Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases.

The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis.

Emergence of High-Level Colistin Resistance in an Acinetobacter baumannii Clinical Isolate Mediated by Inactivation of the Global Regulator H-NS.

Colistin is a crucial last-line drug used for the treatment of life-threatening infections caused by multidrug-resistant strains of the Gram-negative bacterium Acinetobacter baumannii However, colistin-resistant A. baumannii isolates can still be isolated following failed colistin therapy. Resistance is most often mediated by the addition of phosphoethanolamine (pEtN) to lipid A by PmrC, following missense mutations in the pmrCAB operon encoding PmrC and the two-component signal transduction system PmrA/PmrB. We recovered a pair of A. baumannii isolates from a single patient before (6009-1) and after (6009-2) failed colistin treatment. These strains displayed low and very high levels of colistin resistance (MICs, 8 to 16 µg/ml and 128 µg/ml), respectively. To understand how increased colistin resistance arose, we sequenced the genome of each isolate, which revealed that 6009-2 had an extra copy of the insertion sequence element ISAba125 within a gene encoding an H-NS family transcriptional regulator. To confirm the role of H-NS in colistin resistance, we generated an hns deletion mutant in 6009-1 and showed that colistin resistance increased upon the deletion of hns We also provided 6009-2 with an intact copy of hns and showed that the strain was no longer resistant to high concentrations of colistin. Transcriptomic analysis of the clinical isolates identified more than 150 genes as being differentially expressed in the colistin-resistant hns mutant 6009-2. Importantly, the expression of eptA, encoding a second lipid A-specific pEtN transferase but not pmrC, was increased in the hns mutant. This is the first time an H-NS family transcriptional regulator has been associated with a pEtN transferase and colistin resistance.

Apoptotic human neutrophil peptide-1 anti-tumor activity revealed by cellular biomechanics.

Cancer remains a major cause of morbidity and mortality worldwide. Although progress has been made regarding chemotherapeutic agents, new therapies that combine increased selectivity and efficacy with low resistance are still needed. In the search for new anticancer agents, therapies based on biologically active peptides, in particular, antimicrobial peptides (AMPs), have attracted attention for their decreased resistance development and low cytotoxicity. Many AMPs have proved to be tumoricidal agents against human cancer cells, but their mode of action is still controversial. The existence of common properties shared by the membranes of bacteria and tumor cells points to similar lipid-targeting mechanisms in both cases. On the other hand, anticancer peptides (ACPs) also induce apoptosis and inhibit angiogenesis. Human neutrophil peptide-1 (HNP-1) is an endogenous AMP that has been implicated in different cellular phenomena such as tumor proliferation. The presence of HNP-1 in the serum/plasma of oncologic patients turns this peptide into a potential tumor biomarker. The present work reveals the different effects of HNP-1 on the biophysical and nanomechanical properties of solid and hematological tumor cells. Studies on cellular morphology, cellular stiffness, and membrane ultrastructure and charge using atomic force microscopy (AFM) and zeta potential measurements show a preferential binding of HNP-1 to solid tumor cells from human prostate adenocarcinoma when compared to human leukemia cells. AFM also reveals induction of apoptosis with cellular membrane defects at very low peptide concentrations. Understanding ACPs mode(s) of action will certainly open innovative pathways for drug development in cancer treatment.

Good Syndrome in a Young Woman: An Unusual Presentation.

Good Syndrome is a rare disease that comprises the presence of a thymoma, immunodeficiency, and recurrent opportunistic infections. We report the case of a young woman who was diagnosed with Good Syndrome, who had a long-term history of recurrent infections, often due to atypical agents, and who also had a previous history of immunodeficiency and a B1 thymoma invading the large vessels, lung, and pericardium (Masaoka stage IV). She underwent surgical resection of the mediastinal mass, requiring vena cava superior reconstruction due to the extent of invasion, followed by adjuvant radiotherapy and immunoglobulin G supplementation. Despite relative stability in the subsequent years, without serious infections, after three years she had a thymoma recurrence requiring a new therapeutic approach. This case highlights the importance of a thorough investigation of the underlying causes of recurrent infections, which may be the result of an immunodeficiency secondary to malignancy. In young patients, early diagnosis is crucial to avoid disease progression and to reduce mortality rates. To achieve such outcomes, a multidisciplinary team and a comprehensive therapeutic strategy are necessary.

