Insulin-Like Growth Factor Pathway–Targeted Therapy in Breast Cancer

The insulin-like growth factor (IGF) pathway plays an important role in cancer development, survival, metastasis, and resistance to antineoplastic therapies in various malignancies. Components of the IGF pathway are potential targets for novel anticancer therapy. In breast cancer, preclinical and clinical data suggest that IGF signaling is critical for tumor growth and resistance to therapy, leading to poor prognosis. There is also evidence of cross-talk between IGF, estrogen, erbB, and mTOR pathways; a potential mechanism of cancer resistance to hormonal or HER2-targeted therapy. This review discusses the rationale and strategies being evaluated in the clinical development of targeting the IGF pathway. It highlights the potential interactions between the IGF pathway and other therapies in breast cancer, and also focuses on the completed and ongoing clinical trials of different IGF pathway–targeted therapies in breast cancer.     

Suppressor of cytokine signaling-3 Provides a novel interface in the cross-talk between angiotensin II and insulin signaling systems

Angiotensin II inhibits insulin-induced activation of phosphatidylinositol 3-kinase through a mechanism, at least in part, dependent on serine phosphorylation of the insulin receptor and insulin receptor substrates (IRS)-1/2. Recent evidence shows that suppressor of cytokine signaling-3 (SOCS-3) is induced by insulin and angiotensin II and participates in the negative control of further stimulation of each of these signaling systems independently. In the present study, we evaluated the interaction of angiotensin II-induced SOCS-3 with the insulin signaling pathway in the heart of living rats. A single iv dose of angiotensin II promotes a significant increase of SOCS-3 in heart, an effect that lasts up to 180 min. Once induced, SOCS-3 interacts with the insulin receptor, JAK-2, IRS-1, and IRS-2. The inhibition of SOCS-3 expression by a phosphorthioate-modified antisense oligonucleotide partially restores angiotensin II-induced inhibition of insulin-induced insulin receptor, IRS-1 and IRS-2 tyrosine phosphorylation, and IRS-1 and IRS-2 association with p85-phosphatidylinositol 3-kinase and [Ser473] phosphorylation of Akt. Moreover, the inhibition of SOCS-3 expression partially reverses angiotensin II-induced inhibition of insulin-stimulated glucose transporter-4 translocation to the cell membrane. These results are reproduced in isolated cardiomyocytes. Thus, SOCS-3 participates, as a late event, in the negative cross-talk between angiotensin II and insulin, producing an inhibitory effect on insulin-induced glucose transporter-4 translocation.     

Proxy‐reported health‐related quality of life of patients with juvenile idiopathic arthritis: The pediatric rheumatology international trials organization multinational quality of life cohort study

Objective

To investigate the proxy‐reported health‐related quality of life (HRQOL) and its determinants in patients with juvenile idiopathic arthritis (JIA).

Methods

In this multinational, multicenter, cross‐sectional study, HRQOL of patients with JIA was assessed through the Child Health Questionnaire (CHQ) and was compared with that of healthy children of similar age from the same geographic area. Potential determinants of HRQOL included demographic data, physician's and parent's global assessments, measures of joint inflammation, Childhood Health Assessment Questionnaire (CHAQ), and erythrocyte sedimentation rate.

Results

A total of 6,639 participants (3,324 with JIA and 3,315 healthy) were enrolled from 32 countries. The mean ± SD physical and psychosocial summary scores of the CHQ were significantly lower in patients with JIA than in healthy children (physical: 44.5 ± 10.6 versus 54.6 ± 4.0, P < 0.0001; psychosocial: 47.6 ± 8.7 versus 51.9 ± 7.5, P < 0.0001), with the physical well‐being domain being most impaired. Patients with persistent oligoarthritis had better HRQOL compared with other subtypes, whereas HRQOL was similar across patients with systemic arthritis, polyarthritis, and extended oligoarthritis. A CHAQ score >1 and a pain intensity rating >3.4 cm on a 10‐cm visual analog scale were the strongest determinants of poorer HRQOL in the physical and psychosocial domains, respectively.

Conclusion

We found that patients with JIA have a significant impairment of their HRQOL compared with healthy peers, particularly in the physical domain. Physical well‐being was mostly affected by the level of functional impairment, whereas the intensity of pain had the greatest influence on psychosocial health.     

