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Central nervous system (CNS) dissemination is a severe complication in cancer and a leading cause of cancer-related mortality. Brain metastases (BMs) are the most common types of malignant intracranial tumors and are reported in approximately 25% of patients with metastatic cancers. The recent increase in incidence of BMs is due to several factors including better diagnostic assessments and the development of improved systemic therapies that have lower activity on the CNS. However, newer systemic therapies are being developed that can cross the blood–brain barrier giving us additional tools to treat BMs. The guidelines presented here focus on the efficacy of new targeted systemic therapies and immunotherapies on CNS BMs from breast, melanoma, and lung cancers.

Purpose To identify potential correlates of CRF after curative breast cancer (BC) treatment. The hypothesis was that fatigue would be more severe among women treated with cardiotoxic drugs, with poor physical condition and those who exercised less.Methods Prospective observational cross-sectional design. Fatigue was evaluated through Perform Questionnaire (multi-item, multi-dimensional). Patient-reported assessments and objective information regarding clinical data, physical activity (PA) and physical condition were analysed as potential correlates of CRF.Results 180 women who remained free of disease were recruited. Prevalence of fatigue interfering with quality of life was 43%. Weight, BMI, treatment with trastuzumab and time spent walking one mile were positively associated with fatigue. Age, time from diagnosis, self-reported walking time, basal and recovery heart rate were negatively associated. Previous chemo, radio or hormonal therapy, objectively assessed weekly PA, cardio-respiratory condition, muscular strength and adherence to Mediterranean diet were not associated with CRF. However, an interesting unexpected negative association with nut intake was found.Conclusions CRF is a prevalent problem after BC treatment. Objectively assessed PA, cardiorespiratory fitness and muscular strength did not predict CRF. The association of CRF with trastuzumab and low intake of nuts should be confirmed in further studies. A deeper insight in heart rate variability is warranted. Future research should include longitudinal studies and determination of biomarkers. Implications for Cancer Survivors BC survivors, especially younger and overweight women, should be informed about fatigue as a potential persistent symptom through all stages of the cancer trajectory and into survivorship. They also should be routinely screened for CRF.

Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: Hormone Receptor-positive/HER2-negative (HR+/HER2-neg) (10 patients), pelareorep + letrozole. Cohort 2: HR+/HER2-neg (10 patients), pelareorep + letrozole + atezolizumab. Cohort 3: Triple Negative Breast Cancer (TNBC) (6 patients), pelareorep + atezolizumab. Cohort 4: Hormone Receptor-positive/HER2-positive (HR+/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. Cohort 5: Hormone Receptor-negative/HER2-positive (HR-/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score, a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue was examined for pela replication, and changes to the TME were assessed by imaging mass cytometry (IMC), immunohistochemistry, and T cell receptor sequencing (TCR-seq). Peripheral blood was also examined by TCR-seq. Results: Detailed translational research results will be presented from patients in cohort 1, who received just pelareorep and letrozole. CelTIL score increased in 5/10 patients at day 3 biopsies and 6/10 patients at day 21 biopsies. Preliminary results show high levels of viral replication (>50% of tumor cells) while immunohistochemistry and IMC analysis revealed changes to the TME, with increases in CD8+ T cells and upregulation of PD-L1 at both day 3 and day 21 biopsies. Overall, preliminary data from cohort 1 of AWARE-1 demonstrate pela-mediated priming of an adaptive immune response. (NCT04102618) Citation Format: Luis Manso, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan Miguel Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose Luis Alonso, Alejandro Martínez, Rafael Villanueva, Juan Antonio Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca González, Rita Laeufle, Gerard Nuovo, Grey Wilkinson, Matt Coffey, Azucena González, Débora Martínez, Laia Paré, Fernando Salvador, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (REO-027, AWARE-1) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-08.

Circadian rhythms impose daily rhythms a remarkable variety of metabolic and physiological functions, such as cell proliferation, inflammation, and DNA damage response. Accumulating epidemiological and genetic evidence indicates that circadian rhythms’ disruption may be linked to cancer. The integration of circadian biology into cancer research may offer new options for increasing cancer treatment effectiveness and would encompass the prevention, diagnosis, and treatment of this disease. Recent Findings: In recent years, there has been a significant development and use of multi-modal sensors to monitor physical activity, sleep, and circadian rhythms, allowing, for the very first time, scaling accurate sleep monitoring to epidemiological research linking sleep patterns to disease, and wellness applications providing new potential applications. Summary: This review highlights the role of circadian clock in tumorigenesis, cancer hallmarks and introduces the state-of-the-art in sleep-monitoring technologies, discussing the eventual application of insights in clinical settings and cancer research, This work was supported in part by CLARIFY project, within European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 875160, Instituto de Fomento de la Región de Murcia (INFO) and the European Regional Development Fund (FEDER)

Background: Physical fitness (PF) is an expression of the physiological functioning of multiple body components. PF is an important prognostic factor in terms of cardiovascular mortality, cancer mortality, and all-cause mortality. PF has been related to some biomarkers in the general population but not in breast cancer survivors (BCS). Purpose: To evaluate the effects of PF on biomarkers potentially related to physical activity (PA) in a sample of BCS. Methods: Cross-sectional study. A total of 84 BCS (mean age 54) who had finished their treatment were recruited. Different components of PF were evaluated, namely body composition (anthropometry), cardiorespiratory fitness (one-mile walk test), muscular (handgrip and sit-to-stand timed test), and motor (gait speed) components. Sexual hormones, inflammation, and insulin resistance biomarkers were measured. Results: C-Reactive Protein (CRP) was associated with every component of physical fitness: cardiorespiratory fitness (p-value = 0.002), muscular (sit-to-stand timed test, p-value = 0.002) and motor (gait speed, p-value = 0.004) components, and body composition (body mass index, p-value = 0.003; waist, p-value < 0.000; and waist-to-hip index, p-value = 0.012). CRP also was associated with “poor physical condition,” a constructed variable that encompasses all components of physical fitness (p-value < 0.001). Insulin was associated with cardiorespiratory fitness and gait speed (p-values = 0.002 and 0.024, respectively). Insulin-like Growth Factor-1 was negatively associated with waist perimeter and waist-to-hip ratio. Conclusions: CRP can also be considered an indicator of poor PF in BCS. Implications for cancer survivors: in case of elevation of CRP indicating cardiovascular risk, health professionals should recommend lifestyle changes to improve BCS physical condition.

