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La oncología de precisión, definida como la perfilación molecular de los tumores para identificar alteraciones modulables, se ha desarrollado rápidamente para integrarse en la práctica clínica. Las pruebas genómicas involucran diversas partes interesadas que trabajan coordinada y articuladamente para controlar la logística de las muestras de tejido tumoral y desarrollar las pruebas en laboratorios con altos parámetros de calidad, donde el análisis apropiado conduce a resultados reproducibles. Los médicos deben estar familiarizados con las variantes genómicas informadas y con la tecnología utilizada para determinarlas, incluidas las limitaciones de los informes y las metodologías actuales. La interpretación de los hallazgos genómicos se realiza de manera óptima gracias al aporte multidisciplinario, necesario para reducir la incertidumbre de las recomendaciones relacionadas con las variantes documentadas. Los genes 1/2/3 del receptor neurotrópico de la quinasa para la tropomiosina (NTRK) codifican las quinasas del receptor de tropomiosina (TRK) A/B/C, respectivamente. Los reordenamientos cromosómicos que causan fusiones del gen NTRK pueden dar como resultado la activación constitutiva de las proteínas TRK, que actúan como impulsores oncogénicos a través de la activación de diversas vías de crecimiento celular. Las fusiones del gen NTRK ocurren en ~0,3 % de los tumores sólidos, aunque su incidencia varía según el tipo de cáncer. Su prevalencia es >90 % en algunas neoplasias raras como el carcinoma secretor de mama y el carcinoma secretor análogo de la glándula salivar (MASC). Los inhibidores de TRK (larotrectinib, entrectinib y repotrectinib) son activos en los tumores positivos para la fusión de NTRK, y han permitido cambiar el curso natural de múltiples enfermedades. El artítuculo desarrolla una revisión integral sobre la perspectiva de la medicina de precisión y su implementación en pacientes pediátricos y adultos con genes de fusión NTRK en Colombia.

La activación de BIM es esencial para la apoptosis desencadenada por el inhibidor de la tirosina quinasa (TKI) del receptor del factor de crecimiento epidérmico (EGFR) en el cáncer de pulmón de células no pequeñas (CPCNP) con mutación de EGFR. Una deleción en el intrón dos del gen BIM da como resultado la generación de isoformas empalmadas alternativamente que alteran su respuesta apoptótica a los TKI, lo que confiere a las células de NSCLC una resistencia intrínseca a estos medicamentos. Los pacientes con ambas alteraciones tienen mala evolución clínica. El estudio actual tuvo como objetivo investigar la eficacia clínica y la tolerabilidad de EGFR-TKI más bevacizumab (Bev) versus EGFR-TKI solos como tratamiento de primera línea en pacientes con NSCLC avanzado con mutaciones de EGFR y deleciones BIM (BIMdel). MATERIALES Y MÉTODOS Se realizó un análisis retrospectivo. BIMdel se detectó mediante análisis de reacción en cadena de la polimerasa y secuenciación directa de ADN. La expresión de la proteína BIM se investigó mediante inmunohistoquímica y los niveles de ARNm de BIM mediante la reacción en cadena de la polimerasa con transcriptasa inversa. Se compararon las características clínicas, la supervivencia general, la supervivencia libre de progresión (PFS), la tasa de respuesta general (ORR) y los eventos adversos relacionados con el tratamiento entre ambos grupos. RESULTADOS Se incluyeron 33 pacientes; 15 recibieron EGFR-TKI y 18 recibieron EGFR-TKI más Bev. La mediana de edad fue de 63 años, con una mayoría de pacientes mujeres reclutadas. Todos los individuos incluidos tenían una puntuación de rendimiento del Grupo Oncológico Cooperativo del Este de 2 o menos. La adición de Bev resultó en un ORR significativamente más alto (94,4 % versus 40 %, P > 0,001). La mediana de SLP fue más larga con el uso de la terapia combinada (11,12 frente a 7,87 meses; P = 0,001). La mediana de supervivencia general tendió a ser más prolongada en los inhibidores de la tirosina quinasa con EGFR más Bev (30,9 frente a 25,4 meses; P = 0,06), pero no alcanzó significación estadística. La respuesta en términos de PFS parcial y completa, así como en general, se vio afectada favorablemente. CONCLUSIÓN Los EGFR-TKI más Bev confirieron una ORR y una SLP significativamente más altas en pacientes con NSCLC avanzado con mutación de EGFR y BIMdel. Se necesitan más estudios prospectivos para validar estos hallazgos. BIM activation is essential for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions (BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

