Breast Cancer in Young Women in Latin America: An Unmet,Growing Burden

Background.

Breast cancer (BC) is the leading cause of malignancy-related deaths among women aged ≤45 years. There are unexplored and uncertain issues for BC in this particular group in Latin America. The aim of this study is to evaluate BC incidence and mortality among young women and related clinicopathological and survivorship aspects in this region.

Materials and Methods.

Data were obtained from Globocan 2008 and the International Agency for Research on Cancer''s Cancer Incidence in Five Continents series plus databases. We requested collaboration from the 12 different national cancer institutes in Latin America through SLACOM, the Latin American and Caribbean Society of Medical Oncology, and conducted a systematic literature review to obtain local data regarding the prevalence of BC among young women and their characteristics, outcomes, and survivorship-related issues.

Results.

BC incidence and mortality proportions for Latin American women aged <44 years were higher when compared with those of developed countries (20% vs. 12% and 14% vs. 7%, respectively). We found only a few Latin American series addressing this topic, and prevalence varied between 8% and 14%. Stage II and III disease, high histological grade, and triple-negative and HER2 BC were features frequently observed among young Latin American BC patients.

Conclusion.

The rising incidence and mortality of BC in young Latin American women is a call to action in the region. It is necessary to monitor the epidemiological and clinical data through reliable cancer registries and to consider the implementation of protocols for education of patients and health professionals. This unmet, growing burden must be considered as a top priority of the national programs in the fight against BC, and models of specialized units should be implemented for this particular group of patients to provide better care for this emergent challenge.     

Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation

BACKGROUND:

Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD).

METHODS:

The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease‐free survival (DFS) and overall survival (OS).

RESULTS:

Among the 240 treated patients, the 1‐year and 3‐year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1‐year and 3‐year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post‐therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, whereas OS was associated with intraoperative blood loss, margin status, ypT, ypN, number of positive lymph nodes, and AJCC stage. By multivariate analysis, DFS was independently associated with age, number of positive lymph nodes, and AJCC stage, and OS was independently associated with differentiation, margin status, number of positive lymph nodes, and AJCC stage. In addition, the treated patients had better OS and lower frequency of lymph node metastasis than those who had no neoadjuvant therapy.

CONCLUSIONS:

In patients with PDAC who received neoadjuvant chemoradiation and subsequent PD, post‐therapy pathologic AJCC stage and number of positive lymph nodes are independent prognostic factors. Cancer 2012. © 2011 American Cancer Society.     

Icilin induces a hyperthermia in rats that is dependent on nitric oxide production and NMDA receptor activation

Icilin (AG-3-5) is a cold-inducing agent that activates the transient receptor potential channels TRPM8 and TRPA1. Both channels are members of the transient receptor potential (TRP) superfamily of ion channels and are activated by cold. Despite the key role of cold-activated TRPM8 and TRPA1 channels in temperature sensation and other physiological processes, the significance of these channels in thermoregulation in conscious animals is poorly understood. Therefore, in the present study we investigated the effects of icilin on body temperature in rats and tested the hypothesis that cold-activated TRP channel activation by icilin causes a hyperthermia which requires nitric oxide (NO) production and NMDA receptor stimulation. Our experiments revealed that icilin (2.5, 5, 7.5 and 10 mg/kg, i.m.) elicits a dose-related hyperthermia that is rapid in onset and of long duration. Pretreating rats with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) (10, 25 and 50 mg/kg, i.p.), a non-selective NO synthase inhibitor, attenuated the hyperthermia associated with icilin (7.5 mg/kg, i.m.). Pretreatment with (-)-6-[phosphonomethyl-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-2-carboxylate] (LY 235959) (0.25, 0.5 and 1 mg/kg, i.p.), a selective NMDA receptor antagonist, also attenuated the icilin-evoked hyperthermia. The administration of icilin (5 and 100 microg) into the lateral cerebroventricle of rats did not affect body temperature, thus indicating a peripheral site of action. These results indicate that icilin, a TRPM8/TRPA1 agonist, produces a dose-related hyperthermia in rats which requires both NO production and NMDA receptor activation.     

Potentiation of analgesic efficacy but not side effects: co-administration of an α4β2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats

Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4β2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 μmol/kg, i.p.) induced a 6-fold leftward shift of the dose–response of ABT-594 (ED₅₀ = 26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED₅₀ = 26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED₅₀ = 1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose–response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 μmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4β2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4β2 nAChR by PAM may represent a novel analgesic approach.     

