Sphingosine kinase 2 regulates protein ubiquitination networks in neurons.

Two sphingosine kinase isoforms, sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2), synthesize the lipid sphingosine-1-phosphate (S1P) by phosphorylating sphingosine. SPHK1 is a cytoplasmic kinase, and SPHK2 is localized to the nucleus and other organelles. In the cytoplasm, the SPHK1/S1P pathway modulates autophagy and protein ubiquitination, among other processes. In the nucleus, the SPHK2/S1P pathway regulates transcription. Here, we hypothesized that the SPHK2/S1P pathway governs protein ubiquitination in neurons. We found that ectopic expression of SPHK2 increases ubiquitinated substrate levels in cultured neurons and pharmacologically inhibiting SPHK2 decreases protein ubiquitination. With mass spectrometry, we discovered that inhibiting SPHK2 affects lipid and synaptic protein networks as well as a ubiquitin-dependent protein network. Several ubiquitin-conjugating and hydrolyzing proteins, such as the E3 ubiquitin-protein ligases HUWE1 and TRIP12, the E2 ubiquitin-conjugating enzyme UBE2Z, and the ubiquitin-specific proteases USP15 and USP30, were downregulated by SPHK2 inhibition. Using RNA sequencing, we found that inhibiting SPHK2 altered lipid and neuron-specific gene networks, among others. Genes that encode the corresponding proteins from the ubiquitin-dependent protein network that we discovered with mass spectrometry were not affected by inhibiting SPHK2, indicating that the SPHK2/S1P pathway regulates ubiquitination at the protein level. We also show that both SPHK2 and HUWE1 were upregulated in the striatum of a mouse model of Huntington's disease, the BACHD mice, indicating that our findings are relevant to neurodegenerative diseases. Our results identify SPHK2/S1P as a novel regulator of protein ubiquitination networks in neurons and provide a new target for developing therapies for neurodegenerative diseases.

Addressing the unmet needs of women with breast cancer in Mexico: a non-randomised pilot study of the digital ePRO intervention.

OBJECTIVES: This study aimed to explore the acceptability, feasibility, usability, and preliminary effect of an electronic patient-reported outcome (ePRO) intervention for patients with breast cancer in Mexico. DESIGN: We conducted a multimethod non-randomised pilot study. We used a pre-test/post-test design for quantitative assessment of the intervention's effect on patients' supportive care needs and quality of life. We conducted in-depth interviews (IDIs) with participants and healthcare workers to explore the intervention's benefits and barriers and understand its feasibility. PARTICIPANTS: 50 women aged 20-75 diagnosed with stage I-III breast cancer were enrolled within 2 weeks of starting neoadjuvant or adjuvant treatment with chemotherapy or radiotherapy. We excluded illiterate women and those with visual impairment, cognitive disability or severe depression. IDIs were conducted with 18 participants and 10 healthcare providers. SETTING: Oncology services in three public hospitals of the Mexican Social Security Institute. INTERVENTION: The ePRO intervention consisted of a responsive web application for weekly symptom reporting combined with proactive follow-up by nurses guided by predefined clinical algorithms for 6 weeks. RESULTS: 50 women were enrolled out of 66 eligible patients approached (75.8%). All 50 completed the 4-week follow-up assessment (100% retention). Completion of the symptom registry declined from 100% in week 1 to 66% in week 6. Participants experienced decreases in supportive care needs and increased quality of life. The ePRO application was rated highly usable. Participants and health professionals both perceived intervention benefits. Drawbacks included poor fit for women receiving radiotherapy and challenges using the application for women with low digital literacy or experiencing severe symptoms. CONCLUSIONS: This pilot study provided evidence of the high usability and potential efficacy of a web-based ePRO intervention. We revised recruitment during the pilot to include multiple facilities, and we will further revise for the randomised trial to address barriers to successful ePRO implementation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT05925257.

Navigating HER2-Low Testing in Invasive Breast Cancer: Update Recommendations for Pathologists.

The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.

Potential of Kalanchoe pinnata as a Cancer Treatment Adjuvant and an Epigenetic Regulator.

