OVA_323–339‐coated DC matured by coculturing with peptide‐stimulated H2‐M3‐restricted T cells were more efficient in stimulating the proliferation of Ag‐activated OT‐II cells. This study indicates that H2‐M3‐restricted T cells promote immune responses by CD4⁺ T cells by inducing DC maturation and suggests novel mechanisms for vaccine development.     

Abdominal visceral findings in patients with Marfan syndrome.

PURPOSE: Marfan syndrome is an autosomal dominant disorder historically defined by well-characterized features in the cardiovascular, ocular, and skeletal systems. To date, there have been no reports concerning abdominal visceral findings in this disorder. The purpose of this study was to determine the prevalence of abdominal visceral findings in patients with Marfan syndrome. METHODS: Computed tomography or magnetic resonance studies of 69 patients with Marfan syndrome and an age- and sex-matched cohort of control subjects were reviewed. The presence of abdominal visceral findings was noted. Chi-square and Student t tests were used to determine significance of differences between the patient and control groups. This retrospective study was approved by the local institutional review board and determined to be exempt from Health Insurance Portability and Accountability Act reporting requirements. RESULTS: Renal cysts were present in 41 Marfan patients (59.4%) versus 21 control subjects (30.4%), P=0.001. The average number of renal cysts was greater in Marfan patients than controls (2.4 vs. 0.9, P=0.005). Hepatic cysts were present in 24 Marfan patients (34.8%) versus 12 control patients (17.3%), P=0.02. The average number of hepatic cysts was also greater in Marfan patients than controls (0.9 vs. 0.3, P=0.027). Cholelithiasis was present in 12 Marfan patients (18.1%) versus one control patient (1.5%), P<0.001. CONCLUSIONS: Marfan syndrome patients have liver and renal cysts more often, in increased number, and at an earlier age than controls, in addition to an increased prevalence of cholelithiasis. Further study will be needed to relate these findings to recent developments concerning the underlying molecular genetics of this disorder.     

Ultrastructural Observations on Penicillium marneffei in Natural Human Infection

The ultrastructure of Penicillium marneffei and the host response to the infection were studied in two patients. One was immunocompetent and the other an immunosuppressed renal graft recipient. In the immunocompetent patient it was observed that all the yeast cells were phagocytosed and were found either within membrane-bound vacuoles or lying freely within the cytoplasm of the macrophages. It was postulated that continuous lysosomal fusion with the phagolysosomes and multiplication of the fungi within the phagocytic vacuoles might eventually lead to the rupture of the vacuoles with release of the organisms into the cytoplasm of the macrophages. In the second patient, the immunosuppressive effects of corticosteroids might account for the large number of nonphagocytosed fungi in the tissue space, and the failure to form large phagocytic vacuoles.     

Cholesteryl-grafted functional amphiphilic poly(N-isopropylacrylamide-co-N-hydroxylmethylacrylamide): synthesis, temperature-sensitivity, self-assembly and encapsulation of a hydrophobic agent

A thermally responsive amphiphilic grafted copolymer comprised of hydroxyl-containing random poly(N-isopropylacrylamide-co-N-hydroxylmethylacrylamide) as the hydrophilic chain and cholesteryl groups as hydrophobic side arms was developed for the controlled release of hydrophobic drugs. The polymer was temperature-sensitive with a lower critical solution temperature of 40.5 degrees C and a critical micelle concentration of 4 mg/l. Dynamic light-scattering studies showed that the amphiphilic polymer self-assembled into micelles in aqueous media with their mean sizes in the range of 25-34 nm. Transmission electron microscope studies showed that the nanoparticles prepared from the micelle solutions exhibited multiple morphologies including unusual cubic and cuboids-like shapes, and normal spherical shapes, which could be controlled by the formation conditions. Wide-angle X-ray scattering studies showed that these nanoparticles were amorphous in nature but a small crystalline phase existed and the crystallinity of particles increased with the decrease of initial formation concentration. Pyrene was employed as a model hydrophobic agent to examine the encapsulation ability of the polymer with respect to hydrophobic agents in aqueous media. The loading level of the polymer with respect to pyrene was 4.4 mg/g, indicating that the thermally responsive amphiphilic polymer would be able to be used for the encapsulation of hydrophobic drugs.     

Patterns of dysmorphic features in schizophrenia.

Congenital dysmorphic features are prevalent in schizophrenia and may reflect underlying neurodevelopmental abnormalities. A cluster analysis approach delineating patterns of dysmorphic features has been used in genetics to classify individuals into more etiologically homogeneous subgroups. In the present study, this approach was applied to schizophrenia, using a sample with a suspected genetic syndrome as a testable model. Subjects (n = 159) with schizophrenia or schizoaffective disorder were ascertained from chronic patient populations (random, n = 123) or referred with possible 22q11 deletion syndrome (referred, n = 36). All subjects were evaluated for presence or absence of 70 reliably assessed dysmorphic features, which were used in a three-step cluster analysis. The analysis produced four major clusters with different patterns of dysmorphic features. Significant between-cluster differences were found for rates of 37 dysmorphic features (P < 0.05), median number of dysmorphic features (P = 0.0001), and validating features not used in the cluster analysis: mild mental retardation (P = 0.001) and congenital heart defects (P = 0.002). Two clusters (1 and 4) appeared to represent more developmental subgroups of schizophrenia with elevated rates of dysmorphic features and validating features. Cluster 1 (n = 27) comprised mostly referred subjects. Cluster 4 (n = 18) had a different pattern of dysmorphic features; one subject had a mosaic Turner syndrome variant. Two other clusters had lower rates and patterns of features consistent with those found in previous studies of schizophrenia. Delineating patterns of dysmorphic features may help identify subgroups that could represent neurodevelopmental forms of schizophrenia with more homogeneous origins.