The dynamics and the timeline of speciation in the gall-forming aphid Geoica spp. within and among Pistacia host tree species.

Trees of the genus Pistacia serve as obligate hosts for gall-forming aphids (Hemiptera, Aphididae, Fordini). Each aphid species induces a characteristic gall on a single Pistacia host species. The genus Geoica (Fordini) induce similar spherical closed galls on the lower side of the leaflet's midvein, on different Pistacia species. Two species of Pistacia trees that harbor Geoica galls grow naturally in Israel: P. palaestina and P. atlantica. We analyzed the phylogeny and the genetic structure of the Geoica species complex in Israel, and assessed the genetic differentiation and the level of host plant specificity of the aphids between P. atlantica and P. palaestina. We found that the splitting of the genus between P. atlantica and P. palaestina is estimated to have occurred 24-25 Ma (the Oligocene/Miocene boundary). Five different haplotypes suggesting five different species have been further speciating among Geoica spp., galling on P. atlantica, and an additional three species, on P. palaestina.

Transcriptional up-regulation of host-specific terpene metabolism in aphid-induced galls of Pistacia palaestina.

Galling insects gain food and shelter by inducing specialized anatomical structures in their plant hosts. Such galls often accumulate plant defensive metabolites protecting the inhabiting insects from predation. We previously found that, despite a marked natural chemopolymorphism in natural populations of Pistacia palaestina, the monoterpene content in Baizongia pistaciae-induced galls is substantially higher than in leaves of their hosts. Here we show a general up-regulation of key structural genes in both the plastidial and cytosolic terpene biosynthetic pathways in galls as compared with non-colonized leaves. Novel prenyltransferases and terpene synthases were functionally expressed in Escherichia coli to reveal their biochemical function. Individual Pistacia trees exhibiting chemopolymorphism in terpene compositions displayed differential up-regulation of selected terpene synthase genes, and the metabolites generated by their gene products in vitro corresponded to the monoterpenes accumulated by each tree. Our results delineate molecular mechanisms responsible for the formation of enhanced monoterpene in galls and the observed intraspecific monoterpene chemodiversity displayed in P. palaestina. We demonstrate that gall-inhabiting aphids transcriptionally reprogram their host terpene pathways by up-regulating tree-specific genes, boosting the accumulation of plant defensive compounds for the protection of colonizing insects.

Gall-forming aphids are protected (and benefit) from defoliating caterpillars: the role of plant-mediated mechanisms.

BACKGROUND: Interspecific interactions among insect herbivores are common and important. Because they are surrounded by plant tissue (endophagy), the interactions between gall-formers and other herbivores are primarily plant-mediated. Gall-forming insects manipulate their host to gain a better nutrient supply, as well as physical and chemical protection form natural enemies and abiotic factors. Although often recognized, the protective role of the galls has rarely been tested. RESULTS: Using an experimental approach, we found that the aphid, Smynthurodes betae, that forms galls on Pistacia atlantica leaves, is fully protected from destruction by the folivorous processionary moth, Thaumetopoea solitaria. The moth can skeletonize entire leaves on the tree except for a narrow margin around the galls that remains intact ("trimmed galls"). The fitness of the aphids in trimmed galls is unharmed. Feeding trials revealed that the galls are unpalatable to the moth and reduce its growth. Surprisingly, S. betae benefits from the moth. The compensatory secondary leaf flush following moth defoliation provides new, young leaves suitable for further gall induction that increase overall gall density and reproduction of the aphid. CONCLUSIONS: We provide experimental support for the gall defense hypothesis. The aphids in the galls are protracted by plant-mediated mechanisms that shape the interactions between insect herbivores which feed simultaneously on the same host. The moth increase gall demsity on re-growing defoliated shoots.

Biomarker-Driven Therapy in Metastatic Gastric and Esophageal Cancer: Real-Life Clinical Experience.