Unveiling the future: precision pharmacovigilance in the era of personalized medicine.

In the era of personalized medicine, pharmacovigilance faces new challenges and opportunities, demanding a shift from traditional approaches. This article delves into the evolving landscape of drug safety monitoring in the context of personalized treatments. We aim to provide a succinct reflection on the intersection of tailored therapeutic strategies and vigilant pharmacovigilance practices. We discuss the integration of pharmacogenetics in enhancing drug safety, illustrating how genetic profiling aids in predicting drug responses and adverse reactions. Emphasizing the importance of phase IV-post-marketing surveillance, we explore the limitations of pre-marketing trials and the necessity for a comprehensive approach to drug safety. The article discusses the pivotal role of pharmacogenetics in pre-exposure risk management and the redefinition of pharmacoepidemiological methods for post-exposure surveillance. We highlight the significance of integrating patient-specific genetic profiles in creating personalized medication leaflets and the use of advanced computational methods in data analysis. Additionally, we examine the ethical, privacy, and data security challenges inherent in precision medicine, emphasizing their implications for patient consent and data management.

Iris-Claw Anterior Chamber Phakic Intraocular Lens Explantation: A Case Series.

Purpose: To evaluate indications, clinic characteristics, and outcomes in a series of patients who underwent explantation of phakic intraocular lens (pIOL). Methods: Retrospective case series of patients who underwent iris-claw pIOL explantation in our institution from 2018 to 2022. Indications for explantation and visual and refractive outcomes were analyzed. Results: Twenty-three eyes of 14 patients underwent pIOL explantation with a mean time to explantation of 11.7 ± 3.4 years. The mean age at explantation was 46.0 ± 3.9 years. Sixteen Artisan and seven Artiflex IOL were explanted. The main indication for explantation was endothelial cell loss (n = 14) and morphometric significant alterations of endothelial cells other than endothelial cell count decline (n = 5). The mean corrected vision after explantation was 0.4 ± 0.4 logMAR, and around 70% of intervened patients achieved visual acuity of at least 0.3 logMAR (0.5 in decimal scale). Conclusions: In our group series, the main reason for the removal of pIOL was endothelial cell loss. This complication should be monitored and followed, so that early actions, namely IOL explantation, can be performed to avoid the development of deterioration requiring corneal transplantation. In fact, loss of follow-up, found in several cases for many years, continues to be a serious problem.

Exploring new pathways in endocrine-resistant breast cancer.

The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer.

PURPOSE: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. EXPERIMENTAL DESIGN: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. RESULTS: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. CONCLUSIONS: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.

In vivo requirement of the small subunit of U2AF for recognition of a weak 3' splice site.

The U2 snRNP auxiliary factor (U2AF) is an essential splicing factor composed of two subunits, a large, 65-kDa subunit (U2AF(65)) and a small subunit, U2AF(35). U2AF(65) binds to the polypyrimidine tract upstream from the 3' splice site and promotes U2 snRNP binding to the pre-mRNA. Based on in vitro studies, it has been proposed that U2AF(35) plays a role in assisting U2AF(65) recruitment to nonconsensus polypyrimidine tracts. Here we have analyzed in vivo the roles of the two subunits of U2AF in the selection between alternative 3' splice sites associated with polypyrimidine tracts of different strengths. Our results reveal a feedback mechanism by which RNA interference (RNAi)-mediated depletion of U2AF(65) triggers the downregulation of U2AF(35). We further show that the knockdown of each U2AF subunit inhibits weak 3' splice site recognition, while overexpression of U2AF(65) alone is sufficient to activate the selection of this splice site. A variant of U2AF(65) lacking the interaction domain with U2AF(35) shows a reduced ability to promote this splicing event, suggesting that recognition of the weak 3' splice site involves the U2AF heterodimer. Furthermore, our data suggest that, rather than being required for splicing of all pre-mRNA substrates containing a weak polypyrimidine tract, U2AF(35) regulates the selection of weak 3' splice sites in a specific subset of cellular transcripts.

