Antivirales de acción directa contra la hepatitis C: revisión narrativa / Direct acting antivirals against hepatitis C: Literature review

Desde los años ochenta se ha explorado el tratamiento para el virus de la hepatitis C, aunque en ese entonces los medicamentos disponibles eran poco toleradas y poco eficaces. En el 2011, la introducción de antivirales de acción directa transformó significativamente el curso de la enfermedad, logrando tasas de curación superiores al 90 % en los pacientes. Este avance ha permitido prevenir complicaciones futuras con efectos adversos mínimos. La presente revisión aborda la línea de tiempo del descubrimiento de los antivirales, su mecanismo de acción, sus indicaciones y potencial impacto en la salud pública.

Since the 1980s, the treatment of hepatitis C has been explored, although at that time, the available medications were poorly tolerated and ineffective. In 2011, the introduction of direct-acting antivirals significantly transformed the course of the disease, achieving cure rates of over 90% in patients. This advance has made it possible to prevent future complications with minimal adverse effects. This review addresses the timeline of the discovery of antivirals, their mechanism of action, and their impact on medicine.

Germline biallelic BRCA2 pathogenic variants and medulloblastoma: an international cohort study.

Constitutional heterozygous pathogenic variants in genes coding for some components of the Fanconi anemia-BRCA signaling pathway, which repairs DNA interstrand crosslinks, represent risk factors for common cancers, including breast, ovarian, pancreatic and prostate cancer. A high cancer risk is also a main clinical feature in patients with Fanconi anemia (FA), a rare condition characterized by bone marrow failure, endocrine and physical abnormalities. The mainly recessive condition is caused by germline pathogenic variants in one of 21 FA-BRCA pathway genes. Among patients with FA, the highest cancer risks are observed in patients with biallelic pathogenic variants in BRCA2 or PALB2. These patients develop a range of embryonal tumors and leukemia during the first decade of life, however, little is known about specific clinical, genetic and pathologic features or toxicities. Here, we present genetic, clinical, pathological and treatment characteristics observed in an international cohort of eight patients with FA due to biallelic BRCA2 pathogenic variants and medulloblastoma (MB), an embryonal tumor of the cerebellum. Median age at MB diagnosis was 32.5 months (range 7-58 months). All patients with available data had sonic hedgehog-MB. Six patients received chemotherapy and one patient also received proton radiation treatment. No life-threatening toxicities were documented. Prognosis was poor and all patients died shortly after MB diagnosis (median survival time 4.5 months, range 0-21 months) due to MB or other neoplasms. In conclusion, MB in patients with biallelic BRCA2 pathogenic variants is a lethal disease. Future experimental treatments are necessary to help these patients.

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Prevención de la obesidad infantil desde el enfoque de curso de vida en los primeros años / Prevention of childhood obesity from a life course approach in the first years

RESUMEN Se ha estimado que el sobrepeso y la obesidad causan anualmente 3.4 millones de muertes en el mundo. La prevalencia del sobrepeso y la obesidad también se han incrementado sustancialmente en niños y adolescentes en un 47 % en países en vías de desarrollo en los últimos años. Objetivo: Revisar la evidencia disponible para la prevención de la obesidad infantil desde el enfoque de curso de vida en los primeros años de vida. Materiales y métodos: Se realizó una revisión de la literatura en bases de datos indexadas (EMBASE, PubMed, Cochrane, CINAHL, CDSR, DARE, PSYINFO, Central, Clinical Trials y Medline-Ovid) con descriptores tipo MeSH de 2000 a 2019; se encontraron 698 artículos, de los cuales fueron seleccionados 62. Resultados: Son factores de riesgo el estado nutricional de la madre, el consumo de café, el cigarrillo, el perfil metabólico y dieta en la gestación, cesárea, un peso al nacer ≥ 3.86 kg, fórmula láctea, lactancia materna < 12 meses, contaminación ambiental, uso de hormonas sexuales y antibióticos y ciclo de sueño en niños < 12 horas. Conclusiones: La prevención del sobrepeso y la obesidad requiere de acercamientos tempranos y sostenidos a lo largo del tiempo, los cuales deben considerar una amplia gama de factores desde el enfoque de curso de vida, así también el involucramiento con otros actores, para mantener poblaciones saludables y prevenir de manera integral a las enfermedades derivadas de estas condiciones.

