Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer.

PURPOSE: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. EXPERIMENTAL DESIGN: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

EGFR exon 18 delE709_T710insD mutated stage IV non-small cell lung cancer treated with osimertinib: a case report.

Mutations in tyrosine kinase domain of epidermal growth factor receptor (EGFR) are observed in approximately 15% of non-small cell lung cancer adenocarcinoma. Exon 19 deletions or exon 21 L858R mutations are predominant in frequency and show high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Exon 18 mutations are extremely rare and the delE709_T710insD mutation accounts for only 0.16% of mutations when occurring as a sole mutation. This specific mutation in exon 18 seems to respond to certain EGFR TKIs such as afatinib. However, given the rarity of this mutation, determining the most effective TKI for its treatment remains unclear. We report a 70-year-old woman diagnosed with stage IV-A lung adenocarcinoma harboring EGFR delE709_T710insD mutation treated in first-line with Osimertinib using standard schedule and doses experiencing renal toxicity and disease progression after 9 weeks of treatment.

Blood tumor mutational burden and response to pembrolizumab plus chemotherapy in non-small cell lung cancer: KEYNOTE-782.

BACKGROUND: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC. METHODS: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB. RESULTS: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively). CONCLUSIONS: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy.

"Inherited cardiovascular disease mindset" can identify concealed inherited conditions at cardio-oncology evaluation: An opportunistic screening.

INTRODUCTION: Baseline cardiovascular (CV) risk stratification is recommended in all cancer patients. Integrating all clinical information (personal/family history, ECG and echocardiogram) can properly identify high-risk patients. We aimed to evaluate the concealed inherited CV conditions detected in mandatory CV screening performed at a Cardio-Oncology Unit. METHODS: retrospective study of all consecutive cancer patients referred to the Cardio-Oncology Unit for CV evaluation (2020-2023). Inherited CV conditions diagnosis and genetic testing was performed according to guidelines. RESULTS: 1984 cancer patients underwent CV screening. Sanger sequencing was indicated in 1 patient, excluding the genetic family disease. NGS sequencing was performed in 11 cancer patients with normal left ventricular ejection fraction (LVEF): 2 due to aortic syndrome evaluation (identifying 1 vascular Ehrler-Danlos syndrome due to COL3A1 p.Arg242Ter), 4 channelopathies (2 Long QT syndrome and 2 Brugada's), 4 hypertrophic cardiomyopathies and 1 non-dilated left ventricular cardiomyopathy (NDLVC). Among the 12 patients with reduced LVEF, one was diagnosed with NDLVC, and chemotherapy-induced dilated cardiomyopathy was only ascribable in 3 of them. CONCLUSION: Integrating clinical information at mandatory baseline CV toxicity risk cardio-oncology evaluation, can identify high-risk cancer patients with concealed inherited conditions. Keeping an "inherited cardiovascular disease-oriented mindset" to implement opportunist screenings is encouraged.

Marital Status, Living Arrangement, and Survival among Individuals with Advanced Prostate Cancer in the International Registry for Men with Advanced Prostate Cancer.

BACKGROUND: Studies have shown improved survival among individuals with cancer with higher levels of social support. Few studies have investigated social support and overall survival (OS) in individuals with advanced prostate cancer in an international cohort. We investigated the associations of marital status and living arrangements with OS among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). METHODS: IRONMAN is enrolling participants diagnosed with advanced prostate cancer (metastatic hormone-sensitive prostate cancer, mHSPC; castration-resistant prostate cancer, CRPC) from 16 countries. Participants in this analysis were recruited between July 2017 and January 2023. Adjusting for demographics and tumor characteristics, the associations were estimated using Cox regression and stratified by disease state (mHSPC, CRPC), age (<70, ≥70 years), and continent of enrollment (North America, Europe, Other). RESULTS: We included 2,119 participants with advanced prostate cancer, of whom 427 died during up to 5 years of follow-up (median 6 months). Two-thirds had mHSPC. Most were married/in a civil partnership (79%) and 6% were widowed. Very few married participants were living alone (1%), while most unmarried participants were living alone (70%). Married participants had better OS than unmarried participants [adjusted HR: 1.44; 95% confidence interval (CI): 1.02-2.02]. Widowed participants had the worst survival compared with married individuals (adjusted HR: 1.89; 95% CI: 1.22-2.94). CONCLUSIONS: Among those with advanced prostate cancer, unmarried and widowed participants had worse OS compared with married participants. IMPACT: This research highlighted the importance of social support in OS within this vulnerable population.

