Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs. OBJECTIVE: To develop recommendations for the diagnosis and management of DIILD in cancer patients. METHODS: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events. RESULTS: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis. CONCLUSIONS: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

Statins after recent stroke reduces recurrence and improves survival in an aging Mediterranean population without known coronary heart disease.

WHAT IS KNOWN AND OBJECTIVE: The effect of a statin-based medical intervention on prevention of fatal and non-fatal stroke recurrence and the incidence of all-causes mortality have been explored previously in aging populations within the scope of clinical trials research. However, such evidence needs to be explored under conditions of routine clinical practice. The objective of this study was to determine whether statin therapy in patients with a first stroke episode reduces the incidence of 6-year recurrent fatal or non-fatal stroke and all-cause mortality in an aging Mediterranean population without known coronary heart disease followed in routine medical practice. METHODS: A retrospective study was carried out using records on death, hospitalizations owing to stroke and history of statin therapy included in the Badalona Serveis Assistencials (BSA) database. The cohort studied consisted of consecutive patients covered by the BSA health provider plan with a first-ever acute stroke episode during January 2003 until December 2008, for whom there was available information covering the 6-year follow-up period. Recurrence rate (RR) and incidence rate (IR) of fatal/non-fatal stroke and all-causes mortality were computed. Association with statin therapy was assessed by means of calculation of relative risk (RR) and hazard ratio (HR) using multivariate logistic regression and Cox proportional hazards models controlling for confounding covariates. RESULTS AND DISCUSSION: The cohort comprised a series of 601 consecutive patients [57% men, 75·9 (12·4) years old (88% >60 years)]. Of these, 32% received statins, which were associated with lower fatal/non-fatal recurrent stroke RR; 7% vs. 18% [adjusted RR=0·32 (CI: 0·16-0·61), P=0·001] and lower IR; 16·78 vs. 45·22 events/year-1000 subjects [adjusted HR=0·35 (0·19-0·64), P=0·001]. Similarly, observed all-causes mortality was lower in the cohort receiving statins; 11% vs. 16% [adjusted RR=0·29 (CI: 0·08-1·12), P=0·072], and also mortality rate; 26·09 vs. 36·25 deaths/year-1000 subjects [adjusted HR=0·23 (0·08-0·67), P=0·007]. WHAT IS NEW AND CONCLUSIONS: Statin therapy in patients with first-ever acute stroke lowers the risk of 6-year stroke recurrence and improves survival in an aging Mediterranean cohort. These results add additional evidence in routine clinical practice to the observed effects of statins in clinical trials.

Evolución de los serotipos de neumococo a lo largo de tres décadas / Evaluation of the pneumococcal serotypes over three decades

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[Estimation of the prevalence, incidence, comorbidities and direct costs associated to stroke patients requiring care in an area of the Spanish population]. / Estimación de la prevalencia, incidencia, comorbilidades y costes directos asociados en pacientes que demandan atención por ictus en un ámbito poblacional español.

AIM: To determinate the prevalence, incidence, co-morbidities and therapeutic objectives and costs of stroke among Spanish population. PATIENTS AND METHODS: A retrospective study was performed based on data from patients attended for stroke, aged > 30 years, from five Spanish primary care centres and two hospitals in 2006. Comparative group: patients without stroke. Main analysed variables were: age, sex, co-morbidity (cardiovascular/others), clinical parameters and direct costs (pharmacy, derivations, visits, emergencies, procurement, and hospitalisation). An ANCOVA analysis and logistic regression were used to fit the model. RESULTS: A 4.5% of 57.026 patients (n = 2.585; CI 95% = 4.3-4.7%) suffered stroke. The incidence of stroke was 220 new-cases/100.000 populations. Main differences between patients suffering stroke/control group were: age (72.5 vs. 53.5), men (58.2% vs. 44.6%), episodes/year (7,9 vs. 4,8), visits/year (15,8 vs. 8,1), p < 0,001. Stroke had an independent relation with age (OR = 1,4), male (OR = 2,3), diabetes (OR = 1,6), hypertension (OR = 1,5), smoking (OR = 1,5), alcohol (OR = 1,4), depression (OR = 1,4), dyslipidemia (OR = 1,3) and dementia (OR = 1,2). Some of the results were: systolic pressure (134.1 vs. 127.6 mmHg) and LDL-cholesterol (116.4 vs. 126.2 mg/dL), in presence/absence of stroke, p < 0,001. The average of annual costs of stroke was 2,590.36 vs. 985.26 euros, p < 0.001. After the correction of the logistic model results did not change: 1,774.33 (CI 95% = 1,720.10-1.828.55) vs. 1,021.98 euros (CI 95% = 1,010.92-1,033.03), p < 0,001. All components of costs were higher in the stroke group. CONCLUSIONS: Patients that demanded assistance for stroke had a higher number of co-morbidities and a higher total cost/patient/year. Therapeutic objectives could be improved, mainly in primary prevention of cardiovascular risk factors.

