Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma

Background Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. Objectives We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). Search methods We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. Selection criteria Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. Data collection and analysis Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. Main results Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Authors' conclusions Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma.

Sentinel lymph node biopsy in early-stage breast cancer patients: improved survival through better staging?

The objective of this review is to summarize the evidence demonstrating that the sentinel lymph node (SLN) procedure is not only associated with significantly less morbidity compared to the axillary dissection, but may also result in better staging and improved patient outcomes.

TGF-ß1 enhances the BMP-2-induced chondrogenesis of bovine synovial explants and arrests downstream differentiation at an early stage of hypertrophy

BACKGROUND Synovial explants furnish an in-situ population of mesenchymal stem cells for the repair of articular cartilage. Although bone morphogenetic protein 2 (BMP-2) induces the chondrogenesis of bovine synovial explants, the cartilage formed is neither homogeneously distributed nor of an exclusively hyaline type. Furthermore, the downstream differentiation of chondrocytes proceeds to the stage of terminal hypertrophy, which is inextricably coupled with undesired matrix mineralization. With a view to optimizing BMP-2-induced chondrogenesis, the modulating influences of fibroblast growth factor 2 (FGF-2) and transforming growth factor beta 1 (TGF-ß1) were investigated. METHODOLOGY/PRINCIPAL FINDINGS Explants of bovine calf metacarpal synovium were exposed to BMP-2 (200 ng/ml) for 4 (or 6) weeks. FGF-2 (10 ng/ml) or TGF-ß1 (10 ng/ml) was introduced at the onset of incubation and was present either during the first week of culturing alone or throughout its entire course. FGF-2 enhanced the BMP-2-induced increase in metachromatic staining for glycosaminoglycans (GAGs) only when it was present during the first week of culturing alone. TGF-ß1 enhanced not only the BMP-2-induced increase in metachromasia (to a greater degree than FGF-2), but also the biochemically-assayed accumulation of GAGs, when it was present throughout the entire culturing period; in addition, it arrested the downstream differentiation of cells at an early stage of hypertrophy. These findings were corroborated by an analysis of the gene- and protein-expression levels of key cartilaginous markers and by an estimation of individual cell volume. CONCLUSIONS/SIGNIFICANCE TGF-ß1 enhances the BMP-2-induced chondrogenesis of bovine synovial explants, improves the hyaline-like properties of the neocartilage, and arrests the downstream differentiation of cells at an early stage of hypertrophy. With the prospect of engineering a mature, truly articular type of cartilage in the context of clinical repair, our findings will be of importance in fine-tuning the stimulation protocol for the optimal chondrogenic differentiation of synovial explants.

Sugar concentration influences decision making in <i>Apis mellifera</i> L. workers during early-stage honey storage behaviour

Decision making in honeybees is based on in- formation which is acquired and processed in order to make choices between two or more al- ternatives. These choices lead to the expression of optimal behaviour strategies such as floral constancy. Optimal foraging strategies such as floral constancy improve a colony’s chances of survival, however to our knowledge, there has been no research on decision making based on optimal storage strategies. Here we show, using diagnostic radioentomology, that decision mak- ing in storer bees is influenced by nectar sugar concentrations and that, within 48 hours of col- lection, honeybees workers store carbohydrates in groups of cells with similar sugar concentra- tions in a nonrandom way. This behaviour, as evidenced by patchy spatial cell distributions, would help to hasten the ripening process by reducing the distance between cells of similar sugar concentrations. Thus, colonies which ex- hibit optimal storage strategies such as these would have an evolutionary advantage and im- prove colony survival expectations over less efficient colonies and it should be plausible to select colonies that exhibit these preferred traits.

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer.