The American Urological Association 2003 guideline on management of benign prostatic hyperplasia: a Canadian opinion

The 2003 American Urological Association (AUA) guideline on management of benign prostatic hyperplasia (BPH) was released at the AUA annual meeting in Chicago, April 2003 and the diagnosis and treatment recommendations were published later in 2003. It is likely that the 2003 AUA guideline on the management of BPH will have a profound effect on clinical urologic practice in the USA, but its influence on Canadian urological practice will be different because of our socialized medical system, manpower issues, availability of expensive technology and our unique Canadian perspective. The authors review the 2003 AUA guideline on the management of BPH and based on a perspective obtained from recent publications, consensus/consultant meetings, focus groups and anecdotal experience, attempt to put the recommendations into Canadian context. We conclude that the 2003 AUA guideline for the management of BPH is an important document that should be studied, evaluated and understood by Canadian urologists. Although our perspective is clearly different than our US colleagues, it is likely that the guideline will influence the management of BPH in Canada.     

Primary low-grade B-cell lymphoma of the urinary bladder: case report and literature review

The first recorded case of lymphoma of the bladder was reported by Eve and Chaffey in 1885. Malignant lymphoma of the bladder can be classified into one of three different clinical groups: 1) Primary lymphoma localized to the bladder; 2) Lymphoma presenting in the bladder as the first sign of disseminated disease (non-localized lymphoma); 3) Recurrent bladder involvement by lymphoma in patients with a history of malignant lymphoma (secondary lymphoma). Primary extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT type) of the urinary bladder, first described by Kempton et al in 1990, is the most common primary bladder lymphoma and associated with an excellent prognosis. We present a patient with gross hematuria who was found to have a primary bladder lymphoma and review the relevant literature.     

Survival analysis of patients with Hodgkin lymphoma who failed high dose chemotherapy and autologous stem cell transplant

Hodgkin lymphoma (HL) patients failing after high dose chemotherapy (HDC) and auto-SCT have a poor outcome. Some patients may still benefit from further treatments. From 1996 to 2016, 137 HL patients (39.5%) out of 347 transplanted experienced post auto-SCT failure. Males/female 61%:39%, median age at auto-SCT 23.4 years and median follow-up 55.6 months (9–153). Type of failure was progressive (46%), relapsed (35%) or persistent disease/refractory disease (19%). Median overall survival (OS) from the time of failure is 20 months; 35 patients (25.5%) are alive. One hundred and four patients received treatment; the response rate was 45%; complete remission in 41 (30%) and partial remission in 21 (15%) patients. 1st interventions post auto-SCT were chemotherapy (39%), radiation therapy (35%) or best supportive care (24%). Twenty-seven patients with 2nd-SCT (allogeneic (15), auto-SCT (2)) and/or brentuximab (18 patients) had superior OS (50.6 months) vs other treatments (22.5 months, P value 0.037). COX regression multivariate analysis identified post auto-SCT treatment failure before 12 months (hazard ratio (HR) 3.37, CI 1.7–6.6, P value <?0.001), presence of B symptoms (HR 2.55, CI 1.4–4.6, P value 0.002), stages III–IV (HR 2.7, CI 1.5–4.9, P value 0.001), albumin <?4 g/dl (HR 1.76, CI 1.1–2.9, P value 0.027) and tumor >?5 cm (HR 1.1.9, CI 1.13–3.25, P value 0.015) as significant risk factors; P value <?0.001. KM OS with 0–1 factor (148.6 months): 2 factors (23.6 months) and 3–5 factors (9.4 months) (P value <?0.001). OS was 63%:25%:7% respectively with 0–1:2:3–5 factors respectively (P value <?0.001). Despite high-risk factors, 2nd-SCT/brentuximab use post HDC auto-SCT failure may result in durable survival.     

Pulmonary Aspergillosis: Spectrum of Disease

Aspergillus species are ubiquitous in the environment. Aspergillosis is acquired by inhalation of Aspergillus spores. In normal hosts, spore inhalation rarely causes lung disease. Pulmonary Aspergillosis covers a wide spectrum of clinical syndromes depending on the interaction between Aspergillus and the host (immune-status, prior bronchopulmonary disease). It runs the gamut from invasive Aspergillosis to Aspergillus bronchitis. Invasive Aspergillosis usually occurs in severely immunocompromised patients, typically in neutropenic but also in non-neutropenic patients. Chronic pulmonary Aspergillosis affects patients with chronic structural lung disease such as COPD or previous mycobacterial lung disease, but without other significant immunocompromise. Aspergillus bronchitis affects patients with bronchial disease such as bronchiectasis. Allergic bronchopulmonary Aspergillosis affects patients with bronchial asthma or cystic fibrosis, and is due to an allergic response to Aspergillus.