Los avances en el ámbito de la patología y cirugía realizados entre 1500 y 1750 sirvieron como base para su desarrollo en los siglos XVIII y XIX, comprendiendo la naturaleza y composición macroscópica y microscópica de los tumores benignos y malignos. Desde entonces, los conceptos se volvieron a enfocar desde el órgano al tejido y a la célula, afectando el nacimiento de la histopatología que ha dominado esta ciencia durante siglo y medio. Luego, cuando el segundo milenio se acercaba a su fin, nuevas y poderosas tecnologías comenzaron a forzar una nueva revisión de las ideas alrededor de la patología convencional, desde las enfermedades basadas en alteraciones celulares hacia las enfermedades basadas en genes, pasando por el estudio de moléculas individuales y su interacción. El auge de la medicina de precisión comenzó en la década de 1980 con el desarrollo de la inmunohistoquímica. Este método permitió a los patólogos investigar rápidamente la expresión de proteínas en piezas obtenidas de muestras quirúrgicas. Estos niveles de expresión pronto serían relevantes para las subclasificaciones de los tumores que no eran accesibles por la microscopía óptica clásica. Recientemente, la introducción de la patología molecular tuvo un impacto positivo en el manejo de los pacientes con cáncer, especialmente para seleccionar terapias dirigidas y permitir el uso de técnicas como las biopsias líquidas que establecieron un nuevo estándar para los regímenes de monitorización continua durante el curso de la enfermedad. Esta técnica permite la detección de las recurrencias de la enfermedad antes que la radiología, lo que permite adaptar las terapias con anticipación. Además, también puede detectarse el desarrollo de mutaciones somáticas asociadas con la resistencia a las intervenciones realizadas.

Precision medicine has impacted the field of medical oncology by introducing personalized therapies, improving all measurable outcomes. This field, in turn, has expanded to obtaining and analyzing a vast and ever-increasing amount of genomic information. One technique currently applied is the liquid biopsy, which consists of detecting and isolating DNA and exosomes in cancer patients. Newly developed techniques have made it possible to use the liquid biopsy in a wide range of settings. However, challenges regarding the validation of its clinical utility exist because of a lack of standardization across different techniques and tumor types, confounder genomic information, lack of appropriate clinical trial designs, and a non-measured, and therefore not estimated, economic impact on population health. Nowadays, liquid biopsy is not routinely used, but ongoing research is increasing its popularity, and a new era in oncology is developing. Therefore, it is essential to have an in-depth understanding of the liquid biopsy technique. In this review, we summarize the leading techniques and liquid biopsy applications in cancer.

We present the case of a 73-year-old male patient with a history of tobacco use who presented with a central nervous system mass that was confirmed to be a lung adenocarcinoma metastasis. High PD-L1 expression as well as negativity to other targetable drivers led to initiation of pembrolizumab monotherapy and ablative stereotactic radiation therapy on oligo­residual disease, achieving a complete response after 2 years of therapy. Following discontinuation of systemic treatment, the patient developed widespread desquamative plaques. A skin biopsy revealed subepidermal blistering and eosinophilic infiltration in conjunction with C3 and IgG depositions on the basement membrane, detected by immunofluorescence. A diagnosis of bullous pemphigoid was obtained, and systemic corticosteroids were administered with lesion progression. Infliximab was also administered without meaningful clinical improvement. Metronomic cyclophosphamide achieved a complete resolution of skin lesions and up to this day the patient continues with tumor control and is free of dermatological findings. In conclusion, bullous pemphigoid is a very rare dermatological adverse effect related with pembrolizumab treatment. Only two cases, including this one, have been reported, especially with this medication for the treatment of non-small cell lung cancer. With more reported cases, management strategies can be optimized even in the steroid refractory setting.

