Creation and Validation of a New Socio-built Environment Index Measure of Opioid Overdose Risk for Use in Both Non-urban and Urban Settings.

A great deal of literature has examined features of the physical built environment as predictors of opioid overdose and other substance use-related outcomes. Other literature suggests that social characteristics of settings are important predictors of substance use outcomes. However, there is a dearth of literature simultaneously measuring both physical and social characteristics of settings in an effort to better predict opioid overdose. There is also a dearth of literature examining built environment as a predictor of overdose in non-urban settings. The present study presents a novel socio-built environment index measure of opioid overdose risk comprised of indicators measuring both social and physical characteristics of settings - and developed for use in both urban and non-urban settings - and assesses its validity among 565 urban, suburban, and rural New Jersey municipalities. We found that this novel measure had good convergent validity, based on significant positive associations with a social vulnerability index and crime rates, and significant negative associations with a municipal revitalization index and high school graduation rates. The index measure had good discriminant validity, based on lack of association with three different racial isolation indices. Finally, our index measure had good health outcome-based criterion validity, based on significant positive associations with recent overdose mortality. There were no major differences between rural, suburban, and urban municipalities in validity analysis findings. This promising new socio-built environment risk index measure could improve ability to target and allocate resources to settings with the greatest risk, in order to improve their impact on overdose outcomes.

Genitourinary Systems Entangled with Shifting Environments in a Salvadoran Subsistence Farming Community.

Diseases of the genitourinary system are the leading cause of hospital deaths in El Salvador, and chronic kidney disease of unknown origin has been gaining attention as a public health problem among farmers in particular. Epidemiological studies point, in part, to environmental risk factors, which have shifted over time with the deployment of modern agricultural science and ongoing climate change. We examined how diseases of the genitourinary system were situated at several margins of an epidemic in one rural Salvadoran municipality where these environmental and epidemiological changes are occurring, albeit relatively slow. By using this approach to study diseases of the genitourinary system, we illustrate one way in which shifting human/environment entanglements can be experimentally "known" in the context of human diseases associated with them. Our approach offers a unique perspective in thinking with ethnographic data to compliment ongoing epidemiological investigations of kidney disease in El Salvador.

In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy?

BACKGROUND: The Oncotype DX recurrence score (RS) assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy in patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer. Patients with high RS tumors have substantial benefit, and patients with low RS tumors have minimal if any benefit from chemotherapy. Tumor size is used as a key parameter when selecting patients for neoadjuvant chemotherapy. The aim of this study was to assess the distribution of RS in patients selected for neoadjuvant chemotherapy primarily according to tumor size. PATIENTS AND METHODS: Patients with ER-positive and HER2-negative tumors that were node-negative or had no more than 1 positive node from three trials were included in this study. Oncotype DX was performed at Genomic Health, Inc., blinded to the clinical data. Descriptive statistics were calculated for distribution of RS for all cases. RESULTS: Of 277 patients, 96 met eligibility criteria, and 81 had sufficient material for analysis. Median tumor size was 40 mm (interquartile range [IQR], 30-50 mm). Grade I, II, and III were observed in 13, 49, and 17 cases, respectively. There was a wide distribution of RS with a median of 21.4 (IQR, 16.05-26.75). In total, 23 (28.3%) had high, 28 (34.6%) intermediate, and 30 (37%) low RS results. CONCLUSION: The RS may provide relevant information for neoadjuvant treatment decisions in select patients both in clinical practice and in studies. Inclusion of low RS disease patients in neoadjuvant trials will likely only dilute the ability to look at treatment effects.

Identification of Riluzole derivatives as novel calmodulin inhibitors with neuroprotective activity by a joint synthesis, biosensor, and computational guided strategy.

The development of new molecules for the treatment of calmodulin related cardiovascular or neurodegenerative diseases is an interesting goal. In this work, we introduce a novel strategy with four main steps: (1) chemical synthesis of target molecules, (2) Förster Resonance Energy Transfer (FRET) biosensor development and in vitro biological assay of new derivatives, (3) Cheminformatics models development and in vivo activity prediction, and (4) Docking studies. This strategy is illustrated with a case study. Firstly, a series of 4-substituted Riluzole derivatives 1-3 were synthetized through a strategy that involves the construction of the 4-bromoriluzole framework and its further functionalization via palladium catalysis or organolithium chemistry. Next, a FRET biosensor for monitoring Ca2+-dependent CaM-ligands interactions has been developed and used for the in vitro assay of Riluzole derivatives. In particular, the best inhibition (80%) was observed for 4-methoxyphenylriluzole 2b. Besides, we trained and validated a new Networks Invariant, Information Fusion, Perturbation Theory, and Machine Learning (NIFPTML) model for predicting probability profiles of in vivo biological activity parameters in different regions of the brain. Next, we used this model to predict the in vivo activity of the compounds experimentally studied in vitro. Last, docking study conducted on Riluzole and its derivatives has provided valuable insights into their binding conformations with the target protein, involving calmodulin and the SK4 channel. This new combined strategy may be useful to reduce assay costs (animals, materials, time, and human resources) in the drug discovery process of calmodulin inhibitors.