ABSTRACT It has been estimated that overweight and obesity were responsible of 3.4 million deaths worldwide. The prevalence of overweight and obesity has also increased substantially in children and adolescents by 4 7% in low income countries. Objective: Review the available evidence on the prevention of childhood obesity from the life course approach in the first years of life. Materials and methods: A review of the literature in indexed databases (EMBASE, PubMed, Cochrane, CINAHL, CDSR, DARE, PSYINFO, Central, Clinical Trials and Medline-Ovid) was performed with MeSH type descriptors from 2000 to 2019; 698 articles were found, of which 62 were selected. Results: The risk factors for childhood overweight and obesity are nutritional status of the mother, consumption of coffee, cigarette, metabolic profile and diet in pregnancy, caesarean section, birth weight ≥ 3.86 kg, milk formula, breastfeeding <12 months, environmental contamination, use of sex hormones and antibiotics and sleep cycle in children <12 hours. Conclusions: The prevention of overweight and obesity requires early and sustained approaches over time, which should consider a wide range of factors from the life course approach, as well as involvement with other actors, to maintain healthy populations and prevent to the diseases derived from these conditions.

Disparities in refusal of surgery for gynecologic cancer.

OBJECTIVE: To identify sociodemographic and clinical factors associated with refusal of gynecologic cancer surgery and to estimate its effect on overall survival. METHODS: The National Cancer Database was surveyed for patients with uterine, cervical or ovarian/fallopian tube/primary peritoneal cancer treated between 2004 and 2017. Univariate and multivariate logistic regression were used to assess associations between clinico-demographic variables and refusal of surgery. Overall survival was estimated using the Kaplan-Meier method. Trends in refusal over time were evaluated using joinpoint regression. RESULTS: Of 788,164 women included in our analysis, 5875 (0.75%) patients refused surgery recommended by their treating oncologist. Patients who refused surgery were older at diagnosis (72.4 vs 60.3 years, p < 0.001) and more likely Black (OR 1.77 95% CI 1.62-1.92). Refusal of surgery was associated with uninsured status (OR 2.94 95% CI 2.49-3.46), Medicaid coverage (OR 2.79 95% CI 2.46-3.18), low regional high school graduation (OR 1.18 95% CI 1.05-1.33) and treatment at a community hospital (OR 1.59 95% CI 1.42-1.78). Patients who refused surgery had lower median overall survival (1.0 vs 14.0 years, p < 0.01) and this difference persisted across disease sites. Between 2008 and 2017, there was a significant increase in refusal of surgery annually (annual percent change +1.41%, p < 0.05). CONCLUSIONS: Multiple social determinants of health are independently associated with refusal of surgery for gynecologic cancer. Given that patients who refuse surgery are more likely from vulnerable, underserved populations and have inferior survival, refusal of surgery should be considered a surgical healthcare disparity and tackled as such.

Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.

Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated.

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.

PURPOSE: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10-12), immunohistochemistry (86%, P = 4.6 × 10-3), or tumor mutational burden (80%, P = 9.1 × 10-4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD (P = 2.2 × 10-5). CONCLUSION: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Telemedicina en pediatría para el manejo de enfermedades crónicas y de grupos vulnerables / Telemedicine in Pediatrics for Managing Chronic Diseases and Vulnerable Groups

Introducción: La telemedicina es una herramienta para los servicios de atención en pediatría, ya que permite el seguimiento de los pacientes pediátricos en el manejo de enfermedades crónicas y de grupos vulnerables; disminuye los costos y mejora el acceso a los servicios de salud. Objetivo: Explorar, por medio de una revisión sistemática de la literatura, la efectividad de la teleconsulta en el manejo de enfermedades crónicas y grupos vulnerables en la población pediátrica. Métodos: Se realizó una revisión sistemática de la literatura, utilizando los términos MESH pediatrics AND telehealth AND primary care AND control care en las bases Medline PubMed, EMBASE, Scopus, Web of Science, Cochrane, Science Direct. Se incluyeron metaanálisis, revisiones sistemáticas, experimentos clínicos controlados, estudios de cohortes, casos y controles, realizados desde 1998 hasta julio de 2021. Se obtuvieron 54 estudios para la revisión final. Resultados: Los principales resultados de la búsqueda arrojaron beneficios a nivel del control de enfermedades crónicas, control posterior al egreso de la unidad de cuidado intensivo, poscirugía pediátrica, cuidado paliativo, enfermedades mentales, acceso a los servicios de salud de población proveniente de regiones apartadas. Se encontró un beneficio para prevenir las visitas al servicio de urgencias. Conclusiones: La telemedicina tiene una diversidad de utilidades e intervenciones como herramienta de la salud. Se ha encontrado evidencia científica robusta para la atención de enfermedades crónicas y/o seguimiento en pediatría. Asimismo, la prestación de servicios en la modalidad de telemedicina en pediatría debe incluirse en los procesos de atención y guías de práctica clínica de la especialidad(AU)