Background Thymomas are a group of rare neoplasms of the anterior mediastinum. The objective of this study was to describe the demographics, clinical characteristics and treatment approaches in Latin America. Methods This was a retrospective multicenter cohort study including patients with histologically proven thymomas diagnosed between 1997 and 2018. Demographics, clinicopathological characteristics and therapeutic outcomes were collected locally and analyzed in a centralized manner. Results A total of 135 patients were included. Median age at diagnosis was 53 years old (19–84), 53.3% (n = 72) of patients were female and 87.4% had an ECOG performance score ranging from 0–1. A total of 47 patients (34.8%) had metastatic disease at diagnosis. Concurrent myasthenia gravis occurred in 21.5% of patients. Surgery was performed in 74 patients (54.8%), comprising 27 (20%) tumorectomies and 47 (34.8%) thymectomies. According to the Masaoka‐Koga system, overall survival (OS) at five‐years was 73.4%, 63.8% and 51%, at stages I–II, III–IVA and IVB, respectively (p = 0.005). Furthermore, patients with low lactate dehydrogenase (LDH) (≤373 IU/L) at baseline and myasthenia gravis concurrence showed significantly better OS (p = 0.001 and p = 0.008, respectively). In multivariate analysis, high LDH levels (HR 2.8 [95% confidence interval [CI]: 1.1–7.8]; p = 0.036) at baseline and not performing a surgical resection (HR 4.1 [95% CI: 1.3–12.7]; p = 0.016) were significantly associated with increased risk of death. Conclusions Our data provides the largest insight into the clinical characteristics and outcomes of patients with thymomas in Latin America. Survival in patients with thymomas continues to be very favorable, especially when subjected to adequate local control., Here, we report the largest analysis of clinical characteristics of thymomas and outcomes in Latin American patients. Out of 135 patients included in the study, 21.5% (n = 29) concurrently presented myasthenia gravis. Relapse‐free survival rates at five‐years were 58.5% for stage I–II, and 35.4% for stage III. Five‐year overall survival rates were 73.4%, 63.8% and 51%, at stages I–II, III–IVA and IVB, respectively.

Background Nephron hypertrophy and nephrosclerosis may be important determinants of CKD and mortality. However, studies of outcomes associated with these microstructural features have been limited to small tissue specimens from patients selected for either good kidney health or known kidney disease. Methods To determine whether microstructural features are predictive of progressive CKD and mortality outcomes, we studied patients who underwent a radical nephrectomy for a tumor. Large wedge sections of renal parenchyma distal to the tumor were stained and scanned into high-resolution images; we annotated the cortex and all glomeruli to calculate glomerular volume, cortex volume per glomerulus, and percentage of globally sclerotic glomeruli. Morphometric measurements also included percentages of artery luminal stenosis and interstitial fibrosis/tubular atrophy (IF/TA) of the cortex. At follow-up visits every 6-12 months, we determined which patients experienced progressive CKD (defined as dialysis, kidney transplantation, or a 40% decline from postnephrectomy eGFR). Cox models for these outcomes were adjusted for age, sex, body mass index, hypertension, diabetes, smoking, eGFR, and proteinuria. Results Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73 m2), 117 progressive CKD events, 183 noncancer deaths, and 116 cancer deaths occurred during a median follow-up of 6.4 years. Larger glomerular volume, larger cortex per glomerulus, and higher percentage of globally sclerotic glomeruli or IF/TA predicted progressive CKD. Higher percentage IF/TA also predicted noncancer mortality. Microstructural features did not predict cancer mortality or recurrence. Conclusions After a radical nephrectomy, larger nephrons and nephrosclerosis predicted progressive CKD, and IF/TA predicted noncancer mortality. Morphometric analysis of renal parenchyma can predict noncancer clinical events in patients long after their radical nephrectomy.

Due to the widespread use of immune checkpoint inhibitors and the growing research efforts in this area, immune-mediated toxicity is well recognized. Nonetheless, few severe cases of oral or upper gastrointestinal tract mucosal involvement have been documented. Early recognition and prompt treatment are key to the adequate management of these patients. We present a male 93-year-old patient with an advanced head and neck tumor treated with nivolumab who developed severe oral ulcers. After discontinuation of nivolumab, he received initial steroid treatment without any significant improvement. Histopathologic analysis of the lesions revealed a pattern similar to graft versus host disease. Extrapolating the results of colchicine mouth washing in patients with active oral ulcers and Behçet’s disease, this strategy was implemented with concomitant metronomic cyclophosphamide, achieving complete ulcer resolution. Metagenomic oral bacterial sequencing during instauration of the lesions and highest extension revealed a significant decrease in microbiomic diversity and expansion of Haemophilus parainfluenzae similar to patients with active Behçet’s disease. In conclusion, oral ulcers associated with immune checkpoint inhibitors correspond to a difficult-to-treat entity that could physiopathologically be related to both graft versus host disease and Behçet’s disease.

