Evaluation of neurological testing for hand-arm vibration syndrome.

BACKGROUND: The neurological component of hand-arm vibration syndrome (HAVS) uses the Stockholm Workshop Scale sensorineural (SWS SN) stages for classification. Proximal compressive neuropathies are common in HAVS and the symptoms are similar to SN HAVS. The SWS may not be a valid staging tool if a patient has comorbid proximal compression neuropathy. AIMS: To evaluate the prevalence of proximal compression neuropathy in patients presenting for HAVS assessment and examine the association between compressive neuropathies and SWS SN. METHODS: A standardized assessment protocol was used to assess 431 patients for HAVS at St. Michael's Hospital, Toronto, Ontario. The prevalence of median and ulnar compressive neuropathies was determined. The association between proximal compression neuropathies and SWS SN stage (0/1 versus 2/3) was evaluated using Chi-square and Fisher's exact tests as well as multivariable logistic regression. RESULTS: Most patients (79%) reported numbness and 20% had reduced sensory perception (SWS SN Stage 2/3). Almost half (45%) had median neuropathy at the wrist and 7% had ulnar neuropathy. There was no association between the SWS SN stage and median or ulnar neuropathy. CONCLUSIONS: Two neurological lesions should be investigated in patients presenting for HAVS assessment: compressive neuropathy and digital neuropathy. The prevalence of compressive neuropathies is high in patients being assessed for HAVS and therefore nerve conduction studies (NCS) should be included in HAVS assessment protocols. Comorbid proximal neuropathy does not affect the SWS SN stage; therefore, NCS and SWS SN seem to be measuring different neurological outcomes in HAVS patients.

Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.

BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

Erythropoietin modulates striatal antioxidant signalling to reduce neurodegeneration in a toxicant model of Parkinson's disease.

The current study sought to characterize the pro-survival effects of erythropoietin (EPO) in a toxicant model of Parkinson's disease (PD). EPO treatment induced time-dependent elevations of antioxidant glutathione peroxidase (GPx) and anti-apoptotic factors (pAkt and pBad/Bad) within the striatum and substantia nigra pars compacta (SNc). Intriguingly, our results indicated a region- and lesion size- dependence of pro-survival effects of EPO. Indeed, intra-striatal (but not intra-nigral) infusion of EPO was effective at preventing dopaminergic terminal degeneration and sSNc neuronal loss induced by two different doses of 6-OHDA. These neuroprotective consequences were paralleled by a diminution of microglial morphological changes, along with enhanced motor functioning seen through a reduction in apomorphine-induced rotational behaviour. Finally, in the context of the 6-OHDA lesion, EPO again induced anti-apoptotic (Bcl-2) and antioxidant (GPx) factors within the striatum. Taken together, these results raise the possibility of EPO's potential use as an adjuvant therapy in the treatment of PD, or at least, suggest possible brain-region specific targets for the protective effects of EPO.

Scoring of tumor-infiltrating lymphocytes: From visual estimation to machine learning.

The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.

OncotypeDX Recurrence Score Does Not Predict Nodal Burden in Clinically Node Negative Breast Cancer Patients.

BACKGROUND: OncotypeDX recurrence score (RS)® has been found to predict recurrence and disease-free survival in patients with node negative breast cancer. Whether RS is useful in guiding locoregional therapy decisions is unclear. We sought to evaluate the relationship between RS and lymph node burden. METHODS: Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18-30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant. RESULTS: A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23 months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015). CONCLUSIONS: OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.

Quantifying stratosphere-troposphere transport of ozone using balloon-borne ozonesondes, radar windprofilers and trajectory models.