Efficacy and safety of ixabepilone, a novel epothilone analogue.

The epothilones and their analogues are a new class of anticancer agents derived from the fermentation of myxobacterium Sorangium cellulosum. These compounds have some similarities to taxanes in targeting and stabilizing microtubules, but they also have important differences. Among the epothilone family, ixabepilone has emerged to be a semisynthetic epothilone analogue of interest. Ixabepilone has demonstrated consistent preclinical activity and seems active against various taxane-sensible and taxane-resistant cell lines, including those with overexpression of multidrug resistance and with mutations in the beta-tubulin gene. The interest of this ixabepilone has been confirmed clinically. Phase II clinical studies have demonstrated high activity in patients with taxane-resistant metastatic breast cancer and in patients with other chemotherapy-resistant tumor types.

Is there still a role for triple endoscopy as part of staging for head and neck cancer?

PURPOSE OF REVIEW: The use of tobacco and/or alcohol is linked with the occurrence of head and neck squamous cell carcinoma, esophagus cancer and lung cancer. If these carcinogenic factors can induce the development of a cancer in one of these locations, it would seem reasonable that a second cancer could appear in another of those areas, at the same time or at some point in the future. RECENT DEVELOPMENTS: This is the reason why one can consider that triple endoscopy is required as the optimal evaluation in patients with head and neck cancer. Nevertheless, the usefulness of this systematic procedure, which includes nasopharyngoscopy, laryngoscopy, pharyngoscopy, bronchoscopy and esophagoscopy, is debatable. The low number of head and neck cancers associated with synchronous primary cancers in the esophagus and/or lungs reported by several studies does not support this procedure and its morbidity. In contrast, in other studies a higher rate was observed and the authors pointed out the impact of such findings on treatment strategy, suggesting the benefit of routine triple endoscopy. One can conclude that the relevance of routine triple endoscopy is related to the rate of second synchronous primary cancer detected. A search to identify predictive factors of synchronous cancer occurrence will therefore be required. SUMMARY: This review summarizes the available data in the literature and highlights the need for selected patients with head and neck cancer to receive triple endoscopy.

Angiogenesis and tumor microenvironment: bevacizumab in the breast cancer model.

Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes.

Granocyte-colony stimulating factor (G-CSF) has significant efficacy as secondary prophylaxis of chemotherapy-induced neutropenia in patients with solid tumors: results of a prospective study.

AIM: To carry out a prospective, multicenter and observational study describing prophylactic strategies [cycle delay, dose-reduction, (G-CSF) prescription] to prevent recurrence of neutropenic events (NE) in patients with solid tumors, and identify potential predictive factors of NE recurrence. PATIENTS AND METHODS: Patients ≥18 years old with an NE in a previous chemotherapy cycle (cycle A) without G-CSF support, followed for four cycles (B to E) were included in the study. NE was defined as any neutropenia grade 1-4, febrile or not, which impacted on subsequent chemotherapy cycles (cycle delay, or reduction, or prophylactic G-CSF). RESULTS: Data of 548 patients were analyzed, 378 (69%) were female, with a mean (SD) age of 61.7 (12.3) years. WHO PS: 0-1: 88.3%, incidence of breast cancer: 40%, metastatic disease: 53.3%. Following the first NE episode, 44.5% of patients had cycle delay, 22.3% dose reduction and 466 (85%) received prophylactic G-CSF. NE recurrence rates were: 21.2% at cycle B, 18.6% at cycle C, 11.5% at cycle D and 12.9% at cycle E. G-CSF support (hazard ratio: 0.32, 0.24-0.43, p<0.001) was associated with lower NE recurrence. Pegfilgrastim seemed to offer the highest protection (hazard ratio; HR=0.23, 95% CI: 0.16-0.32; p<0.001). CONCLUSION: Secondary G-CSF prophylaxis has significant efficacy in reducing the incidence of NE and should be considered as a valuable option.

[Antibody-drug conjugates in oncology: from the concept to trastuzumab emtansine (T-DM1)]. / Les anticorps conjugués en oncologie : du concept au trastuzumab emtansine (T-DM1).