Background Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. Methods Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. Results The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. Conclusions Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft's "intrinsic quality" at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

Osimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes.This is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival.A total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4-18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden5 mut/Mb.Treatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.

Highlights • The identification of the KRAS G12C mutation in non-small cell lung cancer is relevant with new molecules being introduced for treatment. • The variation of mutation prevalence among different regions indicate that certain populations are more prone to develop KRAS G12C mutations among lung cancer than others. • Using genomic markers traditionally employed for the identification of individuals we managed to construct a model that was predictive for KRAS G12C mutational incidence, further indicating that appearance of KRAS G12C follows population substructures., Background The KRAS exon 2 p. G12C mutation in patients with lung adenocarcinoma has been increasing in relevance due to the development and effectiveness of new treatment medications. Studies around different populations indicate that regional variability between ethnic groups and ancestries could play an essential role in developing this molecular alteration within lung cancer. Methods In a prospective and retrospective cohort study on samples from lung adenocarcinoma from 1000 patients from different administrative regions in Colombia were tested for the KRAS p.G12C mutation. An analysis of STR populations markers was conducted to identify substructure contributions to mutation prevalence. Results Included were 979 patients with a national mean frequency for the KRAS exon 2 p.G12C mutation of 7.97% (95%CI 6.27–9.66%). Variation between regions was also identified with Antioquia reaching a positivity value of 12.7% (95%CI 9.1–16.3%) in contrast to other regions such as Bogota DC (Capital region) with 5.4% (2.7–8.2%) and Bolivar with 2.4% (95%CI 0–7.2%) (p-value = 0.00262). Furthermore, Short tandem repeat population substructures were found for eight markers that strongly yielded association with KRAS exon 2 p.G12C frequency reaching an adjusted R2 of 0.945 and a p-value of < 0.0001. Conclusions Widespread identification of KRAS exon 2 p.G12C mutations, especially in cases where NGS is not easily achieved is feasible at a population based level that can characterize regional and national patterns of mutation status. Furthermore, this type of mutation prevalence follows a population substructure pattern that can be easily determined by population and ancestral markers such as STR.

Background: Mutations in STK11 (STK11(Mut)) and, frequently co-occurring, KEAP1 mutations (KEAP1(Mut)) are associated with poor survival in metastatic Non-small Cell Lung Cancer (mNSCLC) patients treated with immunotherapy. However, there are limited data regarding the prognostic or predictive significance of these genomic alterations among Hispanics. Methods: This retrospective study analyzed a cohort of Hispanic patients (N = 103) diagnosed with mNSCLC from the US and seven Latin American countries (LATAM) treated with immune checkpoint inhibitors (ICI) alone or in combination as first-line (Cohort A). All cases were treated in routine care between January 2016 and December 2021. The main objectives were to determine the association of mutations in STK11 or KEAP1 in these patients' tumors with overall (OS) and progression-free survival (PFS), presence of KRAS mutations, tumor mutational burden (TMB), and other relevant clinical variables. To compare outcomes with a STK11(Wt)/KEAP1(Wt) population, historical data from a cohort of Hispanic patients (N = 101) treated with first-line ICI was used, matching both groups by country of origin, gender, and Programed Death-ligand 1 (PD-L1) expression level (Cohort B). Results: Most tumors had mutations only in STK11 or KEAP1 (45.6%) without KRAS co-mutation or any other genomic alteration. Besides, 35%, 8.7%, 6.8%, and 3.9% were KRAS(Mut) + STK11(Mut), KRAS(Mut) + STK11(Mut) + KEAP1(Mut), STK11(Mut) + KEAP1(Mut), and KRAS(Mut) + KEAP1(Mut), respectively. Based on KRAS status, STK11 alterations were associated with significantly lower PD-L1 expression among those with KRAS(Wt) (p = 0.023), whereas KEAP1 mutations were predominantly associated with lower PD-L1 expression among KRAS(Mut) cases (p = 0.047). Tumors with KRAS(Mut) + KEAP1(Mut) had significantly higher median TMB when compared to other tumors (p = 0.040). For Cohort A, median PFS was 4.9 months (95%CI 4.3-5.4), slightly longer in those with KEAP1(mut) 6.1 months versus STK11(Mut) 4.7 months (p = 0.38). In the same cohort, PD-L1 expression and TMB did not influence PFS. OS was significantly longer among patients with tumors with PD-L1 >= 50% (30.9 months), and different from those with PD-L1 1-49% (22.0 months), and PD-L1 < 1% (12.0 months) (p = 0.0001). When we compared the cohorts A and B, OS was significantly shorter for patients carrying STK1 [STK11(Mut) 14.2 months versus STK11(Wt) 27.0 months (p = 0.0001)] or KEAP1 [KEAP1(Mut) 12.0 months versus KEAP1(Wt) 24.4 months (p = 0.005)] mutations. PD-L1 expression significantly affected OS independently of the presence of mutations in STK11, KEAP1, or KRAS. TMB-H favored better OS. Conclusions: This is the first large Hispanic cohort to study the impact of STK11 and KEAP1 mutations in NSCLC patient treated with ICI. Our data suggest that mutations in the above-mentioned genes are associated with PD-L1 expression levels and poor OS.