In a series of 10-day campaigns in Ontario and Quebec, Canada, between 2005 and 2007, ozonesondes were launched twice daily in conjunction with continuous high-resolution wind-profiling radar measurements. Windprofilers can measure rapid changes in the height of the tropopause, and in some cases follow stratospheric intrusions. Observed stratospheric intrusions were studied with the aid of a Lagrangian particle dispersion model and the Canadian operational weather forecast system. Definite stratosphere-troposphere transport (STT) events occurred approximately every 2-3 days during the spring and summer campaigns, whereas during autumn and winter, the frequency was reduced to every 4-5 days. Although most events reached the lower troposphere, only three events appear to have significantly contributed to ozone amounts in the surface boundary layer. Detailed calculations find that STT, while highly variable, is responsible for an average, over the seven campaigns, of 3.1% of boundary layer ozone (1.2 ppb), but 13% (5.4 ppb) in the lower troposphere and 34% (22 ppb) in the middle and upper troposphere, where these layers are defined as 0-1 km, 1-3 km, and 3-8 km respectively. Estimates based on counting laminae in ozonesonde profiles, with judicious choices of ozone and relative humidity thresholds, compare moderately well, on average, with these values. The lamina detection algorithm is then applied to a large dataset from four summer ozonesonde campaigns at 18 North American sites between 2006 and 2011. The results show some site-to-site and year-to-year variability, but stratospheric ozone contributions average 4.6% (boundary layer), 15% (lower troposphere) and 26% (middle/upper troposphere). Calculations were also performed based on the TOST global 3D trajectory-mapped ozone data product. Maps of STT in the same three layers of the troposphere suggest that the STT ozone flux is greater over the North American continent than Europe, and much greater in winter and spring than in summer or fall. When averaged over all seasons, magnitudes over North America show similar ratios between levels to the previous calculations, but are overall 3-4 times smaller. This may be because of limitations (trajectory length and vertical resolution) to the current TOST-based calculation.

Patient-centred care in an occupational medicine clinic.

BACKGROUND: Patient-centred care (PCC) has been associated with improved patient satisfaction outcomes in a variety of clinical settings. There is a paucity of research addressing the concept of PCC in an occupational medicine context. AIMS: To assess patient perception and compare physician and patient perceptions of patient centredness of the care at a specialty occupational medicine clinic. METHODS: An observational study design using the Patient Perception of Patient Centeredness Questionnaire (PPPC) at an ambulatory tertiary care occupational health clinic. Results were analysed using a standardized coding system. Summary scores were compared to results reported in a primary care setting. Patient and physician scores were compared to detect physician-patient differences in perceived patient centredness of care. RESULTS: Of 47 eligible patients 37 consented to participate and seven were excluded due to incomplete data. Summary scores of patient perceptions of patient centredness were similar but somewhat better than scores reported in a primary care setting. Perceived patient centredness of care was high and there was minimal discordance between patient and physician scores. CONCLUSIONS: This study demonstrated that PCC can be measured in an occupational health setting. In an ambulatory tertiary care occupational health clinic there was a high degree of patient centredness of care which may be explained by a variety of factors. Future research should consider whether similar findings exist in other occupational medicine practice settings.

Multidisciplinary Intraoperative Assessment of Breast Specimens Reduces Number of Positive Margins.

BACKGROUND: Successful breast-conserving surgery requires achieving negative margins. At our institution, the whole surgical specimen is imaged and then serially sectioned with repeat imaging. A multidisciplinary discussion then determines need for excision of additional margins. The goal of this study was to determine the benefit of each component of this approach in reducing the number of positive margin. METHODS: This single-institution, prospective study included ten breast surgical oncologists who were surveyed to ascertain whether they would have taken additional margins based their review of whole specimen images (WSI) and review of serially sectioned images (SSI). These results were compared with the multidisciplinary decisions (MDD) and pathology results. Margin status was defined using consensus guidelines. RESULTS: One hundred surveys were completed. Margins on the original specimen were positive or close in 21%. After WSI, surgeons reported that they would have taken additional margins in 26 cases, reducing the number of positive/close margins from 21 to 13% (p < 0.001). After SSI, 52 would have taken additional margins; however, the number of positive/close margins remained 13%. MDD resulted in additional margins taken in 56 cases, reducing the number of positive/close margins to 7% (p < 0.001 compared with SSI). CONCLUSIONS: While surgeon review of specimen radiographs can decrease the number of positive or close margins from 21 to 13%, more rigorous multidisciplinary, intraoperative margin assessment reduces the number of close or positive margins to 7%.

Magnetic resonance imaging texture analysis classification of primary breast cancer.

