Intraperitoneal drug delivery systems for peritoneal carcinomatosis: Bridging the gap between research and clinical implementation.

Several abdominal-located cancers develop metastasis within the peritoneum, what is called peritoneal carcinomatosis (PC), constituting a clinical challenge in their therapeutical management, often leading to poor prognoses. Current multidisciplinary strategies, including cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC), demonstrate efficacy but have limitations. In response, alternative strategies are explored in the drug delivery field for intraperitoneal chemotherapy. Controlled drug delivery offers a promising avenue, maintaining localized drug concentrations for optimal PC management. Drug delivery systems (DDS), including hydrogels, implants, nanoparticles, and hybrid systems, show potential for sustained and region-specific drug release. The present review aims to offer an overview of the advances and current designs of DDS for PC chemotherapy administration, focusing on their composition, main characteristics, and principal experimental outcomes, highlighting the importance of biomaterial rationale design and in vitro/vivo models for their testing. Moreover, since clinical data for human subjects are scarce, we offer a critical discussion of the gap between bench and bedside in DDS translation, emphasizing the need for further research.

Paraneoplastic Leukemoid reaction in soft tissue sarcoma: A case report and literature review.

INTRODUCTION: Paraneoplastic leukemoid reactions (PLRs) in the context of sarcomas represent a unique clinical entity that poses significant diagnostic challenges and adds valuable insights to the surgical literature. Characterized by an abnormal elevation of white blood cell count, these reactions are often associated with aggressive tumor biology and poor prognosis, emphasizing the need for heightened awareness among clinicians. CASE PRESENTATION: A 48-year-old male presented with a rapidly growing, ulcerated tumor on his thigh. Lab tests revealed an extreme leukocytosis with a white blood cell count of 92,860/mm3. Imaging and biopsy confirmed a high-grade spindle cell sarcoma. CLINICAL DISCUSSION: After excluding other causes of leukocytosis, a PLR secondary to sarcoma was diagnosed. Despite initial antibiotic treatment, leukocytosis persisted, prompting a decision for surgical intervention. The patient underwent successful tumor resection, resulting in a significant decrease in leukocyte count and subsequent stable recovery, supported by adjuvant radiotherapy. CONCLUSION: This case underscores the importance of recognizing PLRs in sarcoma patients as they can significantly impact clinical management and prognosis. It highlights the necessity of a multidisciplinary approach for accurate diagnosis and effective treatment. The case contributes to the surgical literature by detailing the diagnostic process and therapeutic interventions in managing such complex presentations, thereby providing key "take-away" lessons on the importance of considering PLRs in the differential diagnosis of leukocytosis in patients with malignancies.

End-of-life care needs in cancer patients: a qualitative study of patient and family experiences.

BACKGROUND: Cancer is a disease that transcends what is purely medical, profoundly affecting the day-to-day life of both patients and family members. Previous research has shown that the consequences of cancer are greatly aggravated in patients at the end of life, at a time when they must also grapple with numerous unmet needs. The main objective of this study was to obtain more in-depth insight into these needs, primarily in patients with end-stage cancer nearing death. METHODS: Semi-structured interviews were conducted in Spain with cancer patients at the end of life (n = 3) and their family members (n = 12). The findings from the interviews were analyzed using qualitative thematic analysis and a grounded theory approach. RESULTS: Four major themes emerged from the interviews that explored the needs and concerns of patients with cancer at the end of life: (1) physical well-being (2) emotional well-being (3) social well-being and (4), needs relating to information and autonomous decision-making. The interviews also shed light on the specific needs of family members during this period, namely the difficulties of managing increased caregiver burden and maintaining a healthy work-life balance. CONCLUSIONS: A lack of support, information and transparency during a period of immense vulnerability makes the end-of-life experience even more difficult for patients with cancer. Our findings highlight the importance of developing a more in-depth understanding of the needs of this population, so that informed efforts can be made to improve palliative healthcare and implement more comprehensive care and support at the end of life.

SEOM-GEM clinical guidelines for cutaneous melanoma (2023).

Cutaneous melanoma incidence is rising. Early diagnosis and treatment administration are key for increasing the chances of survival. For patients with locoregional advanced melanoma that can be treated with complete resection, adjuvant-and more recently neoadjuvant-with targeted therapy-BRAF and MEK inhibitors-and immunotherapy-anti-PD-1-based therapies-offer opportunities to reduce the risk of relapse and distant metastases. For patients with advanced disease not amenable to radical treatment, these treatments offer an unprecedented increase in overall survival. A group of medical oncologists from the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines, based on a thorough review of the best evidence available. The following guidelines try to cover all the aspects from the diagnosis-clinical, pathological, and molecular-staging, risk stratification, adjuvant therapy, advanced disease therapy, and survivor follow-up, including special situations, such as brain metastases, refractory disease, and treatment sequencing. We aim help clinicians in the decision-making process.