Evaluation of markers out of the steroid profile for the screening of testosterone misuse. Part II: Intramuscular administration

In the fight against doping, the introduction of alternative markers to the steroid profile can be considered as an effective approach to improve the screening capabilities for the detection of testosterone (T) misuse. The aim of this study was to evaluate the potential of several T metabolites (cysteinyl conjugated and glucuronoconjugated resistant to enzymatic hydrolysis) to detect both the transdermal and the intramuscular administration of T. In Part I of the study, we studied the potential of these metabolites for the detection of T transdermal administration. Results revealed that resistant glucuronides can be a suitable complement to the current steroid profile. In this, Part II, dedicated to the intramuscular administration, we studied the potential of cysteinyl conjugated, resistant glucuronoconjugated and 1‐cyclopentenoylglycine (1‐CPG) for the detection of a single intramuscular injection of T cypionate. Possible differences in the excretion profile of all markers were explored between individuals with low basal (n=6) and medium basal (n=6) values of the testosterone/epitestosterone ratio (T/E). The results showed that all tested markers presented low intra‐individual stability in basal conditions. Despite this, all glucuronoconjugated markers and 1‐CPG, but not the cysteinyl conjugated markers, provided detection windows that were similar or longer than those obtained by markers currently included in the steroid profile. Based on the results obtained from the 2 parts of this study and from previously reported data, the potential applicability and the limitations of including these markers in the steroid profile are discussed.     

Photolytic degradation of benorylate: effects of the photoproducts on cultured hepatocytes

The photodegradation of benorylate [4'-(acetamido)phenyl-2-acetoxybenzoate], a drug frequently used in rheumatoid arthritis therapy, has been examined under different sets of experimental conditions. Several photoproducts have been isolated and identified on the basis of their IR, NMR, and MS spectra. The most significant photochemical process is the photo-Fries rearrangement of benorylate, leading to 5-acetamido-2'-acetoxy-2-hydroxybenzophenone (1). This compound undergoes a rapid transacylation to the isomeric 5'-acetamido-2'-acetoxy-2-hydroxybenzophenone (2). A primary culture of rat hepatocytes has been used to evaluate the possible toxicity of these two benzophenones, keeping in mind the following criteria: leakage of cytosolic enzymes, attachment index to culture plates, gluconeogenesis from lactate and fructose, glycogen balance, and albumin synthesis. At the concentrations assayed, neither of the two major photoproducts of benorylate (benzophenones 1 and 2) had significant toxic effects on liver cells in culture.     

Molecular cloning, expression and immunological properties of LiD1, a protein from the dermonecrotic family of Loxosceles intermedia spider venom

The present report describes the identification and molecular characterization of LiD1, a protein expressed in the venom gland of the brown spider Loxosceles intermedia. LiD1 belongs to a family of proteins with dermonecrotic activity and members of this family have been found in spiders from the genus Loxosceles. The necrotic lesions caused by this group of proteins may lead to serious socio-economic problems such as surgical tissue reconstitution and even patient death. LiD1 was cloned using a cDNA library constructed from the venom gland of L. intermedia and antibodies against proteins with dermonecrotic activity isolated from the crude venom of this spider. The amino acid sequence deduced from the cDNA revealed a mature protein of approximately 31 kDa, with a pI of 7.37. The cDNA also revealed the existence of a signal peptide, a propeptide and also an untranslated 3′ region with 218 nucleotides. LiD1 was expressed as a protein fused with β-galactoside protein using the vector pBK-CMV, resulting in the recombinant protein recLiD1 with important immunological properties. recLiD1 was strongly recognised by anti-dermonecrotic antibodies and was also able to generate reactive antibodies against native dermonecrotic proteins isolated from the venom of L. intermedia.     

First case of mesh infection due to Coccidioides spp. and literature review of fungal mesh infections after hernia repair

Fungal mesh infections are a rare complication of hernia repairs with mesh. The first case of Coccidioides spp. mesh infection is described, and a systematic literature review of all known fungal mesh infections was performed. Nine cases of fungal mesh infection are reviewed. Female and male patients are equally represented, median age is 49.5 years, and critical illness and preinfection antibiotic use were common. Fungal mesh infections are rare, but potentially fatal, complications of hernias repaired with mesh.     

Occurrence and outcome of de novo metastatic breast cancer by subtype in a large,diverse population

Purpose

To examine the occurrence and outcomes of de novo metastatic (Stage IV) breast cancer, particularly with respect to tumor HER2 expression.

Methods

We studied all 6,268 de novo metastatic breast cancer cases diagnosed from 1 January 2005 to 31 December 2011 and reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, including estrogen and/or progesterone receptor) expression. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) of Stage IV versus Stage I–III breast cancer; Cox proportional hazards regression was used to assess relative hazard (RH) of mortality.

Results

Five percent of invasive breast cancer was metastatic at diagnosis. Compared to patients with earlier stage disease, patients with de novo metastatic disease were significantly more likely to have HER2+ tumors (HR+/HER2+: OR 1.29, 95 % CI 1.17–1.42; HR?/HER2+: OR 1.40, 95 %CI 1.25–1.57, vs. HR+/HER2?). Median survival improved over time, but varied substantially across race/ethnicity (Asians: 34 months; African Americans: 6 months), neighborhood socioeconomic status (SES) (highest: 34 months, lowest: 20 months), and molecular subtype (HR+/HER2+: 45 months; triple negative: 12 months). In a multivariable model, triple negative (RH 2.85, 95 % CI 2.50–3.24) and HR?/HER2+ (RH 1.60, 95 % CI 1.37–1.87) had worse, while HR+/HER2+ had similar, risk of all-cause death compared to HR+/HER2? breast cancer.

Conclusions

De novo metastatic breast cancer was more likely to be HER2+. Among metastatic tumors, those that were HER2+ had better survival than other subtypes.