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I-II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

Impairments in an early stage of the decision-making process in patients with ventromedial prefrontal damage: preliminary results

Lesions of the ventromedial prefrontal cortex can result in a deficient decision-making behavior. So far, most experimental results in the neuropsychological decision-making research have been obtained with gambling tasks. Due to their high complexity, it is difficult to evaluate the underlying processes of the decision-making deficits. The aim of this study was to assess if patients with ventromedial prefrontal damage compared to patients with dorsolateral prefrontal damage and controls show a deficit in an early stage of the decision-making process. Nine patients with ventromedial prefrontal damage, three with dorsolateral prefrontal damage, and eleven healthy controls were tested with a newly developed decision task in which they had to search actively for the information they needed for their decisions. Our results show that patients with ventromedial prefrontal damage compared to the brain-lesioned dorsolateral prefrontal control group and healthy controls searched less for information with regard to risk defusing operators or consequences of their decisions indicating impairment already in the early stage of the decision-making process.

Predicting 5- and 10-year survival in older women with early-stage breast cancer: self-rated health and walking ability.

OBJECTIVES To determine life expectancy for older women with breast cancer. DESIGN Prospective longitudinal study with 10 years of follow-up data. SETTING Hospitals or collaborating tumor registries in four geographic regions (Los Angeles, California; Minnesota; North Carolina; Rhode Island). PARTICIPANTS Women aged 65 and older at time of breast cancer diagnosis with Stage I to IIIA disease with measures of self-rated health (SRH) and walking ability at baseline (N = 615; 17% aged ≥80, 52% Stage I, 58% with ≥2 comorbidities). MEASUREMENTS Baseline SRH, baseline self-reported walking ability, all-cause and breast cancer-specific estimated probability of 5- and 10-year survival. RESULTS At the time of breast cancer diagnosis, 39% of women reported poor SRH, and 28% reported limited ability to walk several blocks. The all-cause survival curves appear to separate after approximately 3 years, and the difference in survival probability between those with low SRH and limited walking ability and those with high SRH and no walking ability limitation was significant (0.708 vs 0.855 at 5 years, P ≤ .001; 0.300 vs 0.648 at 10 years, P < .001). There were no differences between the groups in breast cancer-specific survival at 5 and 10 years (P = .66 at 5 years, P = .16 at 10 years). CONCLUSION The combination of low SRH and limited ability to walk several blocks at diagnosis is an important predictor of worse all-cause survival at 5 and 10 years. These self-report measures easily assessed in clinical practice may be an effective strategy to improve treatment decision-making in older adults with cancer.

14-3-3 zeta overexpression in early stage breast disease and tumor progression

Recent progress in diagnostic tools allows many breast cancers to be detected at an early pre-invasive stage. Thus, a better understanding of the molecular basis of early breast cancer progression is essential. 14-3-3 is a family of highly conserved and ubiquitously expressed proteins that are expressed in all eukaryotic organisms. In mammals there are seven isoforms, which bind to phosphor-serine/threonine residues regulating essential cellular processes such as signal transduction, cell cycle progression, and apoptosis. Our laboratory has discovered that a particular 14-3-3 family member, Zeta, is overexpressed in over 40% of breast tumor tissues. Furthermore, I examined the stage of breast disease in which 14-3-3ζ overexpression occurs and found that increased expression of 14-3-3ζ begins at the stage of atypical ductal hyperplasia, a very early stage of breast disease that confers increased risk for progress toward breast cancer. To determine whether 14-3-3ζ overexpression is a decisive early event in breast cancer, I overexpressed 14-3-3ζ in MCF10A cells, a non-transformed mammary epithelial cell (MEC) line and examined its impact on acini formation in a three dimensional (3D) culture model which simulates a basic unit of structure in the mammary gland. I discovered that 14-3-3ζ overexpression severely disrupted the acini architecture resulting in the disruption of polarity and luminal filling. Both are critical morphological events in the pre-neoplastic breast disease. This thesis focuses on the molecular mechanism of luminal filling. Proper lumen formation is a result of anoikis, a specific type apoptosis of cells not attached to the basement membrane. I found that 14-3-3ζ overexpression conferred a resistance to anoikis. Additionally, 14-3-3ζ overexpression in MCF10A cells and in MECs from 14-3-3ζ transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3ζ induced hyperactivation of the PI3K/Akt pathway which led to phosphorylation and translocation of the MDM2 to the nucleus resulting in increased p53 degradation. Ectopic expression of p53 restored luminal apoptosis in 14-3-3ζ overexpressing MCF10A acini in 3D cultures. These data suggest that 14-3-3ζ overexpression is a critical event in early breast disease and down-regulation of p53 is one of the mechanisms by which 14-3-3ζ alters MEC acini structure and may increase the risk of progression to breast cancer. ^