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) which associates the selective intracellular targeting of the cytotoxic agent, DM1 (maytansine derivative) to the antitumor activity of trastuzumab. T-DM1 targets the epidermal growth factor receptor 2 (HER2), highly expressed in the most aggressive forms of breast cancer. Current standard of care in HER2-positive advanced or metastatic breast cancers has its limitations, particularly after progression on HER2-targeted approved therapies. T-DM1 showed a significant antitumor activity in vitro and in vivo, and in experimental models resistant to HER2-targeted agents. Phase I and II studies showed that the maximum tolerated dose for T-DM1 is 3.6 mg/kg given intravenously every three weeks. At this recommended dose, T-DM1 provided objective tumor responses and favourable safety profile. A phase II randomised study, evaluating T-DM1 in first line vs trastuzumab plus docetaxel, the current standard of care in advanced or metastatic breast cancers, showed improved tolerability and efficacy. Recently, the results of EMILIA, a phase III randomised study assessing, after prior treatment with trastuzumab and a taxane, the efficacy and the safety of T-DM1 vs lapatinib plus capecitabine, confirmed the therapeutic benefit. T-DM1 appears to be an effective therapeutic option to treat patients with HER2-positive metastatic breast cancer.

[Follow-up in patients with early breast cancer]. / La surveillance du cancer du sein non métastasé

Breast cancer incidence remains the highest among gynaecologic neoplasms. Once they have achieved their treatments, patients should undergo careful follow-up. It aims at detecting early local recurrence or controlateral breast cancer. Based on large cohorts, clinical and radiological follow-up procedures come from guidelines realised by scientific organisations. We evaluated our regional practices in Franche-Comté and compared them to current guidelines. Patients with early breast cancer positive for hormonal receptors filled a questionnaire concerning their follow-up. It included patients treated from 1999 to 2005. When frequency of consultation is evaluated, only half of the patients undergo what is recommended. Whereas mammography and non-validated complementary exams are more regularly realised. Patients consulting more one practician have a better compliance. Our study underlines significant disparities among patients follow-up. Better interactions between physicians and a greater implication of patients in their follow-up would increase its quality.

Ixabepilone, a novel epothilone analog in the treatment of breast cancer.

BACKGROUND: Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing cell death. Ixabepilone (BMS-247550, Ixempra) is an epothilone analog that optimizes the properties naturally observed with epothilone B. OBJECTIVE: To provide an overview of the results achieved by ixabepilone in metastatic breast cancer. METHODS: A PubMed search was performed to provide an extensive review of all published data on ixabepilone, in addition to all data reported from international congresses, from 2003 to 2007. RESULTS/CONCLUSION: There is a clear need for new agents active against resistant metastatic breast cancer and ixabepilone might be a welcome new compound in this situation.

[Pemetrexed development in oncology]. / Perspectives de développement du pemetrexed en oncologie.

The pemetrexed disodium (Alimta), LY231514) is the first antifolate able to inhibit at the same time the synthesis of purins and pyrimidins. Many therapeutic tests were carried out in clinical situations where the methotrexate and the fluorouracil had been the proof of their effectiveness. It then showed an interesting activity in a great number of tumours but with very different profiles of tolerance according to the studies and pathologies. The explanation will come in 2001 by the description from the relation between the vitamin deficiencies among treated patients and occurred from toxicities. The two randomized studies carried out in the malignant pleural mesothelioma and the non small cell lung cancer made it possible to establish its utility and to record the pemetrexed in these clinical situations. Others axes of development remain possible, but the results are stanby or to confirm as in squamous-cell cancer in the head and neck and breast, digestive or urinary tracts cancer. In all the cases, the optimization of the pemetrexed in terms of amount/methods of administration and associations possible because of its profile of tolerance makes of it a molecule of chemotherapy with a future.

[Induction chemotherapy in patients with head and neck cancer]. / Chimiothérapie d'induction chez les patients présentant un cancer des voies aérodigestives supérieures.

Neoadjuvant chemotherapies for patients with advanced head and neck squamous cell carcinoma have been widely studied for twenty years. Despite a high level of activity on the primary tumor, no study has demonstrated a survival benefit suggesting the use of neoadjvant chemotherapy. One can consider that the only benefit of such strategy is for larynx preservation in patients with operable hypopharnx or larynx cancer. Nevertheless, recently the well established preservation strategy based on induction chemotherapy following according to the activity by radiotherapy has been knocked over by a strategy developed by Forastiere et al. using primary concomitant chemoradiotherapy. However, the lack of benefit reported by neoadjuvant chemotherapy has been thwarted by the recent results provided by the EORTC study which assessed the survival benefit of neoadjuvant chemotherapy by docetaxel-cisplatin-fluorouracile. Interestingly, since 2002 the clearly established strategies for patients with advanced head and neck cancer have been challenged and new options are emerging. This paper reviews the standard strategy of the past and the future proposal emerging from recent studies.