BACKGROUND: Precision treatment of cancer uses biomarker-driven therapy to individualize and optimize patient care. OBJECTIVE: To evaluate real-life clinical experience with biomarker-driven therapy in metastatic gastric and esophageal cancer in Israel. PATIENTS AND METHODS: This multicenter retrospective cohort study included patients with metastatic gastric or esophageal cancer who were treated in the participating institutions and underwent biomarker-driven therapy. Treatment was considered to have a benefit if the ratio between the longest progression-free survival (PFS) post biomarker-driven therapy and the last PFS before the biomarker-driven therapy was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. RESULTS: The analysis included 46 patients (61% men; median age, 58 years; 57% with poorly-differentiated tumors). At least one actionable (i.e., predictive of response to a specific therapy) biomarker was identified for each patient. Immunohistochemistry was performed on all samples and identified 1-8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A). Twenty-eight patients received therapy after the biomarker analysis (1-4 lines). In the 1st line after biomarker analysis, five patients (18%) achieved a partial response and five (18%) stable disease; the median (range) PFS was 129 (12-1155) days. Twenty-four patients were evaluable for PFS ratio analysis; in seven (29.2%), the ratio was ≥1.3. In a one-sided exact binomial test vs. the null hypothesis, p = 0.019; therefore, the null hypothesis was rejected. CONCLUSIONS: Our findings demonstrated that implementing biomarker-driven analysis is feasible and could provide clinical benefit for a considerable proportion (~30%) of patients with metastatic gastric or esophageal cancer.

Regional Nodal Irradiation After Breast Conserving Surgery for Early HER2-Positive Breast Cancer: Results of a Subanalysis From the ALTTO Trial.

Background: Two randomized trials recently demonstrated that regional nodal irradiation (RNI) could reduce the risk of recurrence in early breast cancer; however, these trials were conducted in the pretrastuzumab era. Whether these results are applicable to human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with anti-HER2-targeted therapy is unknown. Methods: This retrospective analysis was performed on patients with node-positive breast cancer who were enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). A multivariable cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to investigate the relationship between RNI and DFS. Results: One thousand six hundred sixty-four HER2-positive breast cancer patients were included, of whom 878 (52.8%) had received RNI to the axillary, supraclavicular, and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden and more frequently had tumors larger than 2 cm. At a median follow-up of 4.5 years, DFS was 84.3% in the RNI group and 88.3% in the non-RNI group. No differences in regional recurrence (0.9 % vs 0.6 %) or in overall survival (93.6% vs 95.3%) were observed between the two groups. After adjustment in multivariable analysis, there was no statistically significant association between RNI and DFS (hazard ratio = 0.96, 95% confidence interval = 0.71 to 1.29). Conclusions: Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node-positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials.

Acupuncture and Reflexology for Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer.

BACKGROUND: Treatment of chemotherapy-induced peripheral neuropathy (CIPN), which affects approximately 30% to 40% of patients treated with neuropathy-causing agents, is mainly symptomatic. Currently available interventions are of little benefit. STUDY DESIGN: This study was conducted as a retrospective analysis of the efficacy of acupuncture and reflexology in alleviating CIPN in breast cancer patients. METHODS: Medical records of 30 consecutive breast cancer patients who received both chemotherapy and treatment for CIPN according to our Acupuncture and Reflexology Treatment for Neuropathy (ART-N) protocol between 2011 and 2012 were reviewed. Symptom severity was rated at baseline, during, and after treatment. RESULTS: The records of 30 breast cancer patients who had been concomitantly treated with chemotherapy and ART-N for CIPN were retrieved. Two records were incomplete, leaving a total of 28 patients who were enrolled into the study. Twenty patients (71%) had sensory neuropathy, 7 (25%) had motor neuropathy, and 1 (4%) had both sensory and motor neuropathy. Only 2 (10%) of the 20 patients with grades 1 to 2 neuropathy still reported symptoms at 12 months since starting the ART-N protocol. All 8 patients who presented with grades 3 to 4 neuropathy were symptom-free at the 12-month evaluation. Overall, 26 patients (93%) had complete resolution of CIPN symptoms. CONCLUSION: The results of this study demonstrated that a joint protocol of acupuncture and reflexology has a potential to improve symptoms of CIPN in breast cancer patients. The protocol should be validated on a larger cohort with a control group. It also warrants testing as a preventive intervention.

Differences in Monoterpene Biosynthesis and Accumulation in Pistacia palaestina Leaves and Aphid-Induced Galls.