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80-90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis-relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.

Prevalence and Distribution of MUTYH Pathogenic Variants, Is There a Relation with an Increased Risk of Breast Cancer?

BACKGROUND: MUTYH has been implicated in hereditary colonic polyposis and colorectal carcinoma. However, there are conflicting data refgarding its relationship to hereditary breast cancer. Therefore, we aimed to assess if MUTYH mutations contribute to breast cancer susceptibility. METHODS: We retrospectively reviewed 3598 patients evaluated from June 2018 to June 2023 at the Hereditary Cancer Unit of La Paz University Hospital, focusing on those with detected MUTYH variants. RESULTS: Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2-2.0). Of the 766 patients with breast cancer, 14 patients were carriers of MUTYH mutations (1.8%, 95%CI: 0.5-3.0). The prevalence of MUTYH mutation was significantly higher in the subpopulation with colonic polyposis (11.3% vs. 1.1%, p < 0.00001, OR = 11.2, 95%CI: 6.2-22.3). However, there was no significant difference in the prevalence within the subpopulation with breast cancer (1.8% vs. 1.5%, p = 0.49, OR = 1.2, 95%CI: 0.7-2.3). CONCLUSION: In our population, we could not establish a relationship between MUTYH and breast cancer. These findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in breast cancer risk.

Implication of intestinal microbiota in the etiopathogenesis of fibromyalgia: A systematic review.

Fibromyalgia (FM) is a highly prevalent chronic disease. About 4.7% of the world's population suffers from generalized pain and hypersensitivity, in addition to a wide range of physical and psychological symptoms. The etiopathogenesis of this disease is multifactorial, which makes its diagnosis and treatment challenging. Recently, the increase in the number of studies on microbiota has provided new data that can help to understand the onset and development of FM. An updated systematic review of the causes of FM has been carried out in this work. Particularly in the last decade, research has focused on the gut-brain axis, which has emerged as a crucial mechanism for microbiota-host crosstalk. In FM patients, quantitative imbalances of the intestinal microbiota (dysbiosis) and bacterial metabolites with differential relative abundance have been found, especially short-chain fatty acids and lipopolysaccharides. Furthermore, the microbiota has been found to indirectly influence host neurotransmitter mechanisms, mainly through the serotonin precursor, glutamate, and gamma-aminobutyric acid. Thus, all these mechanisms and their influence on the etiopathogenesis of FM are discussed in this review.

[Reacciones de las mujeres ante el folleto del Programa de Detección Precoz del Cáncer de Mama.] / Women's reactions upon reading a leaflet on Breast Cancer Screening Program.

OBJECTIVE: Breast cancer screening (BCS) leaflets are important for outreach and dissemination of BCS programs. Knowing how women perceive these leaflets is relevant to better understand their attitude towards BCS. The objective of this paper was to explore women's reactions regarding BCS leaflet. METHODS: A simple descriptive qualitative design was performed involving women aged between forty and sixty years of age in Asturias (Spain). Twenty-six semi-structured interviews were conducted with women of different socioeconomic profiles in 2018. Thematic analysis was carried out. RESULTS: Reading the leaflet elicited positive emotions such as peace of mind, well-being or gratitude, in addition to fear or anxiety. The women expressed various beliefs about breast cancer (highly prevalent and high survival rates), about BCS (a program aimed at prevention, a normative activity among their peers) and about the relevant role of health services and the media. Ambivalent attitudes towards BCS were detected, related to emotions. CONCLUSIONS: The emotional response after reading the brochure is ambivalent, although most of the women express positive emotions. Women compare the information with previous beliefs, especially regarding breast cancer (BC) and BCS. It is important to understand how certain emotions (especially negative ones) are closely related to the attitude towards BCS.