Background This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. Materials and Methods This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. Results Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients’ experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. Conclusion The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 Implications for Practice The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

e18734 Background: In the last five years, different immunotherapy (IO) clinical trials have improved overall survival (OS) for stage IV non-small cell lung cancer (NSCLC) without driver mutation. However, it is necessary to check whether outcomes of clinical trials are reproduced in the general population, the true objective of any scientific advance. Methods: We conducted a retrospective observational study selecting all patients with stage IV NSCLC without driver mutation treated in the Medical Oncology Department at Puerta de Hierro University Hospital between 2016 and 2019. Data cut off was June 30, 2021. Our goal was to evaluate treatment changes for NSCLC in clinical practice in our institution with OS in the real-world as the main outcome, in addition to assessing quality of care. Results: Between 2016 and 2019, 317 patients with stage IV NSCLC were diagnosed, 260 without driver mutation and 189 of them received systemic treatment. We observed a higher proportion of stage IVB patients in 2018 and 2019 compared to 2016 and 2017. A progressive greater use of IO was observed, except for a small decrease in 2019 compared to 2018. At the date of analysis, 77.8% of patients had died. With a median follow-up of 40.8 months, we observed a gradual increase in OS, with medians of 12.3, 13.6, and 18.9 months for patients diagnosed in 2016, 2017, and 2018, respectively, with a decrease to 10.4 months for patients diagnosed in 2019. Survival rates over time show the same trend. IO (any line) was significantly associated with a reduced risk of death: HR 0.35 (95% CI: 0.23 - 0.58) in multivariate analysis. The deterioration of the results of the patients diagnosed in 2019 is manifested in the median survival and in the survival rates at different points from 6 months onwards, which should correspond to the excess mortality in the year 2020 in our studied population. Conclusions: Our study shows that IO reduced risk of death: HR 0.35 (95% CI: 0.23 - 0.58) in stage IV NSCLC, observing an increase in overall survival from a median of 12.3 to 18.9 months for patients diagnosed in 2016 and 2018, suggesting that the progressive use of IO for NSCLC in the years 2016, 2017 and 2018 has transferred the benefit observed in clinical trials to the general population. The deterioration of outcomes for patients diagnosed in 2019, with a median OS of 10.4 months and decreased survival at 6, 12 and 18 months, could suggest the negative impact and excess mortality in the pandemic year 2020.[Table: see text]

e18736 Background: Immunotherapy (IO) is increasingly widespread in current clinical practice; however, little is known about its cardiovascular safety profile. The aim of this study is to identify clinical factors that are associated with increased risk of having a cardiac event (CE). Methods: we conducted a retrospective study in a single institution including patients treated with IO from 2014 to 2020. We analyzed their clinical characteristics and the CE developed during IO treatment and compared those who had a registered CE with those who had not. Results: 378 patients were analyzed. After a mean-follow up 15.9 months, we registered the following CE: ECG abnormalities 12.2%, congestive heart failure 3.4%, pulmonary embolism 1.9%, coronary syndrome 0.8%, myocarditis 0.5% and pericarditis 0.5%. The specific cardiac mortality was 0.8%. Results are shown in Table. Conclusions: In our study, elder age, history of ischemic heart disease or arrythmia, and reporting other immune-related adverse events (irAE), appear to be risk factors for developing a CE during IO treatment. Although most are well-known cardiovascular risk factors, the relationship between other irAEs and CE should be highlighted, and prospective studies are needed to delve into this hypothesis.[Table: see text]

Background A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela) in combination with paclitaxel (PTX) versus PTX alone.1 Given that pela is an intravenously delivered immuno-oncolytic reovirus, we hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, we are conducting together with the SOLTI group the AWARE-1 study (a window-of-opportunity study of pela in early breast cancer), which is currently enrolling and for which initial translational research results are presented. Methods AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole; Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HER2+/HR+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HER2+/HR- (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score [2], a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, and changes to the TME are being assessed by immunohistochemistry and T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results Detailed TCR-seq results from peripheral blood and tumor tissue are presented for the ten-patients enrolled into Cohort 1 who received pela and letrozole. In tumor tissue, T cell clonality increased in day 21 biopsies relative to baseline biopsies, with similar increases in T cell fraction (the number of T cells) in the majority of patients. In general, most of the tissue-expanded T cell clones were also seen in the peripheral blood. Conclusions Overall, these preliminary data from cohort 1 of AWARE-1 demonstrate that pela mediates priming of a T cell-based immune response that occurs both systemically and within breast cancer tissue. Trial Registration NCT04102618 Ethics Approval This study was approved by the Spanish Health Authority, protocol number 2018-003345-42. References Bernstein V, et al. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213. Breast Cancer Res Treat 2018;167(2):485-493. Nuciforo P, et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol 2018;29(1):170-177.