Certain insect species can induce gall formation on numerous plants species. Although the mechanism of gall development is largely unknown, it is clear that insects manipulate their hosts' anatomy, physiology, and chemistry for their own benefit. It is well known that insect-induced galls often contain vast amounts of plant defensive compounds as compared to non-colonized tissues, but it is not clear if defensive compounds can be produced in situ in the galled tissues. To answer this question, we analyzed terpene accumulation patterns and possible independent biosynthetic potential of galls induced by the aphid Baizongia pistaciae L. on the terminal buds of Pistacia palaestina Boiss. We compared monoterpene levels and monoterpene synthase enzyme activity in galls and healthy leaves from individual trees growing in a natural setting. At all developmental stages, monoterpene content and monoterpene synthase activity were consistently (up to 10 fold on a fresh weight basis) higher in galls than in intact non-colonized leaves. A remarkable tree to tree variation in the products produced in vitro from the substrate geranyl diphosphate by soluble protein extracts derived from individual trees was observed. Furthermore, galls and leaves from the same trees displayed enhanced and often distinct biosynthetic capabilities. Our results clearly indicate that galls possess independent metabolic capacities to produce and accumulate monoterpenes as compared to leaves. Our study indicates that galling aphids manipulate the enzymatic machinery of their host plant, intensifying their own defenses against natural enemies.

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING: Roche.

Predictive role of hand-foot syndrome in patients receiving first-line capecitabine plus bevacizumab for HER2-negative metastatic breast cancer.

BACKGROUND: Correlations between development of hand-foot syndrome (HFS) and efficacy in patients receiving capecitabine (CAP)-containing therapy are reported in the literature. We explored the relationship between HFS and efficacy in patients receiving CAP plus bevacizumab (BEV) in the TURANDOT randomised phase III trial. METHODS: Patients with HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) who had received no prior chemotherapy for LR/mBC were randomised to BEV plus paclitaxel or BEV-CAP until disease progression or unacceptable toxicity. This analysis included patients randomised to BEV-CAP who received ⩾1 CAP dose. Potential associations between HFS and both overall survival (OS; primary end point) and progression-free survival (PFS; secondary end point) were explored using Cox proportional hazards analyses with HFS as a time-dependent covariate (to avoid overestimating the effect of HFS on efficacy). Landmark analyses were also performed. RESULTS: Among 277 patients treated with BEV-CAP, 154 (56%) developed HFS. In multivariate analyses, risk of progression or death was reduced by 44% after the occurrence of HFS; risk of death was reduced by 56%. The magnitude of effect on OS increased with increasing HFS grade. In patients developing HFS within the first 3 months, median PFS from the 3-month landmark was 10.0 months vs 6.2 months in patients without HFS. Two-year OS rates were 63% and 44%, respectively. CONCLUSIONS: This exploratory analysis indicates that HFS occurrence is a strong predictor of prolonged PFS and OS in patients receiving BEV-CAP for LR/mBC. Early appearance of HFS may help motivate patients to continue therapy.

Cytoreduction surgery with hyperthermic intraperitoneal chemotherapy in recurrent ovarian cancer improves progression-free survival, especially in BRCA-positive patients- a case-control study.

BACKGROUND: Approximately 70% of women diagnosed with advanced-stage ovarian cancer experience disease recurrence. Survival data were compared between a group of recurrent epithelial ovarian cancer (rEOC) patients treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) and a matched group of rEOC patients treated by systemic chemotherapy only (without surgery). Treatment outcome in relation to the patients' BRCA status was compared. METHODS: Twenty-seven rEOC patients treated by cytoreduction and HIPEC were selected from our database and matched (1:3) with 84 rEOC patients treated with chemotherapy only. Progression-free survival (PFS) and overall survival (OS) in the two groups were analyzed and compared. RESULTS: The estimated median PFS was 15 months in the HIPEC group and 6 months in the systemic chemotherapy group (P = 0.001). The median OS following HIPEC treatment has not been reached, since more than 70% of the women were alive at the time of analysis. The 5-year survival rate was significantly higher in the HIPEC treated patients compared to that of the controls (79% vs. 45%, P = 0.016). BRCA status did not affect PFS. CONCLUSIONS: HIPEC after surgical cytoreduction in patients with rEOC appears beneficial compared to systemic chemotherapy treatment alone. The benefit is even greater in BRCA mutation carriers.