OBJETIVO: El folleto del Programa de Detección Precoz del Cáncer de Mama (PDPCM) es una importante herramienta de difusión de ese programa. Conocer la percepción de las mujeres sobre ese material informativo es relevante para entender mejor su actitud hacia el PDPCM. El objetivo del estudio fue explorar las reacciones de las mujeres respecto al folleto del PDPCM. METODOS: Se realizó un estudio cualitativo descriptivo en mujeres de entre cuarenta y sesenta años en Asturias (España). Se realizaron veintiséis entrevistas semiestructuradas a mujeres de diferentes perfiles socioeconómicos en 2018. Se realizó un análisis de contenido para identificar inductivamente las categorías emergentes. RESULTADOS: La lectura del folleto despertó emociones positivas como tranquilidad, bienestar o gratitud, pero también miedo o inquietud. Las mujeres expresaron diversas creencias sobre el CM (enfermedad muy prevalente y de elevada supervivencia), sobre el PDPCM (programa dirigido a la prevención y que suponía una actividad normalizada en su entorno) y sobre el relevante papel de los servicios de salud y los medios de comunicación. Se detectaron actitudes ambivalentes hacia el PDPCM y estas actitudes estaban relacionadas con las emociones. CONCLUSIONES: La respuesta emocional al leer el folleto es ambivalente, aunque la mayoría de las mujeres expresan emociones positivas. Las mujeres comparan la información con sus creencias previas, especialmente respecto al CM y al PDPCM. Es importante entender cómo ciertas emociones (especialmente las negativas) están estrechamente relacionadas con la actitud hacia este programa.

Whole slide imaging of tumour microenvironment in classical Hodgkin's lymphoma: development of a clinical prediction model based on programmed death-ligand 1 and tumorous Reed-Sternberg cells.

AIMS: The prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined. METHODS: Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines were followed. PD-L1+ and CD30+ tumoral Reed-Sternberg cells were quantified through whole slide imaging and digital image analysis in 155 digital histopathological slides of cHL. Univariate and multivariate survival analyses were performed. The analyses were reproduced for patients with advanced stages (IIB, III and IV) using the Advanced-stage cHL International Prognostic Index. RESULTS: The PD-L1/CD30 ratio was statistically significantly associated with survival outcomes. Patients with a PD-L1/CD30 ratio above 47.1 presented a shorter overall survival (mean OS: 53.7 months; 95% CI: 28.7 to 78.7) in comparison with patients below this threshold (mean OS: 105.4 months; 95% CI: 89.6 to 121.3) (p=0.04). When adjusted for covariates, the PD-L1/CD30 ratio retained prognostic impact, both for the OS (HR: 1.005; 95% CI: 1.002 to 1.008; p=0.000) and the progression-free survival (HR: 3.442; 95% CI: 1.045 to 11.340; p=0.04) in a clinical and histopathological multivariate model including the male sex (HR: 3.551; 95% CI: 0.986 to 12.786; p=0.05), a percentage of tumoral cells ≥10.1% (HR: 1.044; 95% CI: 1.003 to 1.087; p=0.03) and high risk International Prognostic Score (≥3 points) (HR: 6.453; 95% CI: 1.970 to 21.134; p=0.002). CONCLUSIONS: The PD-L1/CD30 ratio identifies a group of cHL patients with an increased risk of treatment failure. Its clinical application can be performed as it constitutes an easy to implement pathological information in the diagnostic work-up of patients with cHL.

Biosynthetic gene profiling and genomic potential of the novel photosynthetic marine bacterium Roseibaca domitiana.

Shifting the bioprospecting targets toward underexplored bacterial groups combined with genome mining studies contributes to avoiding the rediscovery of known compounds by revealing novel, promising biosynthetic gene clusters (BGCs). With the aim of determining the biosynthetic potential of a novel marine bacterium, strain V10T, isolated from the Domitian littoral in Italy, a comparative phylogenomic mining study was performed across related photosynthetic bacterial groups from an evolutionary perspective. Studies on polyphasic and taxogenomics showed that this bacterium constitutes a new species, designated Roseibaca domitiana sp. nov. To date, this genus has only one other validly described species, which was isolated from a hypersaline Antarctic lake. The genomic evolutionary study linked to BGC diversity revealed that there is a close relationship between the phylogenetic distance of the members of the photosynthetic genera Roseibaca, Roseinatronobacter, and Rhodobaca and their BGC profiles, whose conservation pattern allows discriminating between these genera. On the contrary, the rest of the species related to Roseibaca domitiana exhibited an individual species pattern unrelated to genome size or source of isolation. This study showed that photosynthetic strains possess a streamlined content of BGCs, of which 94.34% of the clusters with biotechnological interest (NRPS, PKS, RRE, and RiPP) are completely new. Among these stand out T1PKS, exclusive of R. domitiana V10T, and RRE, highly conserved only in R. domitiana V10T and R. ekhonensis, both categories of BGCs involved in the synthesis of plant growth-promoting compounds and antitumoral compounds, respectively. In all cases, with very low homology with already patented molecules. Our findings reveal the high biosynthetic potential of infrequently cultured bacterial groups, suggesting the need to redirect attention to microbial minorities as a novel and vast source of bioactive compounds still to be exploited.

