Treatment of resectable stage IIIA non-small cell lung cancer

Surgical treatment of stage IIIA non-small cell lung cancer (NSCLC) remains a controversial area in the management of lung cancer despite being considered as part of combined modality therapy over the last two decades (1). The heterogeneity of stage III disease and the need for a multidisciplinary approach adds complexity to the treatment of resectable stage III NSCLC. Prospective randomized trials including surgery have consistently faced problems in recruiting. Multicenter trials in different countries: the United Kingdom (2), USA (3), France (4) or Japan (5) were terminated early as a result of poor accrual. This may in part be due to the low frequency of suitable patients for surgical treatment. Two modern randomized studies have been published comparing concurrent chemoradiotherapy (CRT) treatments with and without surgery. In the Intergroup 0139 trial (6), patients with stage III N2 disease were treated with concurrent induction chemotherapy plus radiotherapy. If no progression occurred, patients in the surgical group underwent resection and those in the chemoradiation group continued radiotherapy. A total of 396 eligible patients were randomized and there were no differences in overall survival (OS) between the two groups. However, in an exploratory analysis, survival was improved for the patients who underwent lobectomy, but not pneumonectomy, compared with definitive concurrent chemoradiation. In the ESPATUE trial (7) patients with resectable stage IIIA N2 and selected stage IIIB NSCLC were randomized to surgery or definitive concurrent CRT boost after induction chemotherapy followed by concurrent CRT. A total of 245 eligible patients were recruited to induction therapy over a 10-year period, 161 of them were finally randomized to surgery or tailored dose-scaled CRT. It should be pointed out that 63% of those patients were stage IIIB. There was no difference in OS between the arms. Although both trials were planned to demonstrate superiority in the surgery arm, they failed to show any benefit from surgery in terms of OS. Consequently, definitive concurrent CRT is the only strategy which can be given category 1 recommendation for most stage III NSCLC patients

PET/CT Fusion Scan in Lung Cancer: Current Recommendations and Innovations

Abstract:Combined fluorodeoxyglucose-positron emission tomography (PET)/ computed tomography (CT) imaging has the potential to become the new standard imaging modality for the staging and restaging of patients with lung cancer. PET/CT is superior to PET alone, CT alone, and visual correlation of both techniques separately. In particular, it improves T3 and T4 staging and delineation of tumors associated with atelectasis. CT contrast media enhancement is probably only still needed when a substantial mediastinal tumor component is present and delineation of tumor from vascular structures is relevant. PET/CT is very accurate in detecting mediastinal nodal disease, but false-positive results are sufficiently frequent to require sampling in some positive cases. Whole-body PET/CT is the most sensitive technique for detecting extracranial metastatic disease, unexpected additional primary malignancies, and recurrence. Innovations include therapy monitoring, prognostic information, evaluation of small-cell lung cancer, its use for radiotherapy planning, and four-dimensional respiratory gating acquisition

Fasting plasma glucose is an independent predictor of survival in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy

Background: Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy. Methods: One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and Cox proportional models and log-rank test were used. Results: With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07-1.19, p  8.5%) (HR 4.53; 95% CI 2.21-9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90-5.46 p < 0.001) had significantly independent worse OS. Conclusion: Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association

Elevated Levels of the Complement Activation Product C4d in Bronchial Fluids for the Diagnosis of Lung Cancer

Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95% CI = 0.71-0.94) and 0.67 (95% CI = 0.58-0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95% CI = 0.56-0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.

BACKGROUND: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. METHODS: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. FINDINGS: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). INTERPRETATION: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. FUNDING: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups)

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semiquantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naive and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis nonepithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p< 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies

La lactancia artificial

El verso de las h. en blancoTesis de doctorado leída en la Universidad Central el 10 de marzo de 1904Manuscrito firmado en BarcelonaTesis Doctorales históricasTesis Complutenses históricasmanuscritoFacultad de Medicinatruepu

El Criterio actual sobre las aguas minero-medicinales y algunas consideraciones higiénicas que del mismo se desprenden : discurso de recepción en la Real Academia de Medicina y Cirugía de Barcelona (4 de junio de 1916)

Excmo. Señor, Señores Académicos, Señores: Un ineludible deber, emanado del reglamento por el que se rige esta Ilustre Corporación, me obliga a molestaros por breves momentos. Por un acto de vuestra bondad, más que de justicia, pues una y otra no van en ocasiones de común acuerdo, me elevasteis a un sitial donde jamás soñé llegar, y donde, lo digo sin eufemismo, no debí jamás llegar; pero vuestra benevolencia por un lado, y tal vez vuestro deseo de honrar en mi, un nombre que otros han hecho ilustre en esta Casa, han sido la causa de que me vea en el para mí trabajoso trance presente. No sé cómo saldré de él; mis fuerzas son muy pocas para tan grande empresa, pero me anima a emprenderla, la seguridad de contar de nuevo con vuestra benevolencia, y ello será un motivo que anadir a los muchos que de vosotros tengo ya recibidos y que me obligará, si ello es posible, a aumentar la gratitud de que os soy deudor