Cancer is a global public health problem that is related to different environmental and lifestyle factors. Although the combination of screening, prevention, and treatment of cancer has resulted in increased patient survival, conventional treatments sometimes have therapeutic limitations such as resistance to drugs or severe side effects. Oriental culture includes herbal medicine as a complementary therapy in combination with chemotherapy or radiotherapy. This study aimed to identify the bioactive ingredients in Kalanchoe pinnata, a succulent herb with ethnomedical applications for several diseases, including cancer, and reveal its anticancer mechanisms through a molecular approach. The herb contains gallic acid, caffeic acid, coumaric acid, quercetin, quercitrin, isorhamnetin, kaempferol, bersaldegenin, bryophyllin a, bryophyllin c, bryophynol, bryophyllol and bryophollone, stigmasterol, campesterol, and other elements. Its phytochemicals participate in the regulation of proliferation, apoptosis, cell migration, angiogenesis, metastasis, oxidative stress, and autophagy. They have the potential to act as epigenetic drugs by reverting the acquired epigenetic changes associated with tumor resistance to therapy-such as the promoter methylation of suppressor genes, inhibition of DNMT1 and DNMT3b activity, and HDAC regulation-through methylation, thereby regulating the expression of genes involved in the PI3K/Akt/mTOR, Nrf2/Keap1, MEK/ERK, and Wnt/ß-catenin pathways. All of the data support the use of K. pinnata as an adjuvant in cancer treatment.

An Integrative Bioinformatic Analysis for Keratinase Detection in Marine-Derived Streptomyces.

Keratinases present promising biotechnological applications, due to their ability to degrade keratin. Streptomyces appears as one of the main sources of these enzymes, but complete genome sequences of keratinolytic bacteria are still limited. This article reports the complete genomes of three marine-derived streptomycetes that show different levels of feather keratin degradation, with high (strain G11C), low (strain CHD11), and no (strain Vc74B-19) keratinolytic activity. A multi-step bioinformatics approach is described to explore genes encoding putative keratinases in these genomes. Despite their differential keratinolytic activity, multiplatform annotation reveals similar quantities of ORFs encoding putative proteases in strains G11C, CHD11, and Vc74B-19. Comparative genomics classified these putative proteases into 140 orthologous groups and 17 unassigned orthogroup peptidases belonging to strain G11C. Similarity network analysis revealed three network communities of putative peptidases related to known keratinases of the peptidase families S01, S08, and M04. When combined with the prediction of cellular localization and phylogenetic reconstruction, seven putative keratinases from the highly keratinolytic strain Streptomyces sp. G11C are identified. To our knowledge, this is the first multi-step bioinformatics analysis that complements comparative genomics with phylogeny and cellular localization prediction, for the prediction of genes encoding putative keratinases in streptomycetes.

ADXS11-001 LM-LLO as specific immunotherapy in cervical cancer.

Human papillomavirus (HPV) infection is a well-known cause of cervical cancer. Therapeutic cancer vaccines are part of the current therapeutic options for HPV-associated cancers. Axalimogen filolisbac (ADXS11-001) is an immunotherapy based on live attenuated Listeria monocytogenes-listeriolysin O (Lm-LLO), designed by biological engineering to secrete an antigen-adjuvant fusion protein, composed of a truncated fragment of LLO fused to HPV. The proposed mechanism of action is that Lm-based vectors infect antigen-presenting cells (APC) and secrete HPV-LLO fusion proteins within the APC cytoplasm, these proteins are processed and presented to cytotoxic T lymphocytes (CTL), thus generating a new population of CTLs specific to HPV antigens. These HPV-specific CTLs destroy HPV infected cells. ADXS11-001 has demonstrated safety results in phase I-II studies in women with cervical cancer and is being assessed in clinical trials in patients with HPV-positive anal canal and head and neck cancers.

Recommendations on the pharmacological treatment of epithelial ovarian cancer in Mexico.

Ovarian cancer is the third most frequent gynaecological malignancy worldwide and in Mexico, with a high mortality rate, due to that in many cases its diagnosis is made in advanced stages. Prognosis is important for determining the subtype and the degree of evolution. During lasts years, the management of ovarian cancer has undergone an important evolution with the incorporation of new therapeutic options, which in turn represent an increase in the survival of these patients. We present recommendations for the management of ovarian cancer developed by an expert panel Mexican based on available evidence so far and the characteristics of health care in the country.

El cáncer de ovario es la tercera neoplasia maligna ginecológica más frecuente globalmente y también en México, con una elevada tasa de mortalidad debido a que en muchos casos su diagnóstico se realiza en etapas avanzadas. Para establecer su pronóstico es importante la determinación del subtipo y del grado de evolución. En los últimos años, el manejo del cáncer de ovario ha sufrido una importante evolución con la incorporación de nuevas opciones terapéuticas, que a su vez representan un incremento en la supervivencia de estas pacientes. Se presentan las recomendaciones para el manejo del cáncer de ovario elaboradas por un panel de expertos mexicanos basadas en la evidencia disponible hasta el momento y en las características de la atención sanitaria del país.