The impact of overall radiotherapy treatment time and delay in initiation of radiotherapy on local control and distant metastases in gastric cancer.

OBJECTIVES: To study the impact of time factors on local and distant metastases in stomach cancer. METHODS: 67 patients with gastric cancer who received adjuvant treatment were reviewed for the time to initiation of radiotherapy, overall duration of RT and the events of first local recurrence or distant metastasis. RESULTS: The risk probability of local recurrence is increased by 10% (HR=1.1, p=0.0009) in association with each additional day of radiotherapy and by 3.8% (HR=1.038, p=0.13) per increased day of waiting time before the initiation of RT. The risk probability of distant recurrence was associated with an increase of 7.4% (HR=1.074 p=0.0031) with each additional day of RT time and by 2.3% (HR=1.023, p=0.0598) following the increase of a day of waiting time. Each day of prolongation of RT beyond 36 days was associated with an increased risk of local recurrence by 10% (OR=1.1, p=0.015). Prolongation of waiting time prior to initiation of irradiation retained significance in multivariate analysis. CONCLUSION: There is an association between total treatment time and, to some extent, the time between the surgery and the initiation of radiation on local control and distant metastases.

The combination of gemcitabine and carboplatin shows similar efficacy in the treatment of platinum-resistant and platinum-sensitive recurrent epithelial ovarian cancer patients.

The aim of this study was to evaluate progression-free survival, overall survival (OS), response rate (RR), and clinical benefit in recurrent ovarian cancer patients treated with gemcitabine and carboplatin and to compare the outcome among platinum-resistant and platinum-sensitive patients. A retrospective study using the medical records of patients diagnosed and treated for recurrent epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma with gemcitabine and carboplatin from 2005 through 2012 at the Tel Aviv Sourasky Medical Center. The treatment regimen was carboplatin (area under the curve=5) administered on day 1 and gemcitabine 850 mg/m administered on days 1 and 8 in a 21-day cycle. Seventy patients with a median age of 57 years (range: 38-86) were included in the study. Most patients (94.3%) were initially diagnosed with stage III-IV disease and 44.3% had platinum-sensitive disease. Median progression-free survival in platinum-sensitive patients was 6.3 months [95% confidence interval (CI): 4.3-8.3] and 6.3 months (95% CI: 4.6-7.9) in platinum-resistant patients. Median overall survival was 15.8 months (95% CI: 13.6-18.1) in the platinum-sensitive patients and 18.4 months (95% CI: 10.0-27.8) in the platinum-resistant patients. Platinum-sensitive patients had a RR of 43.2% and platinum-resistant patients had a RR of 39.1%. The clinical benefit was 70.5% in platinum-sensitive patients and 65.2% in platinum-resistant patients. Overall treatment had a favorable safety profile. Gemcitabine and carboplatin demonstrate moderate toxicity with similar efficacy in both platinum-sensitive and platinum-resistant epithelial ovarian cancer, suggesting reversal of platinum resistance by gemcitabine.

Should a loop ileostomy closure in rectal cancer patients be done during or after adjuvant chemotherapy?

BACKGROUND AND OBJECTIVE: The influence of ileostomy closure timing on surgical and oncologic outcome was investigated in patients with locally advanced rectal cancer receiving adjuvant chemotherapy after low anterior resection. METHODS: Consecutive patients diagnosed with T3-4/N+ rectal cancer, treated by neoadjuvant chemoradiation and low anterior resection during 2000-2012 were retrospectively evaluated. Patients undergoing closure during adjuvant chemotherapy (Group A) were compared to patients undergoing closure after completing chemotherapy (Group B). RESULTS: A total of the 165 patients met inclusion criteria, of whom 104 received adjuvant chemotherapy (25 in Group A and 79 in Group B). The pathologic stage was higher in Group B (P = 0.015). The rates of postoperative complications were similar (16% for Group A and 15% for Group B, P = 0.88), as was hospital stay (mean 5.78 days for Group A and 6.25 days for Group B, P = 0.7). There was no significant difference in recurrence rate and overall survival between the groups. CONCLUSIONS: Referral to ileostomy closure in relation to adjuvant chemotherapy is influenced by pathologic stage. Early referral appears to be reserved to a small number of patients with lower pathologic stage. Timing of ileostomy closure does not change short- or long-term results.