To describe the clinical, endoscopic, and histopathology features of esophageal graft-vs-host disease (GVHD).Patients with biopsy-proven esophageal GVHD diagnosed at Mayo Clinic between 2000 and 2021 were included.In 43 esophageal patients, other organ GVHD was present in 58% before and 86% at esophageal GVHD diagnosis. Esophageal specific symptoms were uncommon (dysphagia 26% and odynophagia/heartburn 5%). Esophagogastroduodenoscopy was abnormal in 72% patients demonstrating erosive esophagitis, ulceration, desquamation, or rings/furrows in a diffuse or focal pattern.There should be a low threshold for esophageal biopsies for GVHD because esophageal symptoms and endoscopic findings may be nonspecific or absent.

BACKGROUND: Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. METHODS: We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000–2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm(2) cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6–12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. RESULTS: Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m(2)), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. CONCLUSIONS: Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

Background: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer (NSCLC). Methods: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial NGS panel in liquid biopsy.Results: There were ten males (66.7%), and the median patient’s age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival (OS) of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate (ORR) was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.Conclusions: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were tthe only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

BackgroundLung cancer is a public health problem, and squamous cell carcinoma (SCC) is the second most prevalent subtype of this neoplasm. Compared to other subtypes, including adenocarcinoma, SCC is less well understood in terms of molecular pathogenesis, limiting therapeutic options among targeted agents approved for other disease subgroups. In this study, we sought to characterize the SCC genomic profile using a validated Next Generation Sequencing (NGS) platform.MethodsThe comprehensive NGS assay (TruSight Tumor 170) was used in order to target the full coding regions of 170 cancer-related genes on SCC samples. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako). Clinical outcomes were correlated with molecular profile, including progression free survival (PFS), overall response rate (ORR), and overall survival (OS).ResultsA total of 26 samples were included, median age was 67 years (r, 33–83) and 53.8% were men. Tobacco consumption was identified in all subjects (mean 34-year package). For first-line treatment 80.8% of patients received cisplatin or carboplatin plus gemcitabine. In terms of molecular profile, we identified a high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (38.4%), and NOTCH1 (26.9%). PD-L1 expression ranged from negative, 1, 2–49, and ≥50% in 23.1, 38.5, 26.9, and 11.5%, respectively. Interestingly, the genetic alterations did not have an effect in PFS, OS or ORR in this study. However, PDL1 expression was higher among those who had mutations in TP53 (p = 0.037) and greater expression of PDL1 was related to PIK3CA alterations (p = 0.05).ConclusionsThe genomic profile of SCC encompasses important genes including TP53, PIK3CA and KEAP1. TP53 mutations could be associated with PDL1 expression, generating hypothesis regarding specific treatment options.