Recomendaciones sobre el tratamiento farmacológico del cáncer de ovario epitelial en México / Recommendations on the pharmacological treatment of epithelial ovarian cancer in Mexico

Resumen El cáncer de ovario es la tercera neoplasia maligna ginecológica más frecuente globalmente y también en México, con una elevada tasa de mortalidad debido a que en muchos casos su diagnóstico se realiza en etapas avanzadas. Para establecer su pronóstico es importante la determinación del subtipo y del grado de evolución. En los últimos años, el manejo del cáncer de ovario ha sufrido una importante evolución con la incorporación de nuevas opciones terapéuticas, que a su vez representan un incremento en la supervivencia de estas pacientes. Se presentan las recomendaciones para el manejo del cáncer de ovario elaboradas por un panel de expertos mexicanos basadas en la evidencia disponible hasta el momento y en las características de la atención sanitaria del país.

Abstract Ovarian cancer is the third most frequent gynaecological malignancy worldwide and in Mexico, with a high mortality rate, due to that in many cases its diagnosis is made in advanced stages. Prognosis is important for determining the subtype and the degree of evolution. During lasts years, the management of ovarian cancer has undergone an important evolution with the incorporation of new therapeutic options, which in turn represent an increase in the survival of these patients. We present recommendations for the management of ovarian cancer developed by an expert panel Mexican based on available evidence so far and the characteristics of health care in the country.

Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial.

PURPOSE: A phase II study (ClinicalTrials.gov identifier: NCT00628251) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy. PATIENTS AND METHODS: In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician's choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population. RESULTS: Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2% v 51.4%; odds ratio [OR], 2.53 [95% CI, 1.40 to 4.58]; P = .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 [95% CI, 1.42 to 8.54]). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 [95% CI, 0.43 to 0.91]; P = .013; median, 13.4 v 9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy. CONCLUSION: Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

[Clinical and molecular inflammatory alterations in chronic granulomatous disease]. / Alteraciones inflamatorias clínicas y moleculares en enfermedad granulomatosa crónica.

Chronic granulomatous disease (CGD) is an inborn error of immunity. CGD is characterized by a deficiency in the function of the NADPH oxidase complex. CGD has been an opportunity to study the function of reactive oxygen species (ROS) in the innate immune system. The absence of ROS produced by NADPH oxidase in neutrophils and macrophages leads to an increased susceptibility to bacterial and fungal infections since ROS participate in the elimination of microorganisms. Inflammatory and autoimmune manifestations are also present in CGD; however, the causal connection between the lack of ROS and inflammatory symptoms is not entirely clear. Different in vitro assays have been conducted in humans and clinical trials have been conducted in mice in order to try to understand this relationship. Studies show that ROS react with different molecules of the immune system, either by inhibiting or by stimulating their function, which explains why various inflammation pathways that are not related to each other are affected in CGD; therefore, the described mechanisms of affectation have been diverse, such as a greater production of proinflammatory cytokines, an increase in TH17 lymphocytes, and an alteration in processes like spherocytosis, apoptosis, autophagy, and inflammosome. Understanding the mechanisms that lead to inflammation in the deficiency of the NADPH oxidase complex has led to the proposal of new treatments that act on processes like autophagy, inflammosome, or blocking proinflammatory cytokines. In this review, we describe the different inflammatory manifestations in CGD and the molecular mechanisms through which the lack of ROS leads to hyperinflammation.