Does compartmental resection really impact retroperitoneal soft tissue sarcomas? A retrospective analysis from a Single Referral Center.

BACKGROUND: The treatment of choice for retroperitoneal soft tissue sarcomas (RPS) is surgical resection; the outcomes with more radical surgeries, notably compartmental resection, remains a subject of debate. Arguments against it, include the complexity of the technique and high morbidity. MATERIALS AND METHODS: A retrospective analysis of cases treated in a single center from January 2010 to December 2019 is presented. Two time periods were evaluated: 2010-2015 and 2016-2019, corresponding to before and after the implementation of routine compartmentectomy. We evaluated the short- and long-term outcomes of compartmental resection compared to limited surgeries through a multivariate analysis of prognostic factors. RESULTS: A total of 176 cases were included, of which 102 met the inclusion criteria. The sex distribution was similar. The average age was 52.9 years, and the average tumor size was 24.5 cm. The most frequent histology was liposarcoma (65.7%), followed by leiomyosarcoma (12.7%), and malignant peripheral nerve sheath tumor (8.8%). The median follow-up period was 40 months. We found a lower local recurrence in the group treated in the recent period (compartmentectomy) 42.3% vs 20% p = 0.007. The median overall survival (OS) was 38.7 months, and there was no difference in distant recurrence between the two time periods. Postoperative morbidity was higher in the recent period (25% vs 10% p 0.041), with no difference in 30-day mortality. CONCLUSIONS: The implementation of extensive surgery, specifically compartmentectomy, for retroperitoneal sarcomas has been linked to reduced local recurrence. We recommend considering this surgical approach for RPS in alignment with current expert consensus guidelines, as highlighted by the updated TARPSWG consensus.

MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.

Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.

Efficacy of second and third lines of treatment in advanced soft tissue sarcomas: a real-world study.

BACKGROUND: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison. METHODS: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy). RESULTS: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma. CONCLUSIONS: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.

Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression.

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.

Electrochemical Cellulase-Linked ELASA for Rapid Liquid Biopsy Testing of Serum HER-2/neu.

Non-invasive liquid biopsy assays for blood-circulating biomarkers of cancer allow both its early diagnosis and treatment monitoring. Here, we assessed serum levels of protein HER-2/neu, overexpressed in a number of aggressive cancers, by the cellulase-linked sandwich bioassay on magnetic beads. Instead of traditional antibodies we used inexpensive reporter and capture aptamer sequences, transforming the enzyme-linked immuno-sorbent assay (ELISA) into an enzyme-linked aptamer-sorbent assay (ELASA). The reporter aptamer was conjugated to cellulase, whose digestion of nitrocellulose film electrodes resulted in the electrochemical signal change. ELASA, optimized relative aptamer lengths (dimer vs monomer and trimer), and assay steps allowed 0.1 fM detection of HER-2/neu in the 10% human serum in 1.3 h. Urokinase plasminogen activator and thrombin as well as human serum albumin did not interfere, and liquid biopsy analysis of serum HER-2/neu was similarly robust but 4 times faster and 300 times cheaper than both electrochemical and optical ELISA. Simplicity and low cost of cellulase-linked ELASA makes it a perspective diagnostic tool for fast and accurate liquid biopsy detection of HER-2/neu and of other proteins for which aptamers are available.

Textiloma intrabdominal incidental

Introducción: Los textilomas son cuerpos extraños originados a partir del material quirúrgico textil, olvidado durante una intervención quirúrgica. Son poco frecuentes. Su forma de presentación clínica puede ser aguda o crónica y se manifiestan meses o años después de la operación quirúrgica original. Objetivos: Presentar un caso poco frecuente de textiloma intrabdominal, sus manifestaciones clínicas, diagnóstico y tratamiento. Caso clínico: Paciente masculino de 39 años de edad, con antecedentes de haber sido operado hace 14 años de úlcera duodenal sangrante, asintomático hasta la fecha en que se estudió por síntomas digestivos. Como único elemento positivo al examen físico se constató dolor a la palpación profunda en epigastrio. Durante la endoscopía se diagnosticó una lesión subepitelial gástrica. En la tomografía con doble contraste de abdomen se corroboró una lesión de aspecto tumoral en la curvatura mayor del estómago, dependiente de su pared. Se realizó ultrasonido endoscópico mediante el cual se diagnosticó un tumor mesenquimal del mesenterio, sin poder descartar la posibilidad de un tumor del estroma gastrointestinal gástrico. Se realizó exéresis del tumor. El estudio anatomopatológico informó textiloma. Conclusiones: Los textilomas son accidentes quirúrgicos con consecuencias perjudiciales para la vida del paciente si no se procede rápidamente. Son el resultado de la iatrogenia durante una intervención quirúrgica y lo más importante es su prevención.