This study compared the effects of two supervised concurrent training interventions in breast cancer survivors with cancer-related fatigue at baseline. Twenty-three female breast cancer survivors (50±8 years) were randomized to a high- (n=13) or a moderate-intensity (n=10) training program. Both interventions lasted 16 weeks and included the same resistance exercises, but the aerobic component was supervised and more intense in the former (i.e., rating of perceived exertion of 7–8 vs. 6 on a 1–10 scale for the high and moderate-intensity intervention, respectively). The primary endpoint was fatigue perception. Endpoints were assessed at baseline and after 16 weeks. The p-value for statistical significance was set at 0.004 after Bonferroni correction for multiple comparisons. The high-intensity training program increased lower-limb muscle strength significantly (p=0.002) and tended to improve fatigue perception (p=0.006), waist circumference (p=0.013), neutrophil-to-lymphocyte ratio (p=0.028) and some quality of life items (p=0.011). Although the moderate-intensity training program did not provide such benefits in general (i.e., higher p-values for pre vs post-intervention comparisons), no significant differences were found between interventions (all p>0.004). Further research is needed to elucidate if the benefits provided by high-intensity concurrent training are superior to those elicited by moderate-intensity training in breast cancer survivors.

Breast cancer (BC) survivors are becoming increasingly predisposed to cardiovascular disease (CVD) mortality. Low cardiorespiratory fitness and physical activity (PA) levels, as well as high values of adiposity indices, contribute to CVD risk. We evaluated adiposity, cardiorespiratory profile, and PA levels in two independent cohorts of BC survivors. Methods Data were collected from two groups (99% women) from different areas of Madrid (Spain): group 1, n = 110, age 51.4 ± 9.7 years, median time from diagnosis 365 days (95% confidence interval [CI], 354–401), and group 2, n = 93, age 54.7 ± 8.9 years, 1714 days (95% CI, 1502–1938). We estimated peak oxygen uptake (VO2peak) and measured body mass index (BMI), waist circumference (WC), waist-to-hip index, and accelerometry-determined PA. Results Both groups had values of BMI in the overweight range (25.3 ± 4.3 and 27.1 ± 5.1 kg/m2, p = 0.003). Estimated VO2peak levels were lower in group 2 than in group 1 (28.1 ± 9.1 and 23.7 ± 8.8 ml/kg/min, p

Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, and atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five patient cohorts are being examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole (without atezolizumab); Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HR+/HER2+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HR-neg/HER+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint is CelTIL score [2], a metric for quantifying changes in tumor cellularity and the number of tumor infiltrating lymphocytes (TILs), where an increase in CelTIL score has been associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, changes to the TME by immunohistochemistry (IHC), PD-L1 expression by the Ventana SP142 assay used as the atezolizumab companion diagnostic, and T cell clonality by T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results: Changes in the TME by IHC demonstrate that treatment with pela in the presence of atezolizumab increases the CD8/Treg ratio, a predictor of greater therapeutic efficacy, similar to preclinical breast cancer mouse models [3, 4]. Detailed TCR-seq, Ventana PD-L1 assay results, and IHC analysis will be presented, focusing on differences between patients receiving pela in the absence or presence of atezolizumab (Cohorts 1 and 2, respectively), and between CelTIL scores of responders and non-responders. Overall, these data demonstrate that pela can promote an inflamed tumor phenotype that allows for synergy with checkpoint blockade therapy in breast cancer. References: [1] Bernstein, V., et al. Breast Cancer Res Treat, 2018. 167(2): p. 485-493. [2] Nuciforo, P., et al. Ann Oncol, 2018. 29(1): p. 170-177. [3] Mostafa, A.A., et al. Cancers (Basel), 2018. 10(6). [4] Lee, J., et al. Cancer Research, 2020. 80(16 Supplement): p. 2206-2206. Citation Format: Luis Manso, Fernando Salvador, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan M. Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose L. Alonso, Alejandro Martínez, Rafael Villanueva, Juan A. Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca Gonzalez-Farre, Grey A. Wilkinson, Thomas C. Heineman, Gerard Nuovo, Houra Loghmani, Matt Coffey, Azucena Gonzalez, Débora Martínez, Laia Paré, Tomás Pascual, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT191.

e18751 Background: In the last years, Immunotherapy (IT) has emerged as a standard treatment in an increasing number of tumors. This type of treatment has a specific toxicity profile which is clearly different from chemotherapy, known as an Immuno-related Adverse Event (AEir). We know the data from clinical trials, but little about the incidence and impact of this EAir in our clinical practice. Methods: A retrospective observational study was carried out including all patients from our institution (HUPHM in Madrid) who had received IT, either in monotherapy or in combination between January 2014 and December 2019. A total of 279 patients were included and data were collected between January and July 2020, guaranteeing a minimum 6-month follow-up after receiving the first dose of immunotherapy. The toxicities found were classified into four categories: pulmonary, digestive, endocrine and others, and have been graded according to CTCEA v.5 (Common Terminology Criteria for Adverse Event) published in November 2017 and analyzed according to drug and tumor. Results: The most frequent diagnoses in our patients were: 60% lung carcinoma, 15% melanoma, 8% kidney carcinoma, and 6% bladder carcinoma. 76% of the patients received IT as first or second line in a metastatic context, 6% in the initial stage (clinical trials) and the rest in more advanced lines of treatment (3 or more). 67% received anti-PD1 drug, 6% anti-PDL1, 4% anti-CTL4 monotherapy, 10% a combination of several IT drugs, and 14% an IT combination and chemotherapy. 45% of the total presented EAir (16% grade I, 14% grade II, 11% grade III and 4% grade IV). 1/5 of the patients had manifestations in more than one organ. The incidence of the different toxicities in our population was listed in the table below. These patients reported 8% dermatological toxicities, 6% had renal toxicity (most of them grade III or IV), only 2% had arthralgia or myalgia, and 3% asthenia. Combined IT treatment had significantly higher rates of pneumonitis, colitis, and endocrine toxicities. These differences were not observed between the monotherapy treatment and the combination of immunotherapy plus chemotherapy. Conclusions: Immunotherapy has represented an important advance in oncology, achieving long survivals in a growing group of tumors. Immunotherapy has a unique toxicity profile that is very different from chemotherapy and with which we must become familiar. Most of the adverse events are mild and if they are diagnosed early and with the appropriate treatment, maintenance of IT is possible. Severe toxicity (III-IV) means in most cases the suspension of treatment, compromising its efficacy. Therefore, we must learn to recognize these toxicities early and apply the recommended treatments as soon as possible.[Table: see text]