Early stage breast cancer and comorbidities: Their impact on breast cancer disease-free survival differences by ethnicity

The retrospective cohort study examined the association between the presence of comorbidities and breast cancer disease-free survival rates among racial/ethnic groups. The study population consisted of 2389 women with stage I and II invasive breast cancer who were diagnosed and treated at the M.D. Anderson Cancer Center between 1985 and 2000. It has been suggested that as the number of comorbidities increases, breast cancer mortality increases. It is known that African Americans and Hispanics are considered to be at a higher risk for comorbid conditions such as hypertension and diabetes compared to Caucasian women (23) (10). When compared to Caucasian women, African American women also have a higher breast cancer mortality rate (1). As a result, the study also examined whether comorbid conditions contribute to racial differences in breast cancer disease-free survival. Among the study population, 24% suffered from breast cancer recurrence, 6% died from breast cancer and 24% died from all causes. The mean age was 56 with 41% of the population being women between the ages of 40-55. One or more comorbidities were reported in 84 (36%) African Americans (OR 1.57; 95% CI 1.19-2.10), 58 (31%) Hispanics (OR 1.25; 95% CI 0.90-1.74) compared to the reference group of 531 (27%) Caucasians. Additionally, African American women were significantly more likely to suffer from either a breast cancer recurrence or breast cancer death (OR 1.5; 95% CI 0.70-1.41) when compared to Caucasian women. Multivariate analysis found hypertension (HR 1.22; 95% CI 0.99-1.49; p<0.05) to be statistically significant and a potential prognostic tool for disease-free survival with African American women (OR 2.96; 95% 2.25-3.90) more likely to suffer from hypertension when compared to Caucasian women. When compared to Caucasian women, Hispanics were also more likely to suffer from hypertension (OR 1.33; 95% CI 0.96-1.83). This suggests that comorbid conditions like hypertension could account for the racial disparities that exist when comparing breast cancer survival rates. Future studies should investigate this relationship further.^

Outcomes associated with chemotherapy in elderly patients with early stage operable breast cancer

Background. Various clinical trials have proved the efficacy of adjuvant chemotherapy in women with breast cancer. Chemotherapy efficacy and guidelines for its use differ by stage of tumor and age of the patient with no clear recommendations for patients aged 70 and above. Objective. To examine the clinical and economic outcomes associated with chemotherapy use in and to examine the disparities in treatment and survival in elderly patients with early stage operable breast cancer by age and axillary node status. Methods. We studied a cohort of 23,110 node positive and 31,572 node negative women aged 65 and over diagnosed with incident American Joint Committee on Cancer (AJCC) stage I, II or IIIa breast cancer between January 1, 1991 and December 31, 2002 using SEER-Medicare data. Total patient costs were estimated using the phase of care approach and adjusted cost estimates were obtained from regression analysis using a 3% discount rate. Cox proportional hazard ratio of mortality was used to determine the effectiveness of chemotherapy. Propensity score approach was also used to minimize the bias associated with receipt of chemotherapy. To assess disparity in treatment, multivariate logistic regression analyses were performed to assess the relative odds of receiving surgery, chemotherapy and radiation after BCS for African Americans compared to Whites. Results. Regression adjusted cost estimates for all node positive patients receiving chemotherapy was approximately $2,300 and was significantly higher (p<0.05) than for patients not receiving chemotherapy. Mortality was significantly lower in node positive and node negative women aged 65-74 years receiving chemotherapy. There was a significant difference between African American and White women in receiving BCS and radiation after BCS; however this difference was explained by patient demographics, tumor characteristics and socioeconomic status (SES). African American node positive women were 21% less likely to receive chemotherapy than White women (OR, 0.79; CI, 0.68-0.92) in multivariate analysis. Conclusion. Chemotherapy is associated with increased survival in patients aged 65-74 and total costs attributable to chemotherapy differ by phase and age of the patient. Underutilization of systemic adjuvant chemotherapy in African American women requires attention and may serve as potential areas for appropriate intervention.^