Estimación de la prevalencia, incidencia, comorbilidades y costes directos asociados en pacientes que demandan atención por ictus en un ámbito poblacional español / Estimation of the prevalence, incidence, comorbidities and direct costs associated to stroke patients requiring care in an area of the Spanish population

Estimar la prevalencia e incidencia, así como la comorbilidad, objetivos terapéuticos y costes del ictusen un ámbito poblacional español. Pacientes y métodos. Es un diseño retrospectivo-multicéntrico. Se incluyeron pacientes mayores de 30 años que demandaron asistencia por ictus, pertenecientes a cinco equipos de atención primaria y dos hospitales durante el año 2006. Grupo comparativo: pacientes sin ictus. Principales variables: edad, sexo, casuística/comorbilid (cardiovascular/otras), parámetros bioquímicos y modelo de costes directos (medicamentos, procedimientos, derivaciones, visitas, hospitalizaciones y urgencias). Análisis estadístico: regresión logística y de análisis de covarianza (ANCOVA) para la corrección de los modelos, p < 0,05. Resultados. De los 57.026 pacientes, el 4,5% (n = 2.585; IC 95% = 4,3-4,7%) presentóictus. Incidencia: 220 casos nuevos por cada 100.000 habitantes. Los pacientes con/sin ictus mostraron: edad, 72,5/53,5 años; varones, 58,2/44,6%; episodios al año, 7,9/4,8; visitas al año, 15,8/8,1; p < 0,001. El ictus tuvo relación independiente con: edad (OR = 1,4), varones (OR = 2,3), diabetes (OR = 1,6), hipertensión (OR = 1,5), fumadores (OR = 1,5), alcoholismo(OR = 1,4), depresión (OR = 1,4), dislipemia (OR = 1,3) y demencias (OR = 1,2). Algunos resultados metabólicos fueron: tensión sistólica (134,1 frente a 127,6 mmHg) y colesterol-LDL (116,4 frente a 126,2 mg/dL), en presencia/ausencia de ictus,p < 0,001. El promedio de coste anual fue de 2.590,36 frente a 985,26 euros, p < 0,001, y se mantuvo después de corregir por edad-sexo y comorbilidades: 1.774,33 (IC 95% = 1.720,10-1.828,55) frente a 1.021,98 euros (IC 95% = 1.010,92-1.033,03), p < 0,001. Todos los componentes del coste fueron mayores en el ictus. Conclusiones. Los pacientes que demandaron atenciónpor ictus presentaron un elevado número de comorbilidades y un mayor coste total/paciente/año. Los objetivos terapéuticos de control siguen siendo mejorables, sobre todo en la prevención primaria de los factores de riesgo cardiovascular