RNA interference knockdown of hU2AF35 impairs cell cycle progression and modulates alternative splicing of Cdc25 transcripts.

U2AF is a heterodimeric splicing factor composed of a large (U2AF65) and a small (U2AF35) subunit. In humans, alternative splicing generates two U2AF35 variants, U2AF35a and U2AF35b. Here, we used RNA interference to specifically ablate the expression of each isoform in HeLa cells. Our results show that knockdown of the major U2AF35a isoform reduced cell viability and impaired mitotic progression, leading to accumulation of cells in prometaphase. Microarray analysis revealed that knockdown of U2AF35a affected the expression level of approximately 500 mRNAs, from which >90% were underrepresented relative to the control. Among mRNAs underrepresented in U2AF35a-depleted cells we identified an essential cell cycle gene, Cdc27, for which there was an increase in the ratio between unspliced and spliced RNA and a significant reduction in protein level. Furthermore, we show that depletion of either U2AF35a or U2AF35b altered the ratios of alternatively spliced isoforms of Cdc25B and Cdc25C transcripts. Taken together our results demonstrate that U2AF35a is essential for HeLa cell division and suggest a novel role for both U2AF35 protein isoforms as regulators of alternative splicing of a specific subset of genes.

A Real-World Effectiveness Study Comparing a Priority Appointment, an Enhanced Contact Intervention, and a Psychotherapeutic Program Following Attempted Suicide.

OBJECTIVE: To determine the comparative effectiveness of 3 real-practice preventive programs aimed at lowering the relapse risk following a suicide attempt: a single priority appointment with an outpatient psychiatrist, an enhanced contact intervention, and an individual psychotherapy program. METHODS: This observational study was conducted in a sample of 1,492 suicide attempters from 3 catchment areas in Madrid, Spain, between 2013 and 2017. Relapse was defined as an emergency department return after a new attempt within a 1-year follow-up. Kaplan-Meier survival functions were obtained by intervention, and Cox proportional hazard regression models were used to estimate unadjusted and adjusted risks of relapse by intervention. Sex- and age-stratified analyses were also conducted. Covariates were age, sex, history of suicide attempts, history of psychiatric disorders, main ICD-10 psychiatric diagnostic groups, medical comorbidities, and family support. RESULTS: A total of 133 subjects (8.9%) relapsed. The psychotherapy group had a lower presence of known risk factors for suicide attempt. Individual psychotherapy and enhanced contact were more effective than a single priority appointment at reducing suicide reattempt, with a 40% lower relapse risk in adjusted models. Results did not differ after sex and age stratification. CONCLUSIONS: In a naturalistic clinical setting, patients exposed to individual psychotherapy or an enhanced contact intervention had a similar, lower relapse risk than the single priority appointment group.

Contribution of efflux to colistin heteroresistance in a multidrug resistant Acinetobacter baumannii clinical isolate.

PURPOSE: The mechanisms underlying colistin heteroresistance in Acinetobacter baumannii are not fully understood. Here, we investigated the role of efflux in colistin-heteroresistant populations of a multidrug-resistant (MDR) A. baumannii clinical isolate. METHODOLOGY: Three colistin-resistant A. baumannii strain variants isolated from the same clinical sample were studied for the presence of heteroresistance to colistin by drug susceptibility testing, genotyping and drug resistance target mutation analysis. The existence of active efflux was studied by synergism assays with efflux inhibitors, real-time efflux activity measurements and analysis of the mRNA transcriptional levels of selected efflux pump genes in response to colistin. RESULTS: All of the strain variants belong to the ST218, clonal complex 92, international clonal lineage II. Different colistin susceptibility levels were observed among the three strain variants, indicating that colistin-heteroresistant subpopulations were being selected upon exposure to colistin. No mutations were found in the genes lpxACD and pmrAB, which are associated with colistin resistance. The results showed the existence of synergistic interactions between efflux inhibitors and colistin and ethidium bromide. Real-time efflux assays demonstrated that the three strain variants had increased efflux activity that could be inhibited in the presence of the inhibitors. The efflux pump genes adeB, adeJ, adeG, craA, amvA, abeS and abeM were found to be overexpressed in the strain variants in response to colistin exposure. CONCLUSION: This study shows that efflux activity contributes to colistin heteroresistance in an MDR A. baumannii clinical isolate. The use of efflux inhibitors as adjuvants of the therapy can resensitize A. baumannii to colistin and prevent the emergence of drug resistance.