Impact of systemic cancer treatment on quality of life and mental well-being: a comparative analysis of patients with localized and advanced cancer

Introduction This study investigated the impact of systemic cancer therapy on the quality of life, mental well-being, and life satisfaction of cancer patients. Methods This prospective study was promoted by the Spanish Society of Medical Oncology (SEOM) and enrolled patients with localized, resected, or unresectable advanced cancer from 15 Spanish medical oncology departments. Patients completed surveys on quality of life (EORTC-QoL-QLQ-C30), psychological distress (BSI-18) and life satisfaction (SWLS) before and after systemic cancer treatment. Results The study involved 1807 patients, 944 (52%) having resected, localized cancer, and 863 with unresectable advanced cancer. The mean age was 60 years, and 53% were female. The most common types of localized cancer were colorectal (43%) and breast (38%), while bronchopulmonary (32%), non-colorectal digestive (23%), and colorectal (15%) were the most frequent among those with advanced cancer. Before systemic treatment, patients with advanced cancer had poorer scores than those with localized cancer on physical, role, emotional, cognitive, social limitations, symptoms, psychological distress, and life satisfaction (all p < 0.001), but there were no differences in financial hardship. Patients with localized cancer had greater life satisfaction and better mental well-being than those with advanced cancer before systemic treatment (p < 0.001). After treatment, patients with localized cancer experienced worsening of all scales, symptoms, and mental well-being (p < 0.001), while patients with advanced disease had a minor decline in quality of life. The impact on quality of life was greater on all dimensions except economic hardship and was independent of age, cancer location, and performance status in participants with resected disease after adjuvant chemotherapy (AU)

Concealed Inherited Cardiomyopathies Detected in Cardio-Oncology Screening.

INTRODUCTION: Basal cardiovascular risk assessment in cardio-oncology is essential. Integrating clinical information, ECG and transthoracic echocardiogram can identify concealed inherited cardiomyopathies (ICMPs) with potential added risk of cardiotoxicity. We aimed to evaluate the impact of our Cardio-Oncology Unit design in detecting concealed ICMPs. METHODS: We carried out a retrospective study of all consecutive breast cancer patients referred to the Cardio-Oncology Unit for cardiac evaluation (2020-2022). ICMPs diagnosis was provided according to ESC guidelines and underwent genetic testing. ICMPs prevalence in this cohort was compared to the highest and lowest frequency reported in the general population. RESULTS: Among 591 breast cancer patients, we identified eight patients with ICMPs: one arrhythmogenic cardiomyopathy (ACM), three familial non-ischemic dilated cardiomyopathy (DCM), three hypertrophic cardiomyopathy (HCM) and one left ventricular non-compaction cardiomyopathy (LVNC), which has now been reclassified as non-dilated left ventricular cardiomyopathy. The number of ICMPs identified was within the expected range (neither overdiagnosed nor overlooked): ACM 0.0017 vs. 0.0002-0.001 (p 0.01-0.593); DCM 0.0051 vs. 0.002-0.0051 (p 0.094-0.676); HCM 0.005 vs. 0.0002-0.002 (p < 0.001-0.099); LVCN 0.0017 vs. 0.00014-0.013 (p 0.011-0.015). Genetic testing identified a pathogenic FLNC variant and two pathogenic TTN variants. CONCLUSION: Opportunistic screening of ICMPs during basal cardiovascular risk assessment can identify high-risk cancer patients who benefit from personalized medicine and enables extension of prevention strategies to all available relatives at concealed high cardiovascular risk.

ASTRIS, a large real-world study to evaluate the efficacy of osimertinib in epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer patients: Clinical characteristics and genotyping methods in a Spanish cohort / ASTRIS, un gran estudio en el mundo real para evaluar la eficacia de osimertinib en pacientes de cáncer de pulmón no microcítico positivo a la mutación de T790M del receptor del factor de crecimiento epidérmico: características clínicas y métodos de genotipificación en una cohorte española

PURPOSE: Osimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. METHODS: ASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. RESULTS: The Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. CONCLUSIONS: ASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices

OBJETIVO: Osimertinib ha probado su eficacia en los pacientes de cáncer de pulmón no microcítico (CPNM) positivo a la mutación de EGFR T790M; sin embargo, sus beneficios no han sido evaluados en el mundo real. MÉTODOS: ASTRIS es un estudio de brazo único, abierto y multinacional para evaluar la eficacia y la seguridad de osimertinib para el tratamiento del CPNM positivo a la mutación de EGFR T790M. Presentamos el diseño del estudio y los resultados del análisis del punto de corte (octubre de 2017), que describe las características basales y la metodología de la detección de la mutación de T790M en la cohorte española. RESULTADOS: La cohorte española incluyó 131 pacientes de entre un total de 3.014 sujetos. Cuarenta pacientes (28,1%) seguían en terapia en el momento del punto de corte, el 68,7% eran mujeres y el 97,7% eran caucásicos, con una edad media de 64,8 (DE: 11,7) años. El tipo más común de muestra para evaluar las mutaciones de T790M fue tisular (55%), habiéndose obtenido las muestras del tumor primario en el 61,1% de los casos. El análisis de la mutación fue realizado por parte del laboratorio local en el 60,3% de los casos, utilizando el ensayo Roche Cobas® EGFR en el 43,5% de los casos. CONCLUSIONES: Se espera que ASTRIS confirme los beneficios de osimertinib en el mundo real. Los datos sobre las prácticas en el mundo real para la detección de la mutación de EGFR T790M podrían proporcionar información adicional para aportar directrices sobre las mejores prácticas

Las pinzas cortantes (y II). Clasificación / Cutting Forceps. Classification (y II)

La pauta más común y también la más sencilla para lograr una aproximación eficaz a los instrumentos quirúrgicos consiste en, conocidas sus características físicas, establecer una relación entre cada herramienta y un órgano o tejido, o bien asociarla con una especialidad operatoria determinada, con un técnica específica, etc. De esta manera se acertará en la mayoría de las ocasiones, pues cada especialidad quirúrgica suele optar por un modelo único de pinza cortante en cada sistema de instrumentos tanto para abaratar costes como para reducir el número de instrumentos(AU)

The most common and also the simplest guideline to gain an efficient awareness about existing surgical instruments consists of, once you know their physical characteristics, establishing a relationship between every instrument and every organ or tissue, or otherwise to associate each instrument to a determined operating specialty, having a specified technique, etc. Through this method, a professional will act correctly in the majority of situations since each surgical specialty tends to opt for one unique model of cutting forceps in each instrument system both to reduce costs as to reduce the number of instruments(AU)

Las pinzas cortantes (I). Instrumentos de corte y escisión / Cutting and incision instruments: incising forceps

Las pinzas cortantes permiten cortar, dividir y separar porciones de tejidos con fines terapéuticos y diagnósticos. Su singularidad las hace estar presentes en buen número de especialidades quirúrgicas. Son específicas si actúan sobre tejidos blandos u óseos, también en función de la vía de abordaje en la que se empleen y, sin duda, las más específicas de todas son las empleadas en técnicas endoscópicas y microquirúrgicas. Se expone un recorrido sobre estos instrumentos que esperamos sea de interés para las enfermeras quirúrgicas y para todos los profesionales vinculados al área perioperatoria(AU)

Incising forceps enable one to cut, divide and separate sections of tissue for therapeutic and diagnostic purposes. Their singular usage makes them present in a large number of specialized surgical interventions. They are specialized for use on soft tissue and bone tissue; depending on the manner by which surgeons incise a patient, they are specialized. Moreover, the most highly specialized incising forceps are those used in endoscope techniques and in microsurgery. The author presents a review of these surgical instruments which he hopes will be of interest to surgical nurses and to all professionals connected to operation wards(AU)

La tijera (IV). Clasificación / Scissors (IV). Classification

Acabamos la secuencia dedicada a las tijeras con el tema relativo a su clasificación. Las tijeras de tejidos y las tijeras auxiliares, con todos sus modelos específicos son explicadas en este artículo(AU)

The author finishes his series of articles on scissors with an article dedicated to a classification of scissors. In this article, scissors used to cut tissue and auxiliary scissors in all their specific models are explained(AU)

La Tijera (III). Características estructurales / Scissors (III). Structural characteristics

Algunas características de las tijeras, ya sea su afilado o el grosor de las hojas, bien la longitud específica de los bordes cortantes o la medida total del instrumento, nos hacen intuir sus posibles utilidades. Sin embargo, otras peculiaridades que pasan inadvertidas son decisivas para distinguir la idoneidad de unos modelos frente a otros(AU)