Introduction: Textilomas are foreign bodies originating from the textile surgical material, forgotten during a surgical intervention. They are rare. Its clinical presentation can be acute or chronic, manifesting months or years after the original surgical operation. Objectives: To present a rare case of intra-abdominal textiloma, its clinical manifestations, diagnosis and treatment. Clinical case: A 39-year-old male patient with a history of been operated on 14 years ago for a bleeding duodenal ulcer; asymptomatic until the date he was studied for digestive symptoms. The only positive element in the physical examination was pain on deep palpation of epigastrium. During endoscopy, a gastric subepithelial lesion was diagnosed. The double-contrast abdominal tomography confirmed a tumor-like lesion at the greater curvature of the stomach, depending on its wall. An endoscopic ultrasound was performed, through which a mesenchymal tumor of the mesentery was diagnosed, without being able to rule out the possibility of a gastric gastrointestinal stromal tumor. Excision of the tumor was performed. The anatomopathological study reported a textiloma. Conclusions: Textilomas are surgical accidents with detrimental consequences for the patient's life if not proceeded quickly. They are the result of iatrogenesis during a surgical intervention and the most important thing is their prevention.

GOLVEN peptides regulate lateral root spacing as part of a negative feedback loop on the establishment of auxin maxima.

Lateral root initiation requires the accumulation of auxin in lateral root founder cells, yielding a local auxin maximum. The positioning of auxin maxima along the primary root determines the density and spacing of lateral roots. The GOLVEN6 (GLV6) and GLV10 signaling peptides and their receptors have been established as regulators of lateral root spacing via their inhibitory effect on lateral root initiation in Arabidopsis. However, it was unclear how these GLV peptides interfere with auxin signaling or homeostasis. Here, we show that GLV6/10 signaling regulates the expression of a subset of auxin response genes, downstream of the canonical auxin signaling pathway, while simultaneously inhibiting the establishment of auxin maxima within xylem-pole pericycle cells that neighbor lateral root initiation sites. We present genetic evidence that this inhibitory effect relies on the activity of the PIN3 and PIN7 auxin export proteins. Furthermore, GLV6/10 peptide signaling was found to enhance PIN7 abundance in the plasma membranes of xylem-pole pericycle cells, which likely stimulates auxin efflux from these cells. Based on these findings, we propose a model in which the GLV6/10 signaling pathway serves as a negative feedback mechanism that contributes to the robust patterning of auxin maxima along the primary root.

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238.

PURPOSE: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. PATIENTS AND METHODS: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. RESULTS: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. CONCLUSIONS: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.

Electrochemical ELASA: improving early cancer detection and monitoring.

The discovery of new molecular biomarkers of cancer during the last decades and the development of new diagnostic devices exploiting those have significantly contributed to the clinical analysis of cancer and to improve the outcomes. Among those, liquid biopsy sensors exploiting aptamers for the detection of cancer biomarkers in body fluids are useful and accurate tools for a fast and inexpensive non-invasive screening of population. The incorporation of aptamers in electrochemical sandwich biosensors using enzyme labels, a so-called ELASA, has demonstrated its utility to improve the detection schemes. In this review, we overview the existing ELASA assays for numerous cancer biomarkers as alternatives to the traditional ELISA and discuss their possibilities to reach the market, currently dominated by optical immunoassays.

Liver abscess as a atypical presentation of hepatocellular carcinoma.

We present the case of a 64-year-old male with a history of chronic liver disease due to hepatitis C virus, with a sustained viral response after oral antiviral treatment and without follow-up for 5 years. He was admitted after a one-month history of constitutional symptoms, low-grade fever, abdominal pain and a palpable epigastric tumor. Analysis showed marked elevation of acute phase reactants (48,000 leukocytes and C-reactive protein of 19mg/dl) and dissociated cholestasis. Two lesions were identified by abdominal CT.