OBJECTIVES: Patient-tailored treatments for breast cancer are based on histological and immunohistochemical (IHC) subtypes. Magnetic Resonance Imaging (MRI) texture analysis (TA) may be useful in non-invasive lesion subtype classification. METHODS: Women with newly diagnosed primary breast cancer underwent pre-treatment dynamic contrast-enhanced breast MRI. TA was performed using co-occurrence matrix (COM) features, by creating a model on retrospective training data, then prospectively applying to a test set. Analyses were blinded to breast pathology. Subtype classifications were performed using a cross-validated k-nearest-neighbour (k = 3) technique, with accuracy relative to pathology assessed and receiver operator curve (AUROC) calculated. Mann-Whitney U and Kruskal-Wallis tests were used to assess raw entropy feature values. RESULTS: Histological subtype classifications were similar across training (n = 148 cancers) and test sets (n = 73 lesions) using all COM features (training: 75%, AUROC = 0.816; test: 72.5%, AUROC = 0.823). Entropy features were significantly different between lobular and ductal cancers (p < 0.001; Mann-Whitney U). IHC classifications using COM features were also similar for training and test data (training: 57.2%, AUROC = 0.754; test: 57.0%, AUROC = 0.750). Hormone receptor positive and negative cancers demonstrated significantly different entropy features. Entropy features alone were unable to create a robust classification model. CONCLUSION: Textural differences on contrast-enhanced MR images may reflect underlying lesion subtypes, which merits testing against treatment response. KEY POINTS: • MR-derived entropy features, representing heterogeneity, provide important information on tissue composition. • Entropy features can differentiate between histological and immunohistochemical subtypes of breast cancer. • Differing entropy features between breast cancer subtypes implies differences in lesion heterogeneity. • Texture analysis of breast cancer potentially provides added information for decision making.

THE FIRST TWENTY YEARS (1994-2014) OF OZONE SOUNDINGS FROM RAPA NUI (27°S, 109°W, 51 M A.S.L.).

Ozone (O3) soundings have been performed on Easter Island or Rapa Nui (27°S, 23 109°W, 51 m a.s.l.) since 1994 as part of the Global Atmospheric Watch (GAW) Programme of the World Meteorological Organization (WMO). In this work, we analyze 260 soundings compiled over the period 1994-2014, and make the data available for the international community. We characterize O3 profiles over this remote area of the Pacific by means of statistical analyses that consider, on the one hand, a traditional climatology that describes the data in terms of seasonal cycles based on monthly averages and, on the other hand, a process oriented analysis based on self-organizing maps. Our analyses show the influence of both tropical and subtropical/mid-latitude air masses at Rapa Nui. The former occurs in summer and fall when convective conditions prevail, and the latter in late winter and spring when subsiding conditions are recurrent. The occurrence of stratospheric intrusions in late winter and spring in connection with deep troughs and the presence of the subtropical jet stream is also apparent in the data set. The tropospheric ozone column is in good agreement with the corresponding data derived from satellites but with a systematic overestimate of summer and fall values. We show evidence of an upward trend in ozone near the surface, which suggests the impact of local pollution. We look forward to an enhancement of the Rapa Nui observing site, given its location that offers a privileged position to observe climate change over the sparsely sampled and vast South Pacific Ocean.

The role of azithromycin in healthcare-associated pneumonia treatment.

WHAT IS KNOWN AND OBJECTIVE: Healthcare-associated pneumonia (HCAP) is an important presentation among hospitalized patients. Standardized definitions of this entity are almost a decade old, and practice patterns have shifted from published guidelines to include empiric coverage with a macrolide, such as azithromycin. Azithromycin is oftentimes included in the empiric treatment regimen for HCAP because of the importance of appropriate empiric antimicrobial coverage, the perceived concern regarding atypical organisms, potential anti-inflammatory effects of the medication, and positive clinical data among patients with Streptococcal bacteremia. METHODS: In this review, we systematically investigate data for each of these topics along with clinical data examining the role of azithromycin in HCAP. RESULTS AND DISCUSSION: Our findings indicate that atypical organisms are rare in HCAP, that the anti-inflammatory actions of azithromycin - although promising - have not produced consistently positive effects in many chronic or acute conditions, and that the data available for azithromycin use in bacteremia are of low quality. A single-centre cohort indicated that the clinical benefits of azithromycin did not extend to HCAP compared to community-acquired pneumonia. WHAT IS NEW AND CONCLUSION: Additionally, there are newer data emphasizing the potential cardiotoxicity of azithromycin, particularly among patients at high risk. All of these data indicate that azithromycin should not be part of the standard empiric treatment for HCAP.