A new coronavirus, named severe acute respiratory syndrome-coronavirus-2 by the WHO, has rapidly spread around the world since its first reported case in late December of 2019 from Wuhan, the People's Republic of China. As of mid-April 2020, this virus has affected more than 180 countries and territories, infecting more than 1,650,000 individuals and causing over 100,000 deaths. With approximately 20 million new cases globally per year, cancer affects a substantial portion of the population. Individuals affected by cancer are more susceptible to infections owing to coexisting chronic diseases (cardiovascular, pulmonary, and diabetes), overall poor health status, and systemic immunosuppressive states caused by both cancer and the anticancer treatment. As a consequence, patients with malignancies, especially those with lung cancer who develop coronavirus disease 2019, experience more difficult outcomes. A recent multicenter study carried out by the Hubei Anti-Cancer Association has also documented that patients with lung cancer had an increased risk of death, intensive care unit requirement, risk of presenting severe or critical symptoms, and use of invasive mechanical ventilation. Here, we present two representative cases of patients with lung cancer and coronavirus disease 2019 without respiratory compromise and with atypical and severe skin manifestations-findings that could be influenced by the long-term use of anti-programmed cell death protein 1 antibody.

Effective networking and mentoring are critical determinants of professional satisfaction and success in oncology. There are multiple benefits associated with established mentoring programs. However, these are scarce in Latin America (LATAM). The AAZPIRE project meeting was held to encourage the discussion of mentorship strategies in our region, to create new learning frameworks, and improve cancer care. A group of 30 young oncologists and investigators, together with seven members of LACOG and CLICaP experts of 8 LATAM countries, were reunited to share views and define opportunities, barriers, and possible solutions to implement mentorship programs in LATAM. For each of the mentioned topics, key points were obtained by consensus, and a literature review was conducted to support group conclusions. This article analyses mentoring in LATAM countries and its role on promoting leadership. It will address conceptual frameworks, limitations, and opportunities from the perspectives of both mentor and mentee. The creation of regional and international group stimulation programs and joint projects that impact health policies are attractive, starting points to implement mentorship scenarios.

Background The intestinal microbiota is an important factor in modulating immune‐mediated tumor cell destruction. Alterations in the microbiome composition have been linked to reduced efficacy of immune checkpoint inhibitor (ICI) therapies. Therefore, antibiotic treatment (ATB), which modifies the diversity of the gut bacteria populations, could lead to a reduced efficacy of ICI treatments. Methods This was a retrospective cohort study. Patients with advanced non‐small cell lung cancer (NSCLC) treated with anti‐programmed cell death ligand‐1 (PD‐L1) alone, or in combination in three different countries in Latin America were included. After identification, patients were placed into three groups: Non‐ATB exposed (no‐ATB), exposed within 30 days of the first dose of ICI (pre‐ICI ATB) and patients receiving ATB concomitantly with ICI (ICI‐ATB). Progression‐free survival (PFS), overall survival (OS) and response rates to treatment with ICI were assessed. Results A total of 140 patients were included, of which 32 patients (23%) received ATB treatment. The most common ATB types were fluoroquinolones and B‐lactams. No differences in survival according to antibiotic type were identified. Median OS in patients not exposed to ATB was 40.6 months (95% CI: 32–67.7), compared with 20.3 months (95% CI: 12.1‐non‐reached [NR]) for patients with pre‐ICI ATB treatment and 24.7 months (95% CI: 13‐NR) for patients treated with ATB concomitantly with ICI. There were no significant differences in terms of PFS, or response rates across all treatment groups. Conclusions Antibiotic treatment was associated with reduced OS in Hispanic patients with NSCLC treated with ICIs., Antibiotic treatment has been shown to deter outcomes in patients treated with immune checkpoint inhibitors. The effect of antibiotics is studied for the first time in Latin American patients undergoing ICI therapy. Patients treated with antibiotics prior or during ICI therapy had a significantly shorter overall survival.