Factors governing late-recurrence of disease in a cohort of early-stage breast cancer survivors

Purpose. To determine the risk of late breast cancer recurrence (5 years after treatment) in a population of women diagnosed with early-stage breast cancer at The University of Texas M.D. Anderson Cancer Center (MDACC) between 1985-2000 and to examine the effect of this population’s BMI, smoking history, reproductive history, hormone use, and alcohol intake at the time of diagnosis on risk of late recurrence.^ Methods. Patients included 1,913 members of the Early Stage Breast Cancer Repository recruited at MDACC who had survived without a recurrence for at least five years after their initial diagnosis of early stage breast cancer. Clinical and epidemiological information was ascertained twice on participants during the study—first by medical record abstraction then by patient interview at least five years after receipt of adjuvant treatment. A total of 223 late breast cancer recurrences were captured, with an average follow-up of 10.6 years. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). ^

SABR for early-stage lung cancer: Early-adoption and future directions

Early-stage lung cancer incidence among older adults is expected to increase due to demographic trends and CT-based screening, yet optimal treatment of lung cancer in the elderly remains controversial. There are several accepted strategies for treating lung cancer including surgery, conventional radiation, and stereotactic ablative body radiotherapy (SABR). However, there are currently no randomized controlled trials to help distinguish the comparative effectiveness of these various strategies. This is an unfortunate omission as lung cancer causes the most deaths among all cancers in the United States (as well as the entire world). SABR holds particular promise as it is a completely non-invasive, ambulatory technique for achieving cure without an operation, thus avoiding the risks of surgery and the associated pre-operative and post-operative costs. To provide fair view of the potential effect on SABR on controlling lung cancer in the United States, a systematic review of SABR with a focus on its achieved outcomes, toxicities, and comparison to conventional radiation and surgical options is presented. ^

Signals of resilience to ocean change: high thermal tolerance of early stage Antarctic sea urchins (Sterechinus neumayeri) reared under present-day and future pCO2 and temperature

We tested the hypothesis that development of the Antarctic urchin Sterechinus neumayeri under future ocean conditions of warming and acidification would incur physiological costs, reducing the tolerance of a secondary stressor. The aim of this study is twofold: (1) quantify current austral spring temperature and pH near sea urchin habitat at Cape Evans in McMurdo Sound, Antarctica and (2) spawn S. neumayeri in the laboratory and raise early developmental stages (EDSs) under ambient (-0.7 °C; 400 µatm pCO2) and future (+2.6 °C; 650 and 1,000 µatm pCO2) ocean conditions and expose four EDSs (blastula, gastrula, prism, and 4-arm echinopluteus) to a one hour acute heat stress and assess survivorship. Results of field data from 2011 to 2012 show extremely stable inter-annual pH conditions ranging from 7.99 to 8.08, suggesting that future ocean acidification will drastically alter the pH-seascape for S. neumayeri. In the laboratory, S. neumayeri EDSs appear to be tolerant of temperatures and pCO2 levels above their current habitat conditions. EDSs survived acute heat exposures >20 °C above habitat temperatures of -1.9 °C. No pCO2 effect was observed for EDSs reared at -0.7 °C. When reared at +2.6 °C, small but significant pCO2 effects were observed at the blastula and prism stage, suggesting that multiple stressors are more detrimental than single stressors. While surprisingly tolerant overall, blastulae were the most sensitive stage to ocean warming and acidification. We conclude that S. neumayeri may be unexpectedly physiologically tolerant of future ocean conditions.