To determinate the prevalence, incidence, co-morbidities and therapeutic objectives and costs of strokeamong Spanish population. Patients and methods. A retrospective study was performed based on data from patients attended for stroke, aged > 30 years, from five Spanish primary care centres and two hospitals in 2006. Comparative group: patientswithout stroke. Main analysed variables were: age, sex, co-morbidity (cardiovascular/others), clinical parameters and direct costs (pharmacy, derivations, visits, emergencies, procurement, and hospitalisation). An ANCOVA analysis and logisticregression were used to fit the model. Results. A 4.5% of 57.026 patients (n = 2.585; CI 95% = 4.3-4.7%) suffered stroke. The incidence of stroke was 220 new-cases/100.000 populations. Main differences between patients suffering stroke/control groupwere: age (72.5 vs. 53.5), men (58.2% vs. 44.6%), episodes/year (7,9 vs. 4,8), visits/year (15,8 vs. 8,1), p < 0,001. Stroke had an independent relation with age (OR = 1,4), male (OR = 2,3), diabetes (OR = 1,6), hypertension (OR = 1,5), smoking (OR =1,5), alcohol (OR = 1,4), depression (OR = 1,4), dyslipidemia (OR = 1,3) and dementia (OR = 1,2). Some of the results were: systolic pressure (134.1 vs. 127.6 mmHg) and LDL-cholesterol (116.4 vs. 126.2 mg/dL), in presence/absence of stroke, p <0,001. The average of annual costs of stroke was 2,590.36 vs. 985.26 euros, p < 0.001. After the correction of the logisticmodel results did not change: 1,774.33 (CI 95% = 1,720.10-1.828.55) vs. 1,021.98 euros (CI 95% = 1,010.92-1,033.03), p <0,001. All components of costs were higher in the stroke group. Conclusions. Patients that demanded assistance for stroke had a higher number of co-morbidities and a higher total cost/patient/year. Therapeutic objectives could be improved, mainly inprimary prevention of cardiovascular risk factors

Sepsis y meningitis neumocócica 2001-2003: incidencia, clínica e identificación de serotipos / Pneumococcal sepsis and meningitis, 2001-2003: incidence, clinical features and identification of serotypes

Objetivo: Determinar las tasas de incidencia, características clínicas y serotipos causantes de meningitis y sepsis neumocócica en los últimos años. Material y métodos: Estudio prospectivo de los casos de sepsis y meningitis neumocócica que ingresaron en nuestro hospital entre enero de 2001 y febrero de 2003. Se aisló el germen en cultivo de líquido cefalorraquídeo y/o sangre. Se identificó el serotipo de neumococo en los casos que se produjeron en 2002 y 2003. Se analizan los parámetros epidemiológicos, bacteriológicos y clínicos. Resultados: Se han diagnosticado 14 casos, en 12 niños; dos niños presentaron 2 episodios de meningitis y/o sepsis. La incidencia anual fue de 15,38 casos por cada 100.000 niños menores de 2 años y de 9,16 casos por cada 100.000 niños menores de 5 años de edad. El 67% eran menores de 2 años de edad. Todos los mayores de 2 años presentaban algún factor de riesgo de padecer enfermedad neumocócica invasora. Los serotipos identificados fueron: 6B en cinco casos, 14 en dos y 18C en uno. El 69% de las cepas aisladas presentaba sensibilidad intermedia o resistencia a penicilina y el 54% mostraba resistencia a eritromicina. El 57% de los niños sufrieron complicaciones graves: dos (14%) quedaron con secuelas neurológicas graves y 3 fallecieron (21 %).Conclusiones: Las sepsis y meningitis neumocócicas tienen una alta morbimortalidad. En el último año, hemos observado un aumento importante de su incidencia. Todos los serotipos identificados están incluidos en la vacuna conjugada heptavalente. Actualmente, el método más eficaz para prevenir esta grave enfermedad es el uso generalizado de la vacuna heptavalente