12027 Background: Cancer patients increasingly present an advanced age at diagnosis; 50% of the new cases are over 65 years old, being underrepresented in clinical trials. The safety of immunotherapy has not been adequately evaluated in the subgroup of elderly patient. In this population, with more comorbidities, adverse events may be less well tolerated and have more serious consequences. Methods: A retrospective observational study was developed, including all patients treated with immunotherapy at our center between January 2015 to February 2020. Of the total (279 patients), the analysis was performed with the 105 patients ≥65 years of age who had received at least one cycle (in routine clinical practice or within an unblinded clinical trial). All clinical and radiological data of the patients were collected. Results: From the total, the majority had a lung carcinoma or melanoma, treated with nivolumab or pembrolizumab either in first or second line. 63% had died at the time of the analysis. The frequency of toxicities: digestive (15%), pneumonitis (12%) and endocrine (9%). We divided the population into 65-75 years (76 patients) or > 75 years (29 patients), analyzing the frequency of toxicity and deaths secondary to it. Those > 75 years had more digestive toxicity (25% vs 11%), but less pneumonitis (3% vs 15%). There were 7 deaths (6%) related to treatment: 2 patients with ipilimumab-nivolumab (28%), 2 nivolumab (28%), 2 pembrolizumab (28%), and 1 ipilimumab (16%). 5 patients were > 75 years old (median 78 years) presenting a higher mortality rate in relation to toxicity (4% vs 20%, p 0.02) and a worse median survival (29 vs 23 months). The fatal toxicities were: 3 neurological (2 meningoencephalitis and 1 acute diffuse axonal denervation), 2 hepatic, 1 hemophagocytic syndrome and 1 myocarditis. Conclusions: The most frequent toxicity was digestive, but those that led to death were neurological, hepatic, hematological and cardiac. In our series, neurological and cardiac adverse events accounted for 57% of immunotherapy deaths in older patients. Our data warn that patients over 75 years have a higher risk of death from immune-mediated events. In addition, these would be mainly neurological and cardiac, which represents a diagnostic and treatment challenge for oncologists.[Table: see text]

e13527 Background: The SARS-CoV-2 (COVID19) pandemic has had a huge impact on health care, leading to the declaration of a “state of alarm” in many countries. This situation has possibly conditioned the care of cancer patients, compromising hospitalization resources due to healthcare restraints. We aim to analyze the impact of the COVID19 pandemic on the hospitalization of cancer patients during the “state of alarm” in an Academic Hospital in Madrid, considered one of the most affected regions in the World during the first wave of the pandemic in Europe. Methods: Quasi-experimental study with similar controls collected in the same period of the previous year from cancer patients admitted to the Medical Oncology (MO) department of the Puerta de Hierro University Hospital in Madrid. Patients were selected from diagnoses coded by the ICD-10 obtained from discharge reports in the Admission Department. Cancer and viral pneumonia codes (excluding influenza) were analyzed. Admission to Internal Medicine (IM) department was also explored to describe hospitalization due to COVID19 pneumonia. We defined two groups: pandemic (03/14/20 - 06/20/20) and control (pre-pandemic) (03/14/19 - 06/20/19). Results: 74 cancer patients were admitted to MO department in 2020, while 162 admissions were recorded for the equivalent period in 2019 (- 54%). No differences were observed related to sex and age. In 2020, emergency and programmed admissions decreased by the same proportion, and no difference in mortality was observed. Admissions for all neoplasms decreased, but with higher magnitude in breast cancer. Viral pneumonia (no influenza) in cancer patients were mostly admitted to IM (96%) rather than MO department. 79 cases were identified in 2020, 22 in 2019 (p < 0.001), with a non-significant increase in mortality in patients with pneumonia: 25,3% in 2020 and 13,6% in 2019. Conclusions: The COVID 19 pandemic seriously impacted cancer hospitalization care, decreasing admissions to the MO department in half compared to the equivalent period. We observed a reduction in admissions through all neoplasias. Admissions due to viral pneumonia in cancer patients increased 3.5 times, mostly admitted to IM changing the dynamics of cancer hospitalization burden and compromising resources. A non-significant increase in mortality from viral pneumonia was observed. The analysis of hospitalizations through administrative data can allow better management of resources and facilitate rapid decision-making in a pandemic situation yet to be resolved.[Table: see text]