Quimioterapia con fármacos nuevos en el cáncer de pulmón de célula no pequeña avanzado

[spa] El cáncer de pulmón es el cáncer más frecuente en todo el mundo. A principio de la década de los 90 aparecieron varios fármacos con una actividad prometedora en cáncer de pulmón de célula no pequeña (CPCNP). El núcleo de esta tesis doctoral son dos publicaciones que contribuyen al desarrollo de dos de estos nuevos fármacos: gemcitabina e irinotecan (CPT-11). El primer estudio se titula: Randomized phase III study of gemcitabine-cisplatin versus etoposide cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer y fue publicado en el Journal of Clinical Oncology 1999;17:12-18. El objetivo principal fue comparar la eficacia, en forma de tasa de respuesta, de la combinación de gemcitabina y cisplatino con la de una combinación convencional: etopósido y cisplatino en pacientes con CPCNP avanzado. Un total de 135 pacientes con CPCNP avanzado fueron randomizados a recibir o bien gemcitabina 1250 mg/m2 ev días 1 y 8 o etopósido 100 mg/m2 ev el día 1, en ciclos de 21 días. La tasa de respuesta (validada externamente) fue superior para los pacientes que recibieron gemcitabina-cisplatino que para los pacientes que recibieron etopósido-cisplatino (40.6% versus 21,9%; p=0,02). Esta tasa de respuesta superior se asociaba a un retraso significativo en el tiempo a la progresión (6,9 meses versus 4,3 meses) sin empeoramiento de la calidad de vida. No hay una diferencia estadísticamente significativa en supervivencia entre las dos ramas (8.7 meses para gemcitabina-cisplatino versus 7,2 meses para etopósido-cisplatino; p= 0.18). La toxicidad global para las dos combinaciones fue similar. Las náuseas y vómitos fueron más frecuentes en el brazo de gemcitabina que en el de etopósido, aunque la diferencia no era significativa. Gemcitabina-cisplatino producía menos alopecia grado 3 (13% versus 51%) y menos neutropenia grado 4 (28 versus 56%) pero más trombocitopenia grado 3 y 4 (56 versus 13%) que etopósido-cisplatino. Sin embargo no hubo complicaciones relacionadas con trombocitopenia en el brazo de gemcitabina. El segundo estudio se titula: Three-week schedule of irinotecan and cisplatin in advanced non-small cell lung cancer: a multicentre phase II study y fue publicado en Lung Cancer 2003;39:201-207. El objetivo principal era valorar la eficacia de la combinación, irinotecan-cisplatino en CPCNP avanzado, medida por tasa de respuesta. Se utilizó una pauta nueva de irinotecan y cisplatino consistente en una sola dosis de los dos fármacos cada tres semanas que proporcionaba la mayor dosis-intensidad de ambos agentes. Se reclutaron setenta y cuatro pacientes con CPCNP estadio IIIB (no candidatos a radioterapia) o estadio IV para recibir CPT-11 200 mg/ m2 iv y cisplatin 80 mg/m2 iv el día 1 cada 3 semanas. Las dosis-intensidades relativas para CPT-11 y cisplatino fueron 92% y 95%, respectivamente. No se observaron respuestas completas. Veinticinco pacientes de 73 obtuvieron una remisión parcial (34,2%). Las remisiones parciales se confirmaron en 18 pacientes (24.7%: IC 95%, 15,6-36,1%). La mediana de supervivencia fue de 8,2 meses, 9,7 meses para los pacientes con performance status (PS) 0 y 1, y 4 meses para aquellos con PS=2. La tasa de supervivencia al año fue el 31%. Las toxicidades clínivcas más importantes fueron diarrea retardada grado 3 y 4 (29% de los pacientes) y neutropenia febril (14% de los pacientes). En conclusión: 1) Cuando se compara con etopósido y ciaplatino, gemcitabina y cisplatino proporciona una tasa de respuestas significativamente superior y un retraso en tiempo a la progresión de la enfermedad sin empeorar la calidad de vida. 2) La combinación de CPT-11 y cisplatino una vez cada tres semanas es factible y activa en pacientes con CPCNP avanzado y PS 0 y 1, sin embargo los resultados no parecen superiores a los publicados con otras pautas