Objective. To determine the incidence, clinical features and serotypes implicated in pneumococcal sepsis and meningitis in recent years. Material and methods. We performed a prospective study of cases of pneumococcal sepsis and meningitis that occurred in our hospital between January, 2001 and February, 2003. Streptococcus pneumoniae was isolated from cerebrospinal fluid and/or blood cultures in all the patients. Serotyping was performed in the cases occurring in 2002 and 2003. The epidemiological, bacteriological and clinical characteristics were studied. Results. Fourteen cases were identified in 12 patients. Two children had recurrent meningitis and/or sepsis. From 0 to 2 years of age, the incidence of pneumococcal meningitis was 15.38 cases per 100,000 population per year, and from 0 to 5 years of age, it was 9.16 cases per 100,000 population per year. Eight patients (67%) were aged less than 2 years. All children older than 2 years had a predisposing disease. The most common serotype was 6B (5 cases). Penicillin-resistant strains were detected in 69% of cases and erythromycin-resistant strains in 54%. Fifty-seven percent of the children developed serious complications. Conclusions. Pneumococcal meningitis and sepsis are common causes of morbidity and mortality. Their incidence increased considerably over the past year. All the serotypes isolated were included in the heptavalent conjugate vaccine. The most effective way to combat these severe infections would be through widespread vaccination with the conjugate pneumococcal vaccine

The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement.

The cooperative antitumor effects of IL-12 and IL-15 gene transfer were studied in the N592 MHC class I-negative small cell lung cancer cell line xenotransplanted in nude mice. N592 cells engineered to secrete IL-15 displayed a significantly reduced tumor growth kinetics, and a slightly reduced tumor take rate, while N592 engineered with IL-12 displayed only minor changes in their growth in nude mice. However, N592 cells producing both cytokines were completely rejected, and produced a potent local bystander effect, inducing rejection of coinjected wild-type tumor cells. N592/IL-12/IL-15 cells were completely and promptly rejected also in NK-depleted nude mice, while in granulocyte-depleted animals a slight delay in the rejection process was observed. Immunohistochemical analyses of the N592/IL-12/IL-15 tumor area in intact nude mice revealed the presence of infiltrating macrophages, granulocytes, and NK cells, and expression of inducible NO synthase and of secondary cytokines such as IL-1beta, TNF-alpha, and IFN-gamma, and at higher levels GM-CSF, macrophage-inflammatory protein-2, and monocyte chemoattractant protein-1. In NK cell-depleted nude mice, numerous macrophages and granulocytes infiltrated the tumor, and a strong expression of macrophage-inflammatory protein-2 and inducible NO synthase was also observed. Finally, macrophages cocultured with N592/IL-12/IL-15 produced NO in vitro, and inhibited tumor cell growth, further suggesting their role as effector cells in this model.

Gene transfer of a secretable form of IL-15 in murine adenocarcinoma cells: effects on tumorigenicity, metastatic potential and immune response.

IL-15 is an immunostimulatory cytokine with IL-2-like activities. To exploit the potential role of IL-15 in cancer immuno-/gene therapy, we engineered murine TS/A cells with different IL-15 cDNA constructs. Significant IL-15 secretion was achieved only by the use of a modified cDNA encoding for an IL-15 pre-protein bearing the IgK light chain signal peptide. Different TS/A clones (TS/A IL-15 C6, C23, C29) producing 390 to 1,600 pg/ml biologically active IL-15 showed reduced tumorigenicity when implanted s.c. in syngeneic mice and significantly reduced metastatic potential by i.v. injection. Tumorigenicity of s.c. TS/A IL-15 was restored in animals depleted of CD8(+) lymphocytes or of natural killer cells and partially in CD4(+)-depleted mice. TS/A IL-15 cells displayed a significantly reduced growth rate by s.c. implant in nude mice. Also, >50% syngeneic animals rejecting TS/A IL-15 were resistant to a subsequent rechallenge with wild-type tumor (TS/Apc), indicating induction of protective immunity against TS/A tumor-associated antigens (TAAs). Cytolytic T lymphocyte (CTL) activity, specifically inhibited by anti-CD3 antibodies, was inducible in the splenocytes of TS/A IL-15-immunized animals by mixed lymphocyte/tumor culture (MLTC), and IFN-gamma was released in the supernatant of MLTC, mainly by CD8(+) cells. Immunohistochemistry of the TS/A IL-15 tumor area revealed the presence of an inflammatory infiltrate with predominant natural killer, macrophage, and granulocyte components and expression of IFN-gamma as a distinctive secondary cytokine. Use of TS/A IL-15 mitomycin-treated cells for therapeutic vaccination in experimental TS/A metastasis was effective in 60% of animals treated; these animals showed no metastatic tumor growth.