La enfermedad granulomatosa crónica (EGC) es un error innato de la inmunidad. Se caracteriza por deficiencia en la función del complejo de la NADPH oxidasa. La EGC ha sido una oportunidad para estudiar la función de las especies reactivas de oxígeno (ROS) en el sistema inmune innato. La ausencia de ROS producidas por la NADPH oxidasa en los neutrófilos y en los macrófagos lleva a mayor susceptibilidad a infecciones bacterianas y fúngicas, debido a que las ROS participan en la eliminación de los microorganismos. Las manifestaciones inflamatorias y autoinmunes también están presentes en la EGC, sin embargo, no es del todo clara la relación de causalidad entre la falta de ROS y los síntomas inflamatorios. Se han realizado diversos ensayos in vitro en humanos y experimentales en ratones para tratar de entender esta relación. Los estudios muestran que las ROS reaccionan con diferentes moléculas del sistema inmune, inhibiendo o estimulando su función, lo que explica que en la EGC se afecten varias vías de la inflamación que no están relacionadas entre sí; por lo tanto, han sido diversos los mecanismos de afectación descritos, como por ejemplo una mayor producción de citocinas proinflamatorias, un incremento en los linfocitos TH17 y una alteración en procesos como eferocitosis, apoptosis, autofagia e inflamasoma. El entendimiento de los mecanismos que llevan a la inflamación en la deficiencia del complejo de la NADPH oxidasa ha llevado a plantear nuevos tratamientos que actúan en procesos como la autofagia, el inflamosoma o el bloqueo de citocinas proinflamatorias. En esta revisión describimos las diferentes manifestaciones inflamatorias en EGC y los mecanismos moleculares a través de los cuales la falta de ROS conduce a la hiperinflamación.

Living at the Frontiers of Life: Extremophiles in Chile and Their Potential for Bioremediation.

Extremophiles are organisms capable of adjust, survive or thrive in hostile habitats that were previously thought to be adverse or lethal for life. Chile gathers a wide range of extreme environments: salars, geothermal springs, and geysers located at Altiplano and Atacama Desert, salars and cold mountains in Central Chile, and ice fields, cold lakes and fjords, and geothermal sites in Patagonia and Antarctica. The aims of this review are to describe extremophiles that inhabit main extreme biotopes in Chile, and their molecular and physiological capabilities that may be advantageous for bioremediation processes. After briefly describing the main ecological niches of extremophiles along Chilean territory, this review is focused on the microbial diversity and composition of these biotopes microbiomes. Extremophiles have been isolated in diverse zones in Chile that possess extreme conditions such as Altiplano, Atacama Desert, Central Chile, Patagonia, and Antarctica. Interesting extremophiles from Chile with potential biotechnological applications include thermophiles (e.g., Methanofollis tationis from Tatio Geyser), acidophiles (e.g., Acidithiobacillus ferrooxidans, Leptospirillum ferriphilum from Atacama Desert and Central Chile copper ores), halophiles (e.g., Shewanella sp. Asc-3 from Altiplano, Streptomyces sp. HKF-8 from Patagonia), alkaliphiles (Exiguobacterium sp. SH31 from Altiplano), xerotolerant bacteria (S. atacamensis from Atacama Desert), UV- and Gamma-resistant bacteria (Deinococcus peraridilitoris from Atacama Desert) and psychrophiles (e.g., Pseudomonas putida ATH-43 from Antarctica). The molecular and physiological properties of diverse extremophiles from Chile and their application in bioremediation or waste treatments are further discussed. Interestingly, the remarkable adaptative capabilities of extremophiles convert them into an attractive source of catalysts for bioremediation and industrial processes.

Chemical elemental analysis of single acoustic-levitated water droplets by laser-induced breakdown spectroscopy.

Laser-induced breakdown spectroscopy is presented for trace element detection of liquid samples by analyzing a single droplet levitated by ultrasonic waves. A single liquid droplet is placed in the node of a standing acoustic wave produced by a uniaxial levitator for further chemical analysis. The acoustic levitator consists of a commercial Langevin-type transducer, attached to a concave mechanical amplifier, and a concave reflector. A micro-syringe was used to manually place individual liquid droplet samples in the acoustic levitation system. For chemical analysis, a laser-induced plasma is produced by focusing a single laser pulse on the levitated water droplet after it partially dries. The performance of the acoustic levitator on micron-sized droplets is discussed, and the detection of Ba, Cd, Hg, and Pb at parts per million (milligrams/liter) and sub-parts per million levels is reported. The process, starting from placing the sample in the acoustic levitator and ending on the chemical identification of the traces, takes a few minutes. The approach is particularly interesting in applications demanding limited volumes of liquid samples and relative simple and inexpensive techniques.

Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer.