Introduction: Telemedicine is a tool for pediatric care services, since it allows monitoring of pediatric patients in the management of chronic diseases and vulnerable groups; lowers costs and improves access to health services. Objective: To explore, through a systematic review of the literature, the effectiveness of teleconsultation in the management of chronic diseases and vulnerable groups in the pediatric population. Methods: A systematic review of the literature was carried out, using the MESH terms pediatrics AND telehealth AND primary care AND control care in Medline PubMed, EMBASE, Scopus, Web of Science, Cochrane, Science Direct databases. Meta-analyses, systematic reviews, controlled clinical trials, cohort, case-control studies, conducted from 1998 to July 2021, were included. Fifty-four studies were obtained for the final review. Results: The main results of the search showed benefits at the level of chronic disease control, control after discharge from the intensive care unit, pediatric post-surgery, palliative care, mental illness, access to health services for populations from remote regions. A benefit was found in preventing visits to the Emergency Department. Conclusions: Telemedicine has a diversity of utilities and interventions as a health tool. Robust scientific evidence has been found for the care of chronic diseases and/or follow-up in pediatrics. Likewise, the provision of services in the telemedicine modality in pediatrics should be included in the care processes and clinical practice guidelines of the specialty(AU)

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1.

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

An Integrated Analysis of Clinical, Genomic, and Imaging Features Reveals Predictors of Neurocognitive Outcomes in a Longitudinal Cohort of Pediatric Cancer Survivors, Enriched with CNS Tumors (Rad ART Pro).

Background: Neurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation. Methods: One hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers. Results: CMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains. Conclusion: Presence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.

Hereditary Ovarian Carcinoma: Cancer Pathogenesis Looking beyond BRCA1 and BRCA2.

Besides BRCA1 and BRCA2, several other inheritable mutations have been identified that increase ovarian cancer risk. Surgical excision of the fallopian tubes and ovaries reduces ovarian cancer risk, but for some non-BRCA hereditary ovarian cancer mutations the benefit of this intervention is unclear. The fallopian tubes of women with hereditary ovarian cancer mutations provide many insights into the early events of carcinogenesis and process of malignant transformation. Here we review cancer pathogenesis in hereditary cases of ovarian cancer, the occurrence of pre-invasive lesions and occult carcinoma in mutation carriers and their clinical management.

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

The Bacterial and Fungal Microbiota of the Mexican Rubiaceae Family Medicinal Plant Bouvardia ternifolia.

Bouvardia ternifolia is a medicinal plant considered a source of therapeutic compounds, like the antitumoral cyclohexapeptide bouvardin. It is known that large number of secondary metabolites produced by plants results from the interaction of the host and adjacent or embedded microorganisms. Using high-throughput DNA sequencing of V3-16S and V5-18S ribosomal gene libraries, we characterized the endophytic, endophytic + epiphyte bacterial, and fungal communities associated to flowers, leaves, stems, and roots, as well as the rhizosphere. The Proteobacteria (average 80.7%) and Actinobacteria (average 14.7%) were the most abundant bacterial phyla, while Leotiomycetes (average 54.8%) and Dothideomycetes (average 27.4%) were the most abundant fungal classes. Differential abundance for the bacterial endophyte group showed a predominance of Erwinia, Propionibacterium, and Microbacterium genera, while Sclerotinia, Coccomyces, and Calycina genera predominated for fungi. The predictive metagenome analysis for bacteria showed significative abundance of pathways for secondary metabolite production, while a FUNguild analysis revealed the presence of pathotroph, symbiotroph, and saprotrophs in the fungal community. Intra and inter copresence and mutual exclusion interactions were identified for bacterial and fungal kingdoms in the endophyte communities. This work provides a description of the diversity and composition of bacterial and fungal microorganisms living in flowers, leaves, stems, roots, and the rhizosphere of this medicinal plant; thus, it paves the way towards an integral understanding in the production of therapeutic metabolites.

Diagnóstico y tratamiento multidisciplinario de melanoma temprano y localmente avanzado. Consenso de expertos. Asociación Colombiana de Hematología y Oncología (ACHO) / Diagnosis and multidisciplinary treatment of early-stage and locally advanced melanoma: Expert consensus, Colombian Association of Hemato-Oncology (ACHO)