Survival rates in patients with stage IIIA non-small cell lung cancer (NSCLC) remain low despite curative treatment. This is due to tumor recurrence at distant sites. The aim of neoadjuvant chemotherapy (NA-CT) is to eradicate occult micrometastatic disease and improve survival in patients that are not candidates for surgery following induction therapy. A total of 21 patients with ipsilateral mediastinal node involvement (N2) with potentially resectable disease, who had been diagnosed with stage IIIA (T1-3 N1-2 and T4N0) NSCLC and who had received cisplatin and vinorelbine as induction treatment were included in this retrospective study. Patients who responded to the treatment underwent surgery, and those who were unresponsive received radical radiotherapy. Follow-up was conducted between March 2008 and April 2014. The median age of patients was 61 years, and all patients exhibited a good Eastern Cooperative Oncology Group performance status. The majority of patients were histologically diagnosed with adenocarcinoma (48%) or squamous cell carcinoma (38%), which was a poor prognostic factor for overall survival (OS). A total of 7 patients underwent surgery (of which 6 were down-staged), with a 3-year survival rate of 42.8%. The most significant factor associated with response to induction treatment was multistation nodal involvement. The complete resection rate for surgical patients was 85.7%. Unresectable patients had a 3-year survival rate of 25.8%. OS time for the whole cohort was 28.5 months, and the 3- and 5-year OS rates were 28.5% and 4.7%, respectively. CT-induced toxicity did not affect any treatment regime or surgical procedures. In conclusion, the use of cisplatin plus vinorelbine is feasible in a neoadjuvant setting, with good response rates and acceptable toxicity. Multistation N2 involvement is the main prognostic factor for a poor response to induction treatment.

Bone metastasis is the most common cause of cancer-related pain, and metastatic bone pain (MBP) is not only severe but also progressive in many patients. The aim of this study was to investigate the association between pain management and performance status in patients with metastatic bone cancer in the Spanish clinical setting. A 3-month follow-up prospective, epidemiologic, multicenter study was conducted in 579 patients to assess the evolution of their performance, the impact of pain control on sleep and functionality, and the degree of pain control according to analgesic treatment. In patients with MBP, Eastern Cooperative Oncology Group (ECOG) status (1.5 ± 0.7–1.3 ± 0.7 and 1.3 ± 0.8; p

Background: The addition of H to chemotherapy improved disease outcome in HER2+ MBC. The combination of H and L with chemotherapy improved event free survival (EFS) in the neo-adjuvant setting but not in the adjuvant setting. However, improved EFS did not translate to overall survival benefit. This international trial (ICORG (CTRIAL-IE) 11-10/NCT01526369) compared the efficacy of TH vs. THL in first line treatment of HER2+ MBC. The primary aim of this study was to assess any benefit for the addition of L to TH in an advanced HER2+ breast cancer patient population. Target accrual was not met due to changes to standard of care mid-study. Methods: Patients (Pts) (n= 75 enrolled, randomized 1:1) received weekly T (80mg/m², for 3 weeks of a 4 week cycle) + H (8mg/kg loading dose on cycle 1 day 1 and 4mg/kg every 2 weeks) + L (1,000 mg daily)) until disease progression, unacceptable toxicity or consent withdrawal. The primary outcome measure was progression free survival (PFS). Secondary outcome measure was overall survival (OS). Eligibility criteria included: Female > 18 years, invasive MBC, measurable disease by RECIST criteria V1.1, HER2+ by testing of the primary tumour and if available the biopsied metastatic lesion. No prior systemic therapy for metastatic disease (except one line of hormonal therapy for metastatic disease without H). No recurrence within 12 months (mo) from completion of adjuvant chemotherapy to the development of metastatic disease. No recurrence within 6 mo from completion of adjuvant H to the development of metastatic disease and no prior L treatment. Results: Of the 75 pts enrolled, n=65 (TH n=34, THL n=31) were included in the PFS analysis. Median PFS (95% CI) was numerically higher, but not statistically significant, in THL (24.0 mo (9.5, 34.5)) vs TH (19.3 mo (8.7, 22.7)), HR 0.827, p= 0.601. For OS analysis, n=69 (TH n=35 and THL n=34) were included. 41/69 (59.4%) had no prior therapy. No statistically significant, clinically meaningful improvement in OS (Median (95% CI)) was observed (TH 53.8 mo (41.8, -) vs. THL 45.6 mo (29.7, -), HR 1.048, p=0.891). Analysis of the safety set (n=70 (TH n= 36, THL n=34)) revealed a higher incidence of Grade 3/4 AEs in THL (61.8%) vs. TH (50%), p=0.322. There were 2 on-treatment fatalities due to adverse events (AEs) in the THL arm, one due to respiratory failure, the other due to central nervous system metastasis. There were no on-treatment fatalities in the TH arm. GI disorders were the most prevalent AE, with the incidence of diarrhea significantly higher in the THL arm (88% vs. 42%, p Citation Format: John Crown, William Jacot, Denis M. Collins, Linda Coate, Anna Saetersdal, M John Kennedy, Catherine Kelly, Blanca Cantos Sanchez De Ibarguen, Raquel Andrés Conejero, Luis Costa, Margarida Brito, Maccon Keane, Pedro Sanchez Rovira, Miguel Martin, Miriam O'Connor, Manuel Ramos Vazquez, Elena Alvarez, Seamus O'Reilly, Johanna Mattson, Laura Jolis Lopez, Alvaro Rodriguez Lescure, Esperanza Blanco, Coralia Bueno Muino, Brian Moulton, Norma O'Donovan, Andres Hernando, Marc Nolan, Imelda Parker, Giuseppe Gullo, Bryan Hennessy. A phase III randomized study of paclitaxel (T) and trastuzumab (H) versus T, H and lapatinib (L) in first line treatment of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT212.