Health-care barriers for workers with HAVS in Ontario, Canada.

BACKGROUND: Hand-arm vibration syndrome (HAVS) becomes irreversible unless it is identified early and progression prevented. AIMS: To describe the health-care-seeking behaviours of workers with HAVS and barriers to health care. METHODS: We invited all patients assessed for HAVS between 15 January and 27 March 2013 at a hospital-based occupational health clinic (OHC) in Ontario, Canada, to complete a questionnaire asking why and from whom they sought health care, reasons they waited to seek care and barriers they encountered in accessing care. We analysed the data using descriptive statistics. RESULTS: Forty-one (82%) patients agreed to participate. Thirty-seven had confirmed HAVS; 30 (84%) were Stockholm workshop vascular stage 2 or greater and 35 (97%) were sensorineural stage 1 or greater. The commonest employment sectors were construction [21 (57%)] and mining [6 (17%)]. The main reasons for seeking treatment were pain [11 (30%)], finger numbness [8 (22%)] and functional limitations [5 (14%)]. The commonest initial point of health care was the family physician [23 (66%)]. The mean wait between symptom onset and seeking treatment was 3.4 years, while the mean time between onset and OHC assessment was 9 years. Reasons for delay in seeking care were ignorance of the seriousness and irreversibility of HAVS and ability to continue to work. Family physicians suspected HAVS in 17% of cases and recommended job modification in 34%. CONCLUSIONS: Workers with HAVS in Ontario delay seeking health care. Primary care physicians often fail to recognize HAVS. Barriers to health care include ignorance of HAVS and of the importance of prevention.

Aspirin use and survival after the diagnosis of breast cancer: a population-based cohort study.

BACKGROUND: Aspirin use has been associated with a reduced cancer incidence and fewer deaths from cancer. This study examined whether women with breast cancer prescribed aspirin postdiagnosis had improved survival. METHODS: An observational, population cohort study was undertaken using data linkage of cancer registry, dispensed prescriptions and death records in Tayside, Scotland. All community prescriptions for aspirin in women with breast cancer were extracted and use postdiagnosis for each individual examined using Cox's proportional hazard models. The main outcome measures were all-cause mortality and breast cancer-specific mortality. RESULTS: Four thousand six hundred and twenty-seven patients diagnosed with breast cancer between 1 January 1998 and 31 December 2008 were followed up until 28 February 2010. Median age at diagnosis was 62 (IQR 52-74). One thousand eight hundred and two (39%) deaths were recorded, with 815 (18%) attributed to breast cancer. One thousand and thirty-five (22%) patients were prescribed aspirin postdiagnosis. Such aspirin use was associated with lower risk of all-cause mortality (HR=0.53, 95% CI=0.45-0.63, P<0.001) and breast cancer-specific mortality (HR=0.42, 95% CI=0.31-0.55, P<0.001) after adjusting for age, socioeconomic status, TNM stage, tumour grade, oestrogen receptor status, surgery, radiotherapy, chemotherapy, adjuvant endocrine therapy and aspirin use prediagnosis. CONCLUSIONS: Aspirin use postdiagnosis of breast cancer may reduce both all-cause and breast cancer-specific mortality. Further investigation seeking a causal relationship and which subgroups of patients benefit most await ongoing randomised controlled trials.

Lack of correlation of stem cell markers in breast cancer stem cells.

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer.

Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study.

BACKGROUND: Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease. METHODS: A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000-2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). RESULTS: Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43-7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable. CONCLUSION: Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.

NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

p53-Based cyclotherapy: exploiting the 'guardian of the genome' to protect normal cells from cytotoxic therapy.

Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the side effects of chemotherapy. Low, non-genotoxic doses of known p53 activators can be used to induce p53-dependent cell cycle arrest in normal cells bearing wild-type p53. This cytostatic effect of p53 can protect normal cells from the toxicity of S- or M-phase poisons. Here, we have reviewed existing cyclotherapy regimens using two well-known p53 activators, nutlin-3 and actinomycin D. We have highlighted an exemplar clinical perspective for cyclotherapy in breast cancer. The recent development of novel stapled peptides as activators of p53 without the corresponding cytotoxicity holds great promise for cyclotherapy to enhance the therapeutic window of existing chemotherapy drugs.