INTRODUCTION: Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS. PATIENTS AND METHODS: Patients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of each 14-day cycle) in this open-label, multicenter, phase III study (20100007). RAS and BRAF mutation status were determined using Sanger sequencing. ETS was evaluated as maximum percentage change from baseline to week 8; DpR was calculated as the percentage change for tumor shrinkage at nadir versus baseline. RESULTS: Overall, 270 patients had RAS wild type mCRC (panitumumab with BSC, n = 142; BSC, n = 128). For patients with wild type RAS tumors, median overall survival (OS; hazard ratio [HR], 0.72; P = .015) and progression-free survival (PFS; HR, 0.45; P < .0001) were improved with panitumumab with BSC versus BSC. Similar improvements were seen for patients with wild type RAS, and wild type BRAF tumors (OS: HR, 0.75; P = .04; PFS: HR, 0.45; P < .0001). Median DpR was 16.9% for the evaluable panitumumab with BSC wild type RAS population. Overall, 69.5% experienced any type of tumor shrinkage at week 8; 38.2% experienced ≥ 20% shrinkage. Similar improvements in OS and PFS were seen with stratification according to ETS. CONCLUSION: This analysis showed that panitumumab improved outcomes in wild type RAS mCRC and indicated that ETS and DpR could be used as additional efficacy markers.

Cancer pain management: recommendations from a Latin-American experts panel.

Generating a consensus in the Latin-American region on cancer pain management is a current need. Thus a panel of Latin-American experts met in Madrid in March 2017 in order to review the published literature, discuss the best approach for cancer pain classification and evaluation and also make recommendations of pharmacological and nonpharmacological therapies for cancer pain management improvement in Latin-American countries. The result of that meeting is presented in this document. The experts participating were from Costa Rica, Mexico, Chile, Colombia, Peru, Brazil and Ecuador, and the project coordinator was from Spain.

A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer.

BACKGROUND: We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial. METHODS: Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg-1 Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint. RESULTS: Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57-0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53-0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49-2.00). No new safety signals were observed. CONCLUSIONS: Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.

Use of bevacizumab in metastatic colorectal cancer: report from the Mexican opinion and analysis forum on colorectal cancer treatment with bevacizumab (September 2009).

Colorectal cancer is one of the most common cancers worldwide, and although associated mortality rates in South American countries are generally among the lowest in the world, they are on the rise. The prognosis of patients diagnosed with metastatic colorectal cancer has improved markedly over the last 12 years, increasing from 5 months with best supportive care to almost 2 years with combination chemotherapy plus bevacizumab. New prognostic and predictive biomarkers have been identified to guide therapy. Prognostic markers indicate patient survival independent of therapy and include disease stage, mutational status, and carcinoembryonic antigen. More recently, predictive markers of treatment outcomes have been identified. The most studied are mutations of the KRAS and BRAF genes, which are associated with resistance to epidermal growth factor receptor-targeted therapy. Tumor blood vessels have a number of structural and functional abnormalities that result in increased tumor vascularity and growth driven by angiogenesis. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, which binds to and neutralizes VEGF-A, has become a central part of the treatment of metastatic colorectal cancer. The addition of bevacizumab to fluorouracil (5-FU)/leucovorin, irinotecan plus bolus 5-FU/leucovorin, or irinotecan plus infusional 5-FU/leucovorin significantly improves the overall survival of patients with previously untreated metastatic colorectal cancer. In addition, a significant increase in overall survival is seen when bevacizumab is added to oxaliplatin plus infusional 5-FU/leucovorin (FOLFOX) in patients with metastatic colorectal cancer who progressed on a non-bevacizumab-containing regimen. Although the majority of studies were performed prior to the identification of KRAS and BRAF as predictive biomarkers, subsequent analysis has shown the benefits of bevacizumab occur independently of the mutational status of these genes. In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies. Surgical resection is recommended in patients with metastatic colorectal cancer where complete removal of tumors can be achieved. Perioperative chemotherapy using FOLFOX for 3 months before and 3 months after surgery is associated with a 9% improvement in 3-year survival. The use of chemotherapy in patients initially deemed unresectable has produced resection rates approaching 40%, and the addition of bevacizumab to chemotherapy in this setting is feasible, safe, and effective. In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone. Improvements in patient survival have changed the treatment paradigm for metastatic colorectal cancer. Newer approaches view treatment not as distinct lines of therapy but as a continuum that includes personalized treatment plans offering maintenance therapy and even drug holidays between aggressive treatment periods. This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing.

[Concomitant treatment with gemcitabine and radiotherapy in patients with advanced stages of epidermoid carcinoma originating in the head and neck. A phase II sutdy]. / Tratamiento concomitante con gemcitabina y radioterapia en pacientes con carcinoma epidermoide locorregionalmente avanzado de cabeza y cuello. Estudio fase II.