Some characteristics of scissors, such as their sharpness or blade thickness, the specific length of their cutting edges or the total length of the tool, allow one to guess their possible uses. However, other peculiarities of scissors which are overlooked are decisive to distinguish the best use of one model instead of another(AU)

La Tijera (I) / Scissors. Instruments wich cut and dissect

La tijera representa actualmente el instrumento de disección indiscutido; el resto de herramientas quirúrgicas retiran, sostienen o separan estructuras y tejidos para que una única tijera cumpla la función principal en el acto operatorio. Sin embargo, la tijera ideal, la designada para tareas generales de corte y disección en cualquier territorio orgánico no existe; prueba de ello es su enorme variedad en presentaciones y formas(AU)

Scissors are the unquestionable dissection tool; all other surgical tools retire, hold back or separate structures and tissues so that one lone scissors complies with the main function during an operation. However, the ideal scissors, designed for general cutting tasks and dissection in any place in the body, does not exist; proof of this is the enormous variety of scissors available to surgeons(AU)

El bisturí. Nombres propios / The scalpel: proper names

Algunos instrumentos quirúrgicos, que también son bisturíes, reciben nombres diferentes: se emplean para retirar cuerpos extraños, y también para incidir, seccionar o perforar sobre determinados órganos

Some surgical instruments, which are also called scalpels, have other names. They are used to remove foreign bodies and to cut into, section or perforate determined organs

El bisturí: hojas. Instrumentos de corte e incisión / Cutting and incision tools: the scalpel: blades

Las hojas de bisturí formas un extenso conjunto de láminas cortantes de acero inoxidable con una fenestración donde engarzan los mangos de bisturí con arreglo al sistema referencial, mangos pequeños (número 3), o grandes (número 4)

The blades of a scalpel form an extensive set of stainless steel cutting sheets which have a fenestration where they link to a scalpel's handle comfortably; these handles can be small, number 3 or large, number 4

El bisturí: generalidades. Instrumentos de corte e incisión / Cutting and incision tools: the scalpel and its general characteristics

El bisturí es el instrumento cortante más conocido; su imagen representa por excelencia la técnica quirúrgica. Su utilización más conocida es el trazado de la herida operatoria, aunque su uso en cirugía está más extendido de lo que se supone. A lo largo de éste y otros artículos se efectuará un recorrido -totalmente inédito- por las características de los diferentes modelos; se presentarán las claves para identificarlos y asociarlos según su uso y finalidad. De interés para definir el contenido de las cajas de instrumental para todos aquellos profesionales que deseen ampliar su formación teórica y técnica

The scalpel is the best known cutting tool; surgery techniques image par excellence is the scalpel. Its use to incise an opening in surgery is well-known, although the use of a scalpel in surgery is much wider than commonly thought to be. Throughout this and other articles, up until now unedited, the author plans to review the characteristics of different models; the keys to identify and associate scalpels according to their use and purposes shall be presented. These articles should be of interest as a means to define the contents of tool kits to all those professionals who wish to widen their theoretical and technical development

Instrumentos de corte e incisión (III). Sección ósea / Instruments to cut and make incisions (III). Bone section

Los elementos cortantes que se emplean sobre el hueso cumplen diferentes acciones: diferenciamos aquellos que actúan sobre el tejido óseo (resección de exostosis, extirpación de tumores óseos, eliminación de porciones de hueso para acceder a otros territorios orgánicos, etc.); y aquellos que se emplean para la diéresis de estructuras tendinosas, cartílago y, más abundantemente, tejidos blandos

Cutting tools used on bones fulfill different actions: we distinguish between those which cut bone tissue (dissection of an exostosis, extraction ot bone tumors, to remove pieces of bone in order to have access to other body parts, etc.); and those which are used on tendinous structures, cartilage, and more trequently on soft tissues

Instrumentos de corte e incisión (II) / Instruments to cut and make incisions (II) incisions

El armamentarium quirúrgico dispone de variados instrumentos incisos, algunos de uso frecuente y común en cirugía general y de especialidades: es el caso de bisturís y tijeras. También un número abundante de elementos es considerado como propio y casi exclusivo de determinadas disciplinas quirúrgicas

In a surgeon´s tool chest there are a variety of incision-making tools, some frequent, common use in general or specialized surgery such as scalpels or scissors. There also exists an abundant quantity of instruments considered to pertain exclusively to determined surgical specialities