Window of opportunity treatment in breast cancer

Window of opportunity therapies, which involve short‐term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone‐receptor positive breast cancer, a 2‐week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision‐making regarding treatment options. Changes in short‐term biomarker endpoints such as cell proliferation measured by Ki‐67 can act as surrogate markers of long‐term outcomes. Paired tissues obtained pre‐ and post‐investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.     

Change in male secondary sexual characters in artificial interspecific hybrid populations.

The interfertile Hawaiian species Drosophila silvestris and Drosophila heteroneura were hybridized, forming reciprocal populations; the SH hybrid line was begun with D. silvestris female parents, and the HS hybrid line was begun with D. heteroneura female parents. Mass laboratory cultures were maintained for 14 generations without artificial selection. The species differ strikingly in two male secondary sexual characters, head shape and foreleg tibial cilia number. These characters are known to be quantitative characters that are influenced by both sex-linked and autosomal factors and appear to be involved in sexual selection. In the later generations (4-14), head shape in SH flies changes significantly; cilia number changes in both SH and HS populations. In terms of the parental phenotypes, the SH population evolved toward a heteroneura-like head while simultaneously evolving toward a silvestris-like tibia. In the HS population, there was no significant change in head shape, but cilia number decreased, making it more like the parental heteroneura. Accordingly, these two secondary sexual characters pursue separate evolutionary pathways. We suggest that these changes are brought about by selection occurring naturally during the later generations.     

A heavy metal baseline score predicts outcome in acute myeloid leukemia

Despite abundant epidemiological data linking metals to leukemia and other cancers, baseline values of toxic and essential metals in patients with leukemia and the clinical impact of these metals remain unknown. Thus, we sought to quantify metal values in untreated patients with acute myeloid leukemia (AML) and controls and determine the impact of metal values on AML patients' survival. Serum samples from patients with untreated AML and controls at Hospices Civils de Lyon were analyzed and compared for trace metals and copper isotopic abundance ratios with inductively coupled plasma mass spectrometry. Survival analysis was performed as a function of metal values, and a multi-metal score was developed for patients with AML. Serum samples were collected from 67 patients with untreated AML and 94 controls. Most patients had intermediate-risk cytogenetics (63.1%) without FLT3 internal tandem duplication mutations (75.6%) or NPM1 mutations (68.1%). Most metal values differed significantly between AML and control groups. Patients with lower magnesium and higher cadmium values had the worst survival rates, with only 36% surviving at 6 months (P = .001). The adverse prognostic effect of this combination was maintained on multivariate analysis. Based on this, we developed a novel metal score, which accounts for multiple relative abnormalities in the values of five toxic and five essential metals. Patients with a higher metal score had significantly worse survival, which was maintained on multivariate analysis (P = .03). This baseline metal scoring system was also prognostic when we applied it to a separate population of front-line AML patients.     

Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients

FSGS recurs in approximately 30% of transplanted kidneys and may lead to graft loss. We retrospectively examined the efficacy of early and intensive PP without additional IS in pediatric kidney transplant patients with recurrent FSGS at our center. Seven of 24 patients (29%) had nephrotic proteinuria and histologic evidence of FSGS recurrence within 1–5 days post‐transplantation. PP was initiated early after transplantation and initially performed daily until sustained decline in proteinuria. PP frequency was then individually tapered according to proteinuria. Recurrent FSGS in all seven patients responded to a four‐ to 32‐wk course of PP. Two of seven patients had a second recurrence of FSGS, and both recurrences remitted after an additional 3–6 wk of PP. Median observation period was 4.5 yr (0.8–16.3 yr). Complete remission of recurrent FSGS has been sustained in all seven patients, and all patients have stable graft function with recent plasma creatinine <1.5 mg/dL in six of seven patients. Most recent urine protein/creatinine is 0.13–0.61 mg/mg in six of seven patients. One patient has heavy proteinuria secondary to chronic allograft nephropathy 16 yr post‐transplant. Intensive and prolonged PP, when initiated early in the post‐operative period, is effective in treating recurrent FSGS and preventing graft loss without the use of additional immunosuppressants.     

Fine-needle aspiration of supraclavicular lymph nodes

Malignancies from many primary sites may metastasize to supraclavicular lymph nodes (SCLN). We reviewed 100 fine-needle aspirations (FNAs) of SCLNs. There were three major types of malignancy detected by this method: adenocarcinoma (n=40), squamous cell carcinoma (n=14), and other malignancies (n=29). Adenocarcinomas and other malignancies from all sites tended to metastasize to the left SCLN. Squamous cell carcinomas from all sites, however, tended to appear on the right side. For 61 patients, a previous diagnosis of malignancy had been made within 1 yr of the clinical appearance of the abnormal SCLN. For 20 patients, the primary diagnosis antedated SCLN metastasis by more than 1 yr, particularly patients with adenocarcinoma of the breast. prostate, or thyroid papillary carcinoma. Diagn Cytopathol 1996 14:216-220. © 1996 Wiley-Liss, Inc.     

Oral 2-chlorodeoxyadenosine in psoriatic

Objective. To determine if weekly oral 2-chlorodeoxyadenosine (2-CdA) can induce selective lymphocytopenia, and reduce inflammation, in patients with refractory psoriatic arthritis. Methods. Seven patients with psoriatic arthritis were treated with oral 2-CdA at weekly dosages of 0.3 mg/kg to 0.45 mg/kg for 12 weeks, followed by monthly maintenance therapy. The patients were evaluated after 6 months. Results. The drug treatment produced selective lymphocytopenia, and reduced lymphocyte infiltration into involved skin. One patient did not complete 12 weeks of therapy because of perceived lack of efficacy. Four of the 6 remaining patients had improved joint disease, and 5 of 6 had improved psoriasis. Conclusion. Weekly oral 2-CdA appears to be a well-tolerated regimen for the inducement of peripheral lymphocytopenia in patients with psoriatic arthritis. Larger-scale, controlled trials may be warranted.     

Generation and Characterization of two Monoclonal Self-Associating IgG Rheumatoid Factors from a Rheumatoid Synovium

Objective. To study IgG rheumatoid factor (RF) from rheumatoid synovium. Methods. We fused the K6H6/B5 human—mouse heterohybridoma with unstimulated rheumatoid synovial B cells to generate IgG-RF—secreting hybridomas. Results. The RFs from 2 such hybridomas bound specifically to the Fc fragment of human IgG and self-associated to form immune complexes. Such immune complexes are a major characteristic of the pathogenic IgG-RFs in rheumatoid synovium. Conclusion. IgG-RF—secreting hybridomas have been obtained. Analyses may reveal the underlying mechanisms of the induction of IgG-RF.