BACKGROUND: Surgery, radiotherapy or radiotherapy alone (RTA) constitute conventional treatment regimes for advanced stages of squamous cell carcinoma originating in the head and neck mucosa. Nevertheless, the results in advanced regional carcinoma (ARC) are disappointing. The chemotherapy-radiotherapy (CHT-RT) association has shown to be superior to RTA in irresectable disease and in resectable disease it could substitute initial surgery as a rescue alternative. OBJECTIVE: Our objective is to report the response rate and toxicity of concurrent treatment with Gemcitabine and Radiotherapy (GRT) in patients with ARC. In a prospective design, patients with ARC received concurrent GRT; the global, complete and partial response rate as well as toxicity were assessed. MATERIAL AND METHODS: 15 patients were included, 5 women and 10 men, 73% in stage IVa; 13/15 showed a global response (87%), a complete response was observed in 9 cases (60%) (RC) and 2 showed progress. RESULTS: All patients included showed toxicity, the most frequent one was level 4 mucositis in 46%, of this 40% required nutritional support by catheter or gastrostomy. One patient in RC died due to sepsis. None of them suspended treatment. CONCLUSION: The GRT association offers a complete response rate of 60%; nevertheless morbidity was not insignificant; randomized studies with a larger number of patients will be required to allow us to outline the optimal therapeutic scheme.

Tratamiento concomitante con gemcitabina y radioterapia en pacientes con carcinoma epidermoide locorregionalmente avanzado de cabeza y cuello: estudio fase II / Concomitant treatment with gemcitabine and radiotherapy in patients with advanced stages of epidermoid carcinoma originating in the head and neck: a phase II sutdy

Antecedentes: En casos avanzados el tratamiento clásico del carcinoma epidermoide originado en mucosas de cabeza y cuello es cirugíaradioterapia o radioterapia sola (RTS). Sin embargo los resultados en carcinoma localmente avanzado (CLA) son decepcionantes. La asociación quimioterapia-radioterapia (QT-RT) ha demostrado ser superior a RTS en enfermedad irresecable y, en enfermedad resecable podría sustituir a la cirugía inicial y dejarla como rescate. Objetivo: El objetivo de este estudio es conocer la tasa de respuesta y la toxicidad del tratamiento concomitante Gemcitabina-Radioterapia (GRT) en pacientes con CLA. Material y métodos: Estudio prospectivo en el que pacientes con CLA recibieron GRT concomitante; se evaluó la tasa de respuesta global, completa, parcial y la toxicidad. Se incluyeron 15 pacientes, 5 mujeres y 10 hombres, 73% en etapa IVa. Resultados: Trece de 15 pacientes tuvieron respuesta global (87%), en 9(60%) fue completa (RC) y 2 tuvieron progresión. Todos tuvieron toxicidad, la más frecuente fue mucositis grado 4 en 46%; de éstos 40% requirió apoyo nutricio por sonda o gastrostomía. Un paciente en RC murió por sepsis. Ninguno abandonó el tratamiento. Conclusiones: La asociación GRT ofrece tasa de respuesta completa en 60%; sin embargo, la morbilidad no es despreciable; se requieren estudios aleatorizados con mayor número de pacientes que permitan definir el mejor esquema terapéutico.

BACKGROUND: Surgery, radiotherapy or radiotherapy alone (RTA) constitute conventional treatment regimes for advanced stages of squamous cell carcinoma originating in the head and neck mucosa. Nevertheless, the results in advanced regional carcinoma (ARC) are disappointing. The chemotherapy-radiotherapy (CHT-RT) association has shown to be superior to RTA in irresectable disease and in resectable disease it could substitute initial surgery as a rescue alternative. OBJECTIVE: Our objective is to report the response rate and toxicity of concurrent treatment with Gemcitabine and Radiotherapy (GRT) in patients with ARC. In a prospective design, patients with ARC received concurrent GRT; the global, complete and partial response rate as well as toxicity were assessed. MATERIAL AND METHODS: 15 patients were included, 5 women and 10 men, 73% in stage IVa; 13/15 showed a global response (87%), a complete response was observed in 9 cases (60%) (RC) and 2 showed progress. RESULTS: All patients included showed toxicity, the most frequent one was level 4 mucositis in 46%, of this 40% required nutritional support by catheter or gastrostomy. One patient in RC died due to sepsis. None of them suspended treatment. CONCLUSION: The GRT association offers a complete response rate of 60%; nevertheless morbidity was not insignificant; randomized studies with a larger number of patients will be required to allow us to outline the optimal therapeutic scheme.