Effect of adjuvant trastuzumab among patients treated with anti-HER2-based neoadjuvant therapy

Purpose:

To study the impact of adjuvant trastuzumab among patients achieving a pathologic complete response (pCR) after trastuzumab-based neoadjuvant systemic therapy (NST).

Patients and methods:

Patients with primary HER2-positive breast cancer treated with trastuzumab-based NST were categorised according to adjuvant trastuzumab administration and pCR status. Adjuvant trastuzumab became standard of care in 2006, this was the main reason patients in our cohort did not receive adjuvant trastuzumab. Kaplan–Meier was used to estimate survival. A test for interaction between adjuvant trastuzumab and pCR was completed.

Findings:

Of 589 patients, 203 (34.5%) achieved a pCR. After surgery, 109 (18.5%) patients in the entire cohort did not receive adjuvant trastuzumab. Among patients achieving a pCR, 31.3% received adjuvant trastuzumab compared with 68.8% among those who did not achieve a pCR (P=0.0006). Among patients achieving pCR, adjuvant trastuzumab did not further improve overall survival (OS) or relapse-free survival (RFS) (P=0.35 and P=0.93, respectively). Any benefit of adjuvant trastuzumab in OS and RFS among patients without a pCR did not achieve statistical significance (P=0.3 and P=0.44, respectively).

Conclusions:

In this cohort, patients treated with trastuzumab-based NST who achieved a pCR have excellent outcome regardless of whether they received adjuvant trastuzumab.     

Fisetin,a phytochemical,potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.     

Human papillomavirus testing 2007–2012: Co‐testing and triage utilization and impact on subsequent clinical management

In the United States, high‐risk human papillomavirus (HPV) testing is recommended for women with atypical squamous cells of unknown significance (ASC‐US) cytology, and co‐testing with cytology and HPV is a recommended option for screening women aged ≥30 years. No population‐based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007–2012) in utilization and positivity rates for HPV testing as a routine co‐testing screening procedure and for triage of ASC‐US and other cytologic outcomes. For women aged 30–65 years co‐testing increased from 5.2% in 2007 to 19.1% in 2012 (p < 0.001). Overall 82% of women with ASC‐US cytology who did not receive co‐testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co‐test was done or if it was positive, but this was reduced to 47% with a negative co‐test. Reflex HPV testing for ASC‐US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co‐testing in women aged 30–65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30–65 years attending for screening in 2012. Women receiving co‐testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co‐testing.     

Current role for surgery in treatment of lone atrial fibrillation

The Cox-Maze procedure has been performed successfully since 1987. The original surgery was performed by using the "cut and sew" technique and is considered quite complex and technically demanding; therefore, it never gained popularity among cardiac surgeons and referring cardiologists. As surgical ablation technology improved, the Cox-Maze procedure can now be performed by using new ablation devices that deliver different energy sources (radiofrequency, cryothermia, and others). The use of ablation technology simplified the technical aspects of the procedure and has led to decreased time on cardiopulmonary bypass, easier placement of ablation lines, and the development of various minimally invasive approaches to include off-pump techniques. The Heart Rhythm Society recommends surgical ablation for symptomatic patients, patients who are unable to take anticoagulation therapy, who have failed other therapies to include percutaneous catheter ablation, or by personal request. Therefore, with guidelines in place as to patient selection and newer, easier-to-use technology, more surgeons are tackling surgical ablation of atrial fibrillation, offering another treatment option for patients with lone atrial fibrillation. This article will review the current state of surgery for the ablation of lone atrial fibrillation.     