Thioridazine reduces resistance of methicillin-resistant staphylococcus aureus by inhibiting a reserpine-sensitive efflux pump.

Previous studies suggested that the phenothiazine chlorpromazine (CPZ) could reverse or reduce the antibiotic resistance of bacteria. In some areas of the world, the majority of Staphylococcus aureus isolates are now resistant to methicillin, prompting this study to see whether such resistance can be altered by phenothiazine thioridazine (TZ), an agent with equal antibacterial activity, which is free of the severe side-effects associated with chronic administration of CPZ. The results indicated that, whereas methicillin-sensitive strains of Staphylococcus aureus (MSSA) were not rendered more susceptible to oxacillin, resistance to oxacillin by highly-resistant strains (MRSA) could be significantly reduced by sub-inhibitory concentrations of TZ. Reserpine, an inhibitor of efflux pumps, was also shown to reduce the resistance of MRSA strains to oxacillin in a concentration-dependent manner. The phenothiazines have been shown, by others, to inhibit the efflux pumps of bacteria and the mechanism by which MRSA are rendered more susceptible to oxacillin in the presence of TZ is believed to be due to a similar efflux pump.

Therapy-Induced Cellular Senescence Induces Epithelial-to-Mesenchymal Transition and Increases Invasiveness in Rectal Cancer.

INTRODUCTION: DNA damaging agents and ionizing radiation used in the therapy of human cancers can induce senescence of cancer cells. Senescent cells exhibit a secretory phenotype (senescence-associated secretome [SAS]) that can affect cancer cell behavior and, eventually, clinical prognosis. We assessed the effects of the SAS on the induction of epithelial-to-mesenchymal transition (EMT) in vitro and in clinical samples from patients with rectal cancer who had undergone neoadjuvant chemoradiotherapy (CRT). MATERIALS AND METHODS: Colorectal cancer cells (HCT 116) were induced into senescence by exposure to either 5-fluorouracil (5-FU) or doxorubicin. The senescent state was confirmed by staining for senescence-associated ß-galactosidase (SA-ß-Gal). The paracrine effects of SASs were assessed on proliferating HCT 116 cells. The quantified parameters were cell proliferation, invasive capacity, and induction of EMT. Senescence and EMT in clinical samples were assessed by the expression levels (reverse transcriptase-quantitative polymerase chain reaction) of genes related to senescence and EMT after laser-assisted microdissection of cancer cell clusters that stained either positive or negative for SA-ß-Gal. RESULTS: We have shown that cultured colon cancer cells induced into senescence by exposure to 5-FU exhibit a SAS capable of paracrine induction of EMT in colon and rectal cancer cell lines and increased cell invasion in vitro. Using laser-assisted microdissection, we found that in rectal cancer samples from patients treated with neoadjuvant CRT, tumor cell niches enriched for senescent cells bookmark regions of increased mRNA expression levels of EMT-related proteins (Slug, Snail, vimentin) compared with the nearby senescent-null tumor cell niches. CONCLUSION: We have provided, first-hand, strongly suggestive evidence that senescent cancer cells emerging in the context of neoadjuvant CRT for rectal cancer influenced the tumor microenvironment by promoting EMT by way of short-range interactions.

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04-5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55-12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78-3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42-3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17-1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors.

Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.

Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro.

Mechanisms of antibiotic resistance of bacteria include efflux pumps which extrude the antibiotic prior to reaching its target. Phenothiazines inhibit the activity of some efflux pumps thereby altering the susceptibility of bacteria. This study demonstrated that chlorpromazine and thioridazine reduce the susceptibility of methicillin-resistant strains (MRSA) but not that of methicillin-susceptible Staphylococcus aureus (MSSA) strains to oxacillin (MIC of oxacillin reduced from >500 to 10 mg/l). Reserpine, an inhibitor of antibiotic efflux pumps also reduced the resistance of MRSA strains to oxacillin suggesting the presence of an efflux pump that contributes to antibiotic resistance of MRSA strains.

Clinical concentrations of thioridazine enhance the killing of intracellular methicillin-resistant Staphylococcus aureus: an in vivo, ex vivo and electron microscopy study.

Chlorpromazine (CPZ) is concentrated by human macrophages where it kills intracellular mycobacteria when the concentration outside the macrophage is sub-clinical. We have previously demonstrated that thioridazine (TZ), a much milder phenothiazine, has similar activity and kills intracellular methicillin-susceptible S. aureus at sub-clinical concentrations. We have extended this latter study to include methicillin-resistant S. aureus (MRSA) and show that TZ kills intracellular MRSA at clinically relevant concentrations. The ultrastructure of MRSA exposed to in vitro concentrations of TZ just below its MIC and that of MRSA phagocytosed by macrophages previously exposed to a clinically relevant concentration of TZ was also studied. TZ inhibits the replication of phagocytosed MRSA, affecting the structure of the cell envelope, resulting in lysis of the bacterium 6 hours post-phagocytosis. These ultrastructural changes are identical to those produced in vitro by a TZ concentration that is just below the MIC. Because macrophage intracellular MRSA is not killed by the macrophage and its intracellular location protects it from antibiotics that are unable to reach that site, recurrent infections which result may be successfully managed with the use of TZ.

Fungal meningoencephalitis caused by Alternaria: a clinical case.

Cerebral phaeohyphomycosis is an infrequent infectious condition associated with a high mortality rate. The authors describe a very rare case that occurred in an immunocompetent 18-year-old man who developed severe meningoencephalitis and arachnoiditis caused by Alternaria alternata, which were diagnosed in the context of difficult-to-treat hydrocephalus. Etiological diagnosis was made based on fungal culture and histopathologic examination. Empirical treatment consisted of an early aggressive antifungal combination therapy consisting of intravenous liposomal amphotericin B (5 mg/kg per day) and voriconazole (4 mg/kg every 12 h), which initially induced a favorable response. Following the fungus identification, the choice for the combination of posaconazole (400 mg every 12 h) plus flucytosine (4000 mg/day) proved to be effective in the suppression of the signs and symptoms of this uncommon cerebral mycosis. At a 12-month follow-up visit no recurrence had occurred and posaconazole was then stopped.

Prognostic significance of AKT/mTOR signaling in advanced neuroendocrine tumors treated with somatostatin analogs.

INTRODUCTION: Somatostatin analogs (SSAs) are used as part of standard treatment for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been suggested. Our purpose was to evaluate the activation status of the AKT/mTOR pathway in advanced metastatic NETs and identify biomarkers of response to SSA therapy. PATIENTS AND METHODS: Expression of phosphatase and tensin homolog (PTEN), phosphorylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinicopathological parameters and progression-free survival under treatment with SSAs. RESULTS: A positive association between p-AKT and p-S6 expression was identified (P = 0.01) and higher expression of both markers was observed in pancreatic NETs. AKT/mTOR activation was observed without the loss of PTEN expression. Tumors showing AKT/mTOR signaling activation progressed faster when treated with SSAs: higher expression of p-AKT or p-S6 predicted a median progression-free survival of 1 month vs 26.5 months for lower expression (P = 0.02). CONCLUSION: Constitutive activation of the AKT/mTOR pathway was associated with shorter time-to-progression in patients undergoing treatment with SSAs. Larger case series are needed to validate whether p-AKT(Ser473) and p-S6(Ser240/244) can be used as prognostic markers of response to therapy with SSAs.