e24087 Background: Fatigue is one of the most distressing symptoms among breast cancer survivors (BCS) after finishing their treatment. Besides cancer-related factors, fatigue may be influenced by socio-demographic, physical, medical, psychological and behavioural variables. Exercise is recommended to manage CRF. Methods: PH-UEM02 and PH-UEM06 were prospective observational studies in BCS after finishing their treatments. Fatigue was evaluated through the Perform Questionnaire (12-60, being 60 no fatigue). Anthropometry, physical condition (PC) and physical activity (PA) were objectively evaluated. One-mile walk test (MWT), handgrip and sit to stand were used to assess PC. PA was measured by using accelerometers. Clinical data (treatments) were obtained from the clinical record. Socio-economic, diet (PREDIMED questionnaire) and QoL (EORTC QLQ-C30) were reported by BCS. Results: 201 BCS were recruited (age 51±9, BMI 25.9±4, median time from diagnosis 22 months). 73% had been treated with chemo, 66% anthracyclines, 20% trastuzumab, 66% radiotherapy, 81% hormone (24% aromatase inhibitors). Mean PERFORM score (45.6/60). Adherence to Mediterranean diet (9.1/14). EORTC Global score (68.9/100). No association with age, socio-economic or marital status, previous chemo, anthracyclines or radiotherapy, WPA, estimated VO2max, handgrip, sit to stand or PREDIMED score was found. Weight, trastuzumab and MWT time were positively associated with fatigue (2MAX or muscular strength were associated with fatigue. 3. Regarding previous treatments, only trastuzumab was associated with CRF. 4. Interestingly heart rate (both basal and recovery) and nut intake were strongly associated with CRF. 5. More research is warranted in heart rate variability and potential related biomarkers. [Table: see text]

Background: Efficacy Interim results from PATRICIA phase II trial in HER2+/HR+ advanced breast cancer (BC) showed that PAM50 luminal disease was associated with larger and clinically meaningful progression-free survival (PFS) following palbociclib, trastuzumab and endocrine therapy compared to PAM50 non-luminal disease (Ciruelos E. et al, SABCS 2018). Based on these preliminary results, PATRICIA II was designed to select patients based on PAM50 and to include a randomization to a control arm. Trial Design: PATRICIA II is a randomized open-label, adaptive design, phase II study. Eligible patients must have centrally confirmed HR+/HER2+ and PAM50 Luminal A or B intrinsic subtype tumors and have received at least 1 (and no more than 4) prior lines of anti-HER2 regimens for locally advanced or metastatic BC, including a taxane and trastuzumab. Patients are randomized 1:1 to receive trastuzumab in combination with palbociclib at a standard dose of 125 mg/day orally 3 weeks on/1 week off and endocrine therapy (cohort C1) or treatment of physician’s choice (TPC): TDM1 or chemotherapy (gemcitabine, vinorelbine, capecitabine, eribulin, paclitaxel or docetaxel) in combination with trastuzumab (cohort C2). ET options are either an aromatase inhibitor, fulvestrant or tamoxifen. Premenopausal patients (pts) must receive ovarian suppression. Stratification factors include number of previous regimens for advanced BC (1-2 vs 3-4) and the presence of visceral disease (yes vs no). The primary objective is to assess whether the combination of palbociclib, trastuzumab and endocrine therapy is superior to TPC in terms of progression-free survival (PFS) in HER2+, PAM50 Luminal patients. The study has an 80% power with two-sided alpha=0.05 to detect a hazard ratio of 0.62 in favor of the palbociclib arm. An adaptive design will be used to compare both treatment arms. An interim analysis (IA) adjusted for multiplicity from O’Brien-Fleming method and an estimation of the conditional power (CP) will be performed at 70% of the events by an Independent Data Monitoring Committee (IDMC). Key secondary objectives are response rate, overall survival, safety, and Quality of Life. Tumor tissue and blood samples will be collected for biomarker analyses. A total of 516 patients will be screened and 232 patients will be recruited. The trial was activated in June 2019 and the recruitment is ongoing in 20 sites in Spain. The study is sponsored by SOLTI and financially supported by Pfizer. Citation Format: Eva Ciruelos, Patricia Villagrasa, Mafalda Oliveira, Sonia Pernas, Javier Cortes, Silvia Vazquez, Noelia Martínez, Antonia Perello, Begoña Bermejo, Eduardo Martínez, Isabel Garau, Mireia Melé, Alvaro Montaño, Estela Vega, Blanca Cantos, María Jose Echarri, Tomás Pascual, Jordi Canes, Pamela Céliz, Xavier González, Aleix Prat. Palbociclib in combination with trastuzumab and endocrine therapy (ET) versus treatment of physician's choice (TPC) in metastatic HER2-positive and hormone receptor-positive (HER2+/HR+) breast cancer with PAM50 luminal intrinsic subtype (SOLTI-1303 PATRICIA II): A multi-center, randomized, open-label, phase II trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-06.