A physiotherapist-delivered integrated exercise and pain coping skills training intervention for individuals with knee osteoarthritis: a randomised controlled trial protocol

ABSTRACT: BACKGROUND: Knee osteoarthritis (OA) is a prevalent chronic musculoskeletal condition with no cure. Pain is the primary symptom and results from a complex interaction between structural changes, physical impairments and psychological factors. Much evidence supports the use of strengthening exercises to improve pain and physical function in this patient population. There is also a growing body of research examining the effects of psychologist-delivered pain coping skills training (PCST) in improving pain and psychological impairments particularly in other chronic pain conditions. Though typically provided separately, there are resource and personnel advantages of exercise and PCST being delivered together by a single healthcare professional. Physiotherapists are a logical choice to be trained to deliver a PCST intervention as they already have expertise in administering exercise for knee OA and are cognizant of the need for a biopsychosocial approach to management. No studies to date have examined the effects of an integrated exercise and PCST program delivered solely by physiotherapists in this population. The aim of this randomised controlled trial is to investigate whether an integrated 12-week PCST and exercise treatment program delivered by physiotherapists is more efficacious than either program alone in treating pain and physical function in individuals with knee OA. METHODS: This will be an assessor-blinded, 3-arm randomised controlled trial of a 12-week intervention involving 10 physiotherapy visits together with home practice. Participants with symptomatic and radiographic knee OA will be recruited. Participants will be randomised into one of three groups: exercise alone, PCST alone, or integrated PCST and exercise. Primary outcomes will be pain measured by a Visual Analogue Scale (VAS) and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index subscale. Measurements will be taken at baseline and immediately following the intervention (12 weeks) as well as at 32 weeks and 52 weeks to examine maintenance of any intervention effects. Specific assessment of adherence to the treatment program will also be made at weeks 22 and 42. The study will be conducted at two sites, Melbourne and Brisbane, Australia to facilitate generalizabilty of the results and to ensure timely recruitment. CONCLUSION: The findings from this randomised controlled trial will provide evidence for the efficacy of an integrated PCST and exercise program delivered by physiotherapists in the management of painful and functionally limiting knee OA. The trial design will conform to CONSORT requirements for non-pharmacological treatment. Trial Registration: Australian New Zealand Clinical Trials Registry reference number: ACTRN12610000533099.     

Trunk lean gait modification and knee joint load in people with medial knee osteoarthritis: The effect of varying trunk lean angles

Objective

To evaluate whether increased lateral trunk lean toward the symptomatic lower extremity during gait in people with medial knee osteoarthritis (OA) immediately alters symptoms or medial knee load, as measured by the external knee adduction moment (KAM).

Methods

Participants with medial knee OA (n = 22) underwent 3‐dimensional gait analysis to measure KAM peaks (early and late stance) and KAM impulse. Following the analysis of natural gait, participants were trained to lean their trunk toward the symptomatic leg during ipsilateral stance over 3 randomly ordered conditions (6°, 9°, and 12° lean). A projection screen displayed real‐time trunk angles and target levels. Pain/discomfort in the knees, the hip, and the back were measured across conditions. Load‐modifying effects of increasing lean magnitudes were investigated using linear mixed models. Mediating effects of peak lean timing and participant characteristics (pain and malalignment) were evaluated.

Results

Increased trunk lean reduced all KAM measures (P < 0.001), with larger lean angles achieving greater reductions. Efficacy of load reduction improved with later peak lean timing for all measures of the KAM. Participant characteristics did not mediate the effect of trunk lean on the KAM, and symptoms did not change across conditions (P > 0.05).

Conclusion

Increased trunk lean reduced medial knee load in a dose‐response manner. Slightly later achievement of peak trunk lean improved the load‐modifying effect of this gait strategy. No immediate symptomatic changes were identified. Future research should determine if long‐term implementation of this gait strategy is feasible and whether it can modify disease symptoms and OA progression.     

Successful partnerships are the key to improving Aboriginal health

Partnership is a process that must be recognised as a fundamental part of any strategy for improving health outcomes for Aboriginal people. Addressing the inequities in health outcomes between Aboriginal people and other Australians will require a sustained, coordinated and well-informed approach that works to a set of goals and targets developed with input from the Aboriginal community. Partnerships provide the most effective mechanism for obtaining this essential input from Aboriginal communities and their representative organisations, enabling Aboriginal people to have an influence at all stages of the health-care process. Within the health sector, effective partnerships harness the efforts of governments and the expertise of Aboriginal Community Controlled Health Services, which offer the most effective means of delivering comprehensive primary health care to Aboriginal people.