Dissimilar anti-tumour reactions induced by tumour cells engineered with the interleukin-2 or interleukin-15 gene in nude mice.

Interleukin (IL)-15 shares immuno-stimulatory properties with IL-2 and is a potent inducer of natural killer (NK) cell function. The major histocompatibility complex (MHC) class I-negative human small cell lung cancer (SCLC) cell line N592, engineered to express a modified IL-15 cDNA (N592/IL-15), secreted biologically active IL-15 (300-500 pg/ml), capable of boosting T-cell proliferation and NK activity 'in vitro'. The effect of IL-15 gene transfer on natural immunity 'in vivo' was assessed by xenotransplants in nude mice and compared with that of the IL-2 gene. N592 cells engineered with IL-2 (N592/IL-2) were promptly rejected, while N592/IL-15 displayed a significant delay in tumour growth and a slightly reduced take rate. However, in NK-depleted nude mice, N592/IL-15 displayed the same growth kinetics as unmodified N592 cells, and N592/IL-2 grew with slightly reduced kinetics. An impressive reactive cell infiltration, consisting mainly of macrophages and granulocytes, was associated with N592/IL-2 tumour rejection, while a more evident recruitment of NK cells was found in N592/IL-15 tumours. In both N592 transfected tumours, we found expression of chemoattractant molecules, such as granulocyte macrophage-colony stimulating factor (GM-CSF) and monocyte chemoattractant protein (MCP)-1, while macrophage inflammatory protein (MIP)-2 was produced by endothelial cells only in N592/IL-2 tumours. In this tumour, very few and severely damaged microvessels were found, while microvessels were numerous in N592/IL-15 tumours. The potent recruitment of NK cells mediated by IL-15 gene transfer suggests its possible therapeutic use in tumours lacking MHC class I.

Chromosomal abnormalities in women with breast cancer after autologous stem cell transplantation are infrequent and may not predict development of therapy-related leukemia or myelodysplastic syndrome.

We determined prospectively the incidence of chromosomal abnormalities in patients with high-risk breast cancer (HRBC) after high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), and correlated the cytogenetic abnormalities with the development of post-transplant myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). From 1990 to 1999, 229 women with HRBC underwent ASCT. Cytogenetic analysis of bone marrow (BM) cells was performed 12-59 months after ASCT in 60 consecutive women uniformly treated with six courses of FAC/FEC followed by HDCT and ASCT. With a median follow-up of 36 months after ASCT, there were no cases of MDS/AML among the 229 patients. In the selected cohort of 60 patients, three (5%) showed clonal chromosomal abnormalities (two single trisomy X and one t(1;6)), whereas two additional patients showed non-clonal reciprocal translocations. Two of the patients with clonal aberrations had blood cytopenias as well as subtle dysplastic pictures in BM which were not classifiable as MDS according to the FAB criteria. Similar dysplastic features were also observed in four patients with normal karyotypes. All cytogenetic aberrations were transient and disappeared, except a +X detected by FISH in a residual cell population in one of the patients. Retrospective cytogenetic and FISH studies of samples obtained after six cycles of FAC/FEC and before transplant demonstrated no chromosomal abnormalities in any of the five patients with post-ASCT karyotypic changes. Early changes in karyotype detected in breast cancer patients following ASCT are transient and do not correlate with or predict development of MDS/AML. As these aberrations were not present before ASCT, they may be related to the HDCT regimen or transplant procedure rather than to the prior adjuvant therapy. Our results suggest that ASCT may be less likely to cause MDS or AML in breast cancer patients as compared to other malignancies. Bone Marrow Transplantation (2000) 25, 1203-1208.