In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted ...therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses.
KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS).
The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67, non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence.
T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.
•Baseline PN was associated with longer on-study PN and a lower resolution rate in both study arms.•Prior platinum was associated with more grade 3-4 thrombocytopenia with T-DM1, but not with more grade ≥3 hemorrhage.•IDFS benefit with T-DM1 versus trastuzumab was similar irrespective of neoadjuvant therapy containing anthracyclines.•T-DM1 was not associated with an increased overall risk of CNS recurrence.•The T-DM1 IDFS benefit was maintained in high-risk tumors defined by operable status, nodal involvement, and HR status.
Background: Accumulation of molecular alterations, including mutations in Kirsten-ras (K-ras), p53, and adenomatous polyposis coli (APC), contribute to colorectal carcinogenesis. Our group has ...previously characterised a panel of sporadic colorectal adenocarcinomas for mutations in these three genes and has shown that p53 and K-ras mutations rarely occur in the same colorectal tumour. This suggests that mutations in these genes are on separate pathways to colorectal cancer development and may influence patient prognosis independently. Aims: To correlate the presence or absence of mutations in K-ras, p53, and APC with survival in a cohort of colorectal cancer patients. Patients: A series of 107 inpatients treated surgically for colorectal cancer in Tayside, Scotland between November 1997 and December 1999. Methods: Colorectal tumours were characterised for mutations in K-ras, p53, and APC. Kaplan-Meier survival curves were constructed using overall survival and disease specific survival as the primary end points. Patient survival was analysed using the log rank test and Cox proportional hazards model. Results: Patients with K-ras mutations had significantly poorer overall survival than patients without K-ras mutations (p = 0.0098). Multivariate analysis correcting for Dukes’ stage, age, and sex confirmed this (hazard ratio 2.9 (95% confidence interval 1.4–6.2); p = 0.0040). K-ras mutations were also significantly associated with poorer disease specific survival. The presence of APC and p53 mutations did not affect survival in this cohort of patients (p = 0.9034 and p = 0.8290, respectively). Conclusions: Our data indicate that the presence of K-ras mutations predicts poor patient prognosis in colorectal cancer, independently of tumour stage.
Development of brain metastasis in patients with breast carcinoma correlates with poor outcome. Identification of tumor characteristics associated with breast cancer brain metastases (BCBM) could ...help identify patients at risk.
We studied 209 patients with BCBM. We evaluated a panel of proteins relevant to the biology of breast carcinoma on tissue microarrays of 133 primary tumors and 56 BCBM, including paired samples from 43 patients, and correlated the findings with the clinical outcome.
The median survival after BCBM diagnosis was 19 months (95% confidence interval, 13–23 months). Patients presenting with solitary metastasis had a significantly longer median survival than those with multiple lesions (25 versus 11 months, P ≤ 0.0001). We found no significant discordance in the expression of tested markers, but identified a possible association between the expression of basal cytokeratin CK5/6 in the primary carcinoma and the development of multiple rather than solitary brain metastases.
Expression of antigens commonly associated with breast carcinoma does not differ significantly between the primary tumor and the corresponding brain metastases. Although no specific immunoprofile identifies breast carcinomas that develop brain metastases, we observed a possible association between CK5/6 expression in the primary tumor and multiple versus solitary BCBM.
Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for ...chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy.
We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation.
With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. clinical settings.
NCT04496739
Force fluctuations on a solid body are associated with unsteadiness in the wake, e.g. vortex shedding. Therefore, the control of force fluctuations can be realised by suppressing the flow ...unsteadiness. A NACA0024 aerofoil closed with a round trailing edge is chosen to represent the solid body throughout this investigation, with the Reynolds number fixed at Re = 1000 and angle of attack α ≤ 15
o
, at which the uncontrolled flow is two-dimensional. A linear optimal control is calculated by analysing the distribution of sensitivity of unsteadiness to control around the entire surface of the body. The nonlinear effects of the calculated control, which can be actuated through surface-normal suction and blowing across the surface of the aerofoil, are tested through two-dimensional direct numerical simulations. It is observed that a surface-normal velocity control with a maximum magnitude less than 8% of the free stream velocity completely suppresses unsteadiness at α = 10° with an overall drag reduction of 14% and a 138% increase of lift.
Residual cancer after induction therapy for HER2-positive breast cancer is associated with a worse prognosis than no residual cancer. In a randomized trial, trastuzumab emtansine was superior to ...trastuzumab with respect to invasive disease–free survival.
Pentosan Polysulfate Sodium (PPS) is commonly used in the treatment of interstitial cystitis/bladder pain syndrome. Recently there have been reported cases of retinal toxicity associated with ...long-term PPS use. We present a case of a 42-year-old female taking PPS for the last 10 years who was found to have signs of retinal toxicity, but was completely asymptomatic. PPS was discontinued after these retinal findings were discovered.
The ``disease-specific'' (dsp) region next to the hrp gene cluster of Erwinia amylovora is required for pathogenicity but not for elicitation of the hypersensitive reaction. A 6.6-kb apparent operon, ...dspEF, was found responsible for this phenotype. The operon contains genes dspE and dspF and is positively regulated by hrpL. A BLAST search revealed similarity in the dspE gene to a partial sequence of the avrE locus of Pseudomonas syringae pathovar tomato. The entire avrE locus was sequenced. Homologs of dspE and dspF were found in juxtaposed operons and were designated avrE and avrF. Introduced on a plasmid, the dspEF locus rendered P. syringae pv. glycinea race 4 avirulent on soybean. An E. amylovora dspE mutant, however, elicited a hypersensitive reaction in soybean. The avrE locus in trans restored pathogenicity to dspE strains of E. amylovora, although restored strains were low in virulence. DspE and AvrE are large (198 kDa and 195 kDa) and hydrophilic. DspF and AvrF are small (16 kDa and 14 kDa) and acidic with predicted amphipathic α helices in their C termini; they resemble chaperones for virulence factors secreted by type III secretion systems of animal pathogens.
Three experiments investigated the roles of resource-sharing and intrinsic memory demands in complex working memory span performance in 7- and 9-year-olds. In Experiment 1, the processing complexity ...of arithmetic operations was varied under conditions in which processing times were equivalent. Memory span did not differ as a function of processing complexity. In Experiment 2, complex memory span was assessed under three conditions designed to vary both processing and intrinsic storage demands: mental arithmetic (significant attentional demands–requires storage), odd/even judgments (significant attentional demands–no storage required), and articulatory suppression (minimal attentional demands–no storage required). The highest memory spans were found in the articulatory suppression task. Span was at an intermediate level with arithmetic processing and was lowest for processing involving odd/even judgments. This difference in memory span for processing tasks involving arithmetic processing and odd/even judgments was eliminated in Experiment 3 when the pacing requirements of the arithmetic and odd/even processing tasks were equated. The results are consistent with the view that complex memory span performance is disrupted by processing activities that divert attentional resources from storage.
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