Weekly carboplatin with paclitaxel compared to standard three-weekly treatment in advanced epithelial ovarian carcinoma--a retrospective study.

OBJECTIVE: To retrospectively compare primary treatment with weekly carboplatin/paclitaxel (PC-W) to the standard 3-weekly carboplatin/paclitaxel (PC-3 W) in women with advanced epithelial ovarian cancer, tubal carcinoma and primary peritoneal carcinoma. METHODS: Medical records were assessed for age, stage of disease, tumor histology and grade, BRCA mutation status, and platinum sensitivity. Patients were treated with either paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every three weeks (PC-3 W; 133 patients), or with weekly paclitaxel (80 mg/m(2)) and weekly carboplatin (AUC 2) on days 1, 8, and 15 every 28 days (PC-W; 267 patients). RESULTS: Patient baseline characteristics were similar in both groups. Median overall survival (OS) was similar for PC-W and PC-3 W (64.5 months vs. 61.5 months), but PC-W had longer median progression-free survival [PFS: 27.4 months (95% CI, 22.7-31.4) vs. 19.5 months (95% CI, 15.6-22.2) for PC-3 W, p = 0.0024] and a longer median platinum-free interval [PFI: 22.1 months (95% CI, 16.0-24.5) vs. 14.2 months (95% CI, 10.7-17.2) for PC-3 W, p = 0.0075]. PC-W showed a significantly higher response rate (86.4% vs. 77.9% for PC-3 W, p = 0.0435). Multivariate analysis including for age at diagnosis, stage of disease, optimal debulking, histology, BRCA status, pretreatment CA-125 and PFI revealed that the PC-W women had lower risk of death (HR = 0.587, 95% CI, 0.402-0.857, p = 0.0058), lower risk of disease progression (HR = 0.494, 95% CI, 0.359-0.680, p < 0.0001), higher 2- and 3-year survival rates, and decreased grade II hair loss, neuropathy and thrombocytopenia compared with the PC-3 W women. CONCLUSION: The PC-W protocol improved PFS and had a similar OS as PC-3W.

Determinants of adherence to screening by colonoscopy in individuals with a family history of colorectal cancer.

OBJECTIVE: Although first-degree relatives (FDRs) of colorectal cancer (CRC) patients, as a high-risk population, have the most to gain from colonoscopy screening, their adherence is suboptimal. Thus, an assessment of the determinants of adherence to screening is of potential importance. METHODS: A cross-sectional study was conducted among 318 FDRs of 164 CRC patients treated at Tel-Aviv Sourasky Medical Center. Interviews were conducted with a questionnaire using I-Change Model. RESULTS: Adherence to interval colonoscopy was low with only 73 FDRs (23.0%). Greater adherence was associated with socio-demographic variables (older age, siblings, having spouse, higher level of education and income) and behavioral variables (healthier lifestyle, utilization of preventive health services). Family physicians and kin were identified as the most influential figures on uptake. Intention, affective barriers, positive attitudes, social support, cues to action, age, and health maintenance were the strongest determinants of participation in CRC screening. CONCLUSION: Adherence to colonoscopy is determined by multiple variables. Medical staff can play a key role in increasing adherence to colonoscopy. PRACTICE IMPLICATIONS: Future interventions should focus on fostering positive attitudes, overcoming barriers, enhancing social support and providing a medical recommendation. Special efforts should be invested in young FDRs, those of low socio-economic status and those who underutilize preventive medicine.

Do individuals with a family history of colorectal cancer adhere to medical recommendations for the prevention of colorectal cancer?