Background In Spain luminal metastatic Breast Cancer accounts for more than 3000 deaths yearly. Ribociclib+letrozole has shown efficacy on prolonging progression free survival (PFS) vs placebo+letrozol in two phase 3 trials. However, data on efficacy and tolerability is lacking for a broader population. We present interim data from CompLEEment-1, an ongoing, open-label, phase 3b trial evaluating ribociclib+letrozole as first-line endocrine therapy in an expanded population of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Methods Patients treated with ≤1 line of prior chemotherapy and no prior endocrine therapy for advanced disease received ribociclib 600 mg/day (3-weeks-on/1week-off) + letrozole (2.5 mg/day; plus monthly goserelin or leuprolide in men and premenopausal women). The primary objective was safety and tolerability. Here we report a sub-analysis of CompLEEment-1 for the Spanish population. Results 526 patients were evaluated over a median follow-up of 10.3 months. Baseline characteristics indicated a diverse population with median age of 55.6 years (range 24-85); 0.8% of patients were male, 34.6% female pre-menopausal and 64.6% female post-menopausal. 71% had visceral metastasis, in 8 cases at the CNS. 55.9% had measurable disease at baseline. The rate of all-grade and grade ≥ 3 treatment-related adverse events (AEs) was 98.5% and 70.0%, respectively. Treatment-related serious AEs occurred in 12.2% of patients. All-grade and grade ≥ 3 AEs leading to ribociclib discontinuation occurred in 13.7% and 8.2% of patients, respectively. Rates of ≥ 3 AEs of special interest (AESI) were 59.5% for neutropenia, 6.8% for increased alanine aminotransferase, 4.8% for increased aspartate aminotransferase, and 0.6% for QTcF prolongation. Patient health-related quality of life was maintained versus baseline. Conclusions Initial results from the Spanish cohort in CompLEEment-1 are consistent with previous data showing efficacy and a manageable safety profile of ribociclib plus letrozole as a first-line treatment option in a diverse group of patients with HR+, HER2– ABC. Acknowledgement: Dr. J. Gavila-Gregori, Dr. M.J. Martinez-Serrano and Dr. M. Perello contributed equally to this study. Clinical trial identification NCT02941926. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure E.M. Ciruelos: Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Pfizer. R. Villanueva Vazquez: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche. F. Moreno: Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. I. Alvarez: Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. S. Gonzalez-Santiago: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): AstraZeneca. A. Barnadas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Genomic Health; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre. B. Cantos: Research grant / Funding (institution), Study enrollment: Fundacion para la Investigacion del Hospital Puerta de Hierro de Majadahonda; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy: AstraZeneca. M. Bellet Ezquerra: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly. M. Martin: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Taiho Oncology; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Puma. N. Martinez: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Palliative care units (PCU) have shown an improvement in the quality of life of patients with cancer by reducing overtreatments at the end of life and increasing symptomatic care at home, avoiding unnecessary emergency room visits and decreasing the number of hospital admissions. Methods A retrospective observational study was conducted, selecting all patients with a first consultation in the Medical Oncology Unit of the Puerta de Hierro University Hospital (HUPdH) between 2014 and 2015 and died before December 31st 2017. Assessment by PCU, number of hospital admissions and re-admissions and most frequent symptoms for admission in the last 6 months of life were reviewed. The main objective was to know if there were differences between those who were valued by PCU or not. Results A total of 662 patients were selected. From them, 86 (13%) patients had never been admitted at HUPdH, 312 (47%) had been admitted once, 169 (26%) twice and 95 (14%) three or more times. Before death, 474 (72%) had been valued by PCU and 302 did not received PCU visit before the second hospital admission episode. The three most frequent causes of admission were deterioration of the general condition, infections and uncontrollable pain. In those with an assessment by PCU before the second admission process, there was a significant decrease in the number of readmissions (25% versus 68%). Moreover, in these patients, there was a statistically significant decrease in the number of re-admissions because of the three main causes of admission but also in others, such as dyspnea, neurological worsening, bleeding and nauseas and vomiting. (Table). Table . 1606P PCU: Percentage of patients re-admitted with an assessment by palliative care unit by the time of re-admission; Non PCU: Percentage of patients re-admitted without assessment by palliative care units before re-admission Symptom PCU Non PCU Risk Ratio Deterioration of the general condition 9% 21% RR 0.41, 95% CI 0.27-061, p Dyspnea 3% 13% RR 0.24, 95% CI 0.12-0.45, p Neurological worsening 2% 8% RR 0.25, 95% CI 0.11-0.56, p Infections 5% 24% RR 0.20, 95% CI 0.12-0.32, p Uncontrollable pain 5% 15% RR 0.35, 95% CI 0.21-0.59, p Nauseas and vomiting 2% 7% RR 0.32, 95% CI 0.14-0.71, p Bleeding 2% 7% RR 0.34, 95% CI 0.15-0.75%, p Conclusions In our cohort, in patients with an assessment by PCU before the second admission episode, was observed a decrease in number and severity of re-admissions. An optimization of the symptomatic treatment at home implies a decrease in hospital-acquired or nosocomial complications which leads to a reduction in costs and above all, an improvement in the quality life both of patients and their families. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Lung cancer is the most common cancer in the world. 15 % of all patients with lung cancer are diagnosed at an early stage, and surgery is the treatment of choice for them. 40 % of all patients survive more than 5 years after surgery, and most of them die as a result of systemic disease. Half of all recurrences are diagnosed within the first 24 months after curative treatment, and 90 % in the first 5 years. Despite this, it is not standardized who should do the monitoring, what additional tests are needed and how often should they be performed. We present here a review on the various recommendations in clinical guidelines.

Resumen Introduccion La afectacion del intestino delgado por Clostridium difficile constituye una entidad clinica infrecuente. Metodo Se presenta el primer caso de enteritis por C. difficile diagnosticado en Espana y se realiza una revision de la literatura medica. Resultados Varon de 30 anos de edad intervenido por recidiva de un tumor germinal retroperitoneal. Siete dias despues presento vomitos, diarrea y, finalmente, obstruccion intestinal por seudomembranas originadas por enteritis por C. difficile. En la literatura medica han sido descritos otros 57 casos de enteritis por C. difficile. La edad media era de 52 ± 17 anos con un rango desde 18 a 86 anos. Veintinueve pacientes (50%) presentaban enfermedad inflamatoria intestinal. Cuarenta y siete (81%) tenian antecedentes de cirugia de colon o intestino delgado. La mortalidad fue mas acusada en pacientes de mayor edad y en los que no presentaban enfermedad inflamatoria intestinal. Conclusion La enteritis por C. difficile se caracteriza por su elevada gravedad y mortalidad.

Positron emission tomography with 2-((18)F)-fluoro- 2-deoxy-D-glucose (FDG-PET) is a metabolic imaging technique. FDG-PET is more accurate than CT for the evaluation of mediastinal involvement in patients with nonsmall- cell lung cancer, offering a high negative predictive value. It can detect occult metastases in 11% of patients, although the etiology of the extrathoracic isolated uptakes needs confirmation. Theoretically, FDG-PET can influence the planning volume for radiotherapy, primarily in patients with atelectasis. Quantification of metabolic activity using FDG-PET is influenced by the size of the lesion, glucose levels and the time elapsed since the isotope injection. More clinical trials are required to standardize the methods for performing PET, assess its use as a prognostic factor and for the evaluation of treatment response.