Resumen Introducción: El melanoma ocasiona el 75% de las muertes por cáncer de piel. Según GLOBOCAN, en 2018 se presentaron 287.723 casos nuevos de melanoma, con una mortalidad de 60.712 casos, que equivale al 20% del total de los casos incidentes. Las alternativas para el tratamiento del melanoma se fundamentan en la estatificación de la enfermedad, y en las características moleculares de la enfermedad. Objetivo: Consensuar, por común acuerdo de expertos, sugerencias para el diagnóstico y manejo de melanoma temprano basadas en la evidencia y ajustadas al contexto colombiano. Métodos: Se llevó a cabo un consenso de expertos multidisciplinario, constituido por 19 oncólogos clínicos, 2 cirujanos de mama y tejidos blandos, 2 dermatólogos, 2 patólogos y 2 radioterapeutas, miembros activos de la Asociación Colombiana de Hemato Oncología (ACHO). Este consenso se realizó en 4 etapas: 1. Estructuración de 29 preguntas, que se calificaron de 1 a 9. 2. Reenvío de las preguntas no consensuadas. 3. Análisis y discusión de las respuestas. 4. Las respuestas no consensuadas se llevaron a un consenso nominal. Resultados: Se discutieron 29 preguntas relacionadas con el diagnóstico y tratamiento de melanoma temprano, se construyeron sugerencias basadas en evidencia utilizada por los expertos y en guías de manejo de oncología reconocidas internacionalmente, adaptadas al contexto y realidad colombianos. Conclusiones: Se presentan sugerencias multidisciplinarias para el diagnóstico y tratamiento de melanoma temprano, las cuales debe considerarse para orientar la toma de decisiones y homogenizar la práctica clínica de acuerdo al contexto colombiano y a las características propias del sistema de salud del país. Este es un documento académico y no regulatorio.

Abstract Introduction: Melanoma causes 75% of deaths from skin cancer. In 2018, according to GLOBOCAN, 287,723 new melanoma cases were registered, with a mortality of 60,712 cases, which is equivalent to 20% of all incident cases. Alternatives for the treatment of melanoma are based on disease staging and the molecular characteristics of the disease. Objective: To establish a consensus by common agreement of experts and construct suggestions for the diagnosis and management of early-stage melanoma based on evidence and adjusted to the Colombian context. Methods: A multidisciplinary expert consensus was established, wth the participation of 19 clinical oncologists, 2 soft tissue surgeons, 2 dermatologists, 2 pathologists, and 2 radiotherapists, active members of the Colombian Association of Hemato-Oncology (ACHO). This consensus was carried out in four stages: 1) Structuring of 29 questions, which were scored from 1 to 9; 2) Resubmission of non-consensual questions; 3) Analysis and discussion of responses; and 4) Validation of non-consensual responses by nominal consensus. Results: Twenty-nine questions related to the diagnosis and treatment of early-stage melanoma were discussed in order to construct suggestions based on evidence proven by experts, as well as on internationally recognized oncology management guidelines adapted to the Colombian context and reality. Conclusions: Multidisciplinary suggestions are offered for the diagnosis and treatment of early-stage melanoma, which should be considered in order to guide decision-making and homogenize clinical practice according to the Colombian context and the characteristics of the Colombian health care system. This is an academic and non-regulatory document.

Renal Amyloidosis and Crohn Disease.

Background: Secondary amyloidosis, a rare complication of Crohn disease (CD), is triggered by persistent systemic inflammation. Kidney involvement is the most frequent manifestation and is often characterized by nephrotic syndrome and kidney failure. This complication usually appears in patients with long-standing disease and is associated with increased morbidity and mortality risk. Diagnosis is by microscopic amyloid observation of tissue biopsy, and when the diagnosis is confirmed, the therapeutic objective is disease activity control. Response assessment is challenging because of a lack of reliable biomarkers. Case Report: A 56-year-old male with a long-standing history of CD treated with a tumor necrosis factor-α inhibitor presented with an acute elevation of creatinine in association with clinical and laboratory markers of nephrotic syndrome. Kidney biopsy revealed renal amyloidosis. After treatment adjustment, although a stable creatinine was achieved, the patient had persistent impaired glomerular filtration rate. Conclusion: As a systemic chronic inflammatory disorder, CD may present multisystemic morbidity, for which increased awareness among gastroenterologists is warranted. Renal amyloidosis is an infrequent extraintestinal complication of CD that may lead to chronic kidney impairment. Although evidence-based treatment is lacking, disease activity control is pivotal for management.

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma.

PURPOSE: Selective RAF-targeted therapy is effective in some patients with BRAFV600E-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms. EXPERIMENTAL DESIGN: Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples (N = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAFV600E-mutant glioma cell lines. RESULTS: Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving ERRFI1, BAP1, ANKHD1, and MAP2K1). We performed functional validation of mechanisms of resistance, including loss of NF1, PTEN, or CBL, in BRAFV600E-mutant glioma lines, and demonstrate they are capable of conferring resistance in vitro. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes. CONCLUSIONS: Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.