Individuals with a family history of colorectal cancer (CRC), have a two-to-five-fold increased lifetime risk to develop CRC. Thus, they are particularly likely to benefit from adherence to medical recommendations for CRC prevention. Despite this increased risk, previous studies have shown an underutilization of colonoscopy for screening and a paucity of data on lifestyle habits that could enhance colonoscopy rates in this population. The primary aims were (a) to assess CRC screening patterns and lifestyle choices among siblings and children of CRC patients, (b) to ascertain discrepancies between actual behavior and medical recommendations, and (c) to identify family members with multiple unhealthy lifestyle habits. The secondary aim was to test for possible associations between utilization rates for CRC screening and other preventive health services. A cross-sectional study was conducted among 318 first-degree relatives (FDRs) of 164 CRC patients treated at the Tel Aviv Sourasky Medical Center. Interviews were conducted with a structured questionnaire. There was significant underutilization of colonoscopy for screening with only 73 FDRs (23.0%) adhering to the recommended screening schedule. This rate was slightly improved (N = 58, 31.9%) among subjects aged 40 years and above, although it was still far below the optimum. A similar result (N = 70, 21.7%) was observed for other cancer screening tests and routine medical check-ups. A significant association (P < 0.0001) was found for healthful lifestyles, overall use of preventive health services, and adherence to CRC screening recommendations. CRC screening is significantly underutilized among FDRs of CRC patients. FDRs who do not comply with CRC screening guidelines, lead unhealthy lifestyles, and avoid other cancer screening tests are at increased risk and should be addressed specifically in future interventions.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79­1·02] during years 5­9 and 0·75 [0·62­0·90] in later years; breast cancer mortality RR 0·97 [0·79­1·18] during years 5­9 and 0·71 [0·58­0·88] in later years). The cumulative risk of recurrence during years 5­14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5­14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89­1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13­3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83­1·36), ischaemic heart disease 0·76 (0·60­0·95, p=0·02), and endometrial cancer 1·74 (1·30­2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5­14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: a prospective, randomized, phase II trial.

OBJECTIVE: This study reports the efficacy and safety of zoledronic acid (ZOL) in preventing bone loss in postmenopausal patients receiving an aromatase inhibitor (AI) following tamoxifen. METHODS: Postmenopausal patients with stage I-III hormone receptor-positive breast cancer who received tamoxifen for 2.5-3 years were randomized to receive letrozole (2.5 mg/day) with (n = 47) or without (n = 43) ZOL (4 mg i.v. every 6 months) for 2 years. The primary endpoint was percent change from baseline in lumbar spine (LS) bone mineral density (BMD) up to 60 months. RESULTS: Ninety patients (86 evaluable) with a median age of 59 years (42.9-83.6), 50/86 of whom had previously been treated with chemotherapy, were followed for a median time of 41.4 months. While the control group showed a significant decrease in LS T-score (p = 0.0005), the ZOL group presented an increase over time (p = 0.0143). Change over time in LS T-score was significantly different between groups, favoring ZOL (p < 0.0001 at 24 and 48 months). No fractures, renal dysfunction or osteonecrosis of the jaw were reported. The toxicity profile was similar to those previously reported for each drug. CONCLUSION: The addition of ZOL to letrozole was safe and efficacious in maintaining LS BMD in postmenopausal patients with hormone receptor-positive breast cancer and who were receiving letrozole following 2.5-3 years of tamoxifen.

Distinct antimicrobial activities in aphid galls on Pistacia atlantica.

Gall-formers are parasitic organisms that manipulate plant traits for their own benefit. Galls have been shown to protect their inhabitants from natural enemies such as predators and parasitoids by various chemical and mechanical means. Much less attention, however, has been given to the possibility of defense against microbial pathogens in the humid and nutrient-rich gall environment. We found that the large, cauliflower-shaped, galls induced by the aphid Slavum wertheimae on buds of Pistacia atlantica trees express antibacterial and antifungal activities distinct from those found in leaves. Antibacterial activity was especially profound against Bacillus spp (a genus of many known insect pathogen) and against Pseudomonas aeruginosa (a known plant pathogen). Antifungal activity was also demonstrated against multiple filamentous fungi. Our results provide evidence for the protective antimicrobial role of galls. This remarkable antibacterial and antifungal activity in the galls of S. wertheimae may be of agricultural and pharmaceutical value.