Precision oncology is the field that places emphasis on the diagnosis and treatment of tumors that harbor specific genomic alterations susceptible to inhibition or modulation. Although most alterations are only present in a minority of patients, a substantial effect on survival can be observed in this subgroup. Mass genome sequencing has led to the identification of a specific driver in the translocations of the tropomyosin receptor kinase family (NTRK) in a subset of rare tumors both in children and in adults, and to the development and investigation of Larotrectinib. This medication was granted approval by the US Food and Drug Administration for NTRK-positive tumors, regardless of histology or age group, as such, larotrectinib was the first in its kind to be approved under the premise that molecular pattern is more important than histology in terms of therapeutic approach. It yielded significant results in disease control with good tolerability across a wide range of diseases including rare pediatric tumors, salivary gland tumors, gliomas, soft-tissue sarcomas, and thyroid carcinomas. In addition, and by taking different approaches in clinical trial design and conducting allocation based on biomarkers, the effects of target therapies can be isolated and quantified. Moreover, and considering developing nations and resource-limited settings, precision oncology could offer a tool to reduce cancer-related disability and hospital costs. In addition, developing nations also present patients with rare tumors that lack a chance of treatment, outside of clinical trials. This, in turn, offers the possibility for international collaboration, and contributes to employment, education, and health service provisions. The reviews of this paper are available via the supplemental material section.

PROPÓSITO En medio de una pandemia mundial, la evidencia sugiere que, al igual que otras infecciones virales respiratorias graves, los pacientes con cáncer tienen un mayor riesgo de infectarse por COVID-19 y tienen un pronóstico más precario. MÉTODOS Hemos modelado la mortalidad y el requerimiento de la unidad de cuidados intensivos (UCI) para la atención de pacientes con cáncer infectados por COVID-19 en América Latina. Se construyó un modelo dinámico de Markov multiestatal. Las probabilidades de transición se estimaron sobre la base de informes publicados para la probabilidad acumulada de complicaciones. Los valores del número reproductivo básico (R0) se modelaron con R utilizando el paquete EpiEstim. Las estimaciones de los días de necesidad de UCI y la mortalidad absoluta se calcularon imputando el número de casos acumulados en el modelo de Markov. RESULTADOS El tiempo medio estimado de necesidad de UCI fue de 12,7 días, el tiempo medio hasta la mortalidad fue de 16,3 días después de la infección y el tiempo medio hasta el episodio grave fue de 8,1 días. La ocupación máxima de la UCI para pacientes con cáncer se calculó a los 16 días después de la infección. El análisis de sensibilidad determinista reveló un intervalo de mortalidad entre el 18,5% y el 30,4%. Con la tendencia de incidencia real, se esperaría que América Latina perdiera aproximadamente 111,725 pacientes con cáncer por SARS-CoV-2 (rango, 87,116-143,154 pacientes) para el día 60 desde el inicio del brote. Las pérdidas calculadas varían entre el 1% y el 17,6% de todos los pacientes con cáncer de la región. CONCLUSIÓN Los casos relacionados con el cáncer y las muertes atribuibles al SARS-CoV-2 ejercerán una gran presión sobre los sistemas de salud en América Latina. La implementación temprana de intervenciones sobre la base de datos proporcionados por modelos de enfermedades podría mitigar tanto las infecciones como las muertes entre los pacientes con cáncer. PURPOSE In the midst of a global pandemic, evidence suggests that similar to other severe respiratory viral infections, patients with cancer are at higher risk of becoming infected by COVID-19 and have a poorer prognosis. METHODS We have modeled the mortality and the intensive care unit (ICU) requirement for the care of patients with cancer infected with COVID-19 in Latin America. A dynamic multistate Markov model was constructed. Transition probabilities were estimated on the basis of published reports for cumulative probability of complications. Basic reproductive number (R0) values were modeled with R using the EpiEstim package. Estimations of days of ICU requirement and absolute mortality were calculated by imputing number of cumulative cases in the Markov model. RESULTS Estimated median time of ICU requirement was 12.7 days, median time to mortality was 16.3 days after infection, and median time to severe event was 8.1 days. Peak ICU occupancy for patients with cancer was calculated at 16 days after infection. Deterministic sensitivity analysis revealed an interval for mortality between 18.5% and 30.4%. With the actual incidence tendency, Latin America would be expected to lose approximately 111,725 patients with cancer to SARS-CoV-2 (range, 87,116-143,154 patients) by the 60th day since the start of the outbreak. Losses calculated vary between , 1% to 17.6% of all patients with cancer in the region. CONCLUSION Cancer-related cases and deaths attributable to SARS-CoV-2 will put a great strain on health care systems in Latin America. Early implementation of interventions on the basis of data given by disease modeling could mitigate both infections and deaths among patients with cancer.