Central nervous system involvement in Hodgkin´s lymphoma is extremely rare. We report three cases who had a relapse from the disease involving CNS. The most frequent causes are skull contiguity, meningeal invasion and via the hematogenous route. It is frequent that the association between Epstein–Barr Virus and Hodgkin´s lymphoma, and a biopsy for confirmation, is always required. Diagnostic imaging tests like CT and MRI are useful. The standard treatment remains holocraneal radiotherapy combined with chemotherapy.

Survival in Hodgkin lymphoma (HL) has significantly increased, and most relapses occur in the first 2 years. We analyzed the proportion of relapses occurring after 5 years, the method of detection, and survival in the database of patients with HL in our hospital (1967-2005). We undertook a retrospective study of clinical and molecular characteristics with the use of 12 different antibodies (Abs): CD30, CD15, CD20, CD3, BCL-2, BCL-6, CD57, EMA, p53, Ki-67, Aurora kinase A, and PAX-5. We studied 534 patients with HD and found 150 relapses (28%), 30 of which occurred 5 years after the end of treatment. The relapses were detected during a scheduled appointment in 16 (54%) asymptomatic patients. Seven of 30 patients relapsed with a different histological type. There were no statistically significant differences in survival between those patients with a late relapse and new remission and those who never relapsed. None of the molecular markers were associated with relapse. Long-term survival was not significantly different in relapsed patients with remission after treatment compared with patients who never relapsed. We need to maintain active follow-up in order to detect late and recoverable relapses.

Purpose: Hodgkin's disease is considered a model of curable illness. However, long-term studies show excessive mortality in relation to the general population. We studied the various causes of death by use of competing risks and their evolution over the years. Experimental Design: All patients diagnosed with Hodgkin's disease at our institution between 1967 and 2003 were included. The competing risks of causes of death and their vital situation were examined in three time periods: cohort A with patients treated before 1980, cohort B with patients treated from 1981 to 1986, and cohort C with patients treated from 1986 onwards. Results: We studied 534 patients, with a median follow-up time of 9.1 years for the whole cohort. The 5-year, 15-year, and 20-year Kaplan-Meier survival estimates for all patients were 81%, 72%, and 65%, respectively. At the close of the study, 337 (63.1%) were alive and 170 (31.8%) patients had died. The most common cause of death was the progression of Hodgkin's disease, followed by deaths due to a second tumor. Survival was significantly worse in the first period than in the other two (P < 0.001), and in the three periods, the main cause of death was tumor progression. Conclusions: The progression of Hodgkin's disease is the main cause of death. Over time, a reduction in death related to infection and the acute toxicity of treatment was seen. A lot of patients still die for reasons linked to delayed side effects of radiotherapy, such as second tumors and heart disease, which is important to plan preventive activities and clinical research.

Filgrastim is a granulocyte colony-stimulating factor commonly used in the prophylaxis and treatment of neutropenia associated with chemotherapy in cancer patients. It is a well-tolerated and safe drug but some unusual serious adverse effects may occur. We expose a case of a 37-year-old woman who was hospitalized with severe pancitopenia after the first cycle of chemotherapy with a cisplatin doublet and bevacizumab. Filgrastim was administered for 3 days with the aim of increasing neutrophils and not delay the next chemotherapy cycle. Due to acute respiratory failure she was transferred to the Intensive Care Unit for symptomatic control where required oxygen therapy. Fungal and bacterial culture were made and so blood serologies, all of them were negative. It was diagnosed as pneumonitis secondary to a probable side effect of filgrastim. Although the case was resolved properly it is important monitor the administration of filgrastim because of the severity of these events.

To evaluate the risk factors associated with lung cancer (LC) and other second neoplasms (SN) in Hodgkin lymphoma (HL) survivors. We retrospectively analyzed the clinical characteristics and outcomes of 604 patients treated in our institution between 1968 and 2012. 90 out of 604 patients developed SN: 27 LC and 63 other SN. The median time elapsed until LC and other SN was 16.5 and 11.8 years, respectively (p = 0.003). In the LC group, 85.5 % of patients were male and 84.6 % smokers (HR 7, 95 % CI 2.4–20.7, p

About 25-50% of women with Cowden disease, a syndrome associated with germ-line mutations of the PTEN gene (at 10q23), develop breast cancer (BC), but PTEN mutations have been found in only 5% of sporadic BCs. However, 29-48% of BCs display loss of heterozygosity in 10q23, and about 40% of BCs show a decrease or absence of PTEN protein levels at the time of diagnosis. Promoter hypermethylation has been identified as an alternative mechanism of tumor-suppressor gene inactivation, but its importance in PTEN silencing in sporadic BC is unknown. We investigated PTEN promoter hypermethylation in 90 sporadic BCs and its correlations with 11 molecular and pathologic parameters, including mRNA levels of PTEN. The study, a methylation-specific PCR assay, was carried out with methylated specific primers designed in a region with scarce homology with the psiPTEN pseudogene. Expression was analyzed by real-time PCR. We found that the PTEN promoter was hypermethylated in 43 BCs (48%). PTEN hypermethylation was associated with ERBB2 overexpression, larger size, and higher histologic grade (P=0.012, 0.03, and 0.009, respectively). We concluded that PTEN promoter hypermethylation is a common event in sporadic BC, correlating with other well-established prognostic factors of this malignancy. Additionally, PTEN mRNA expression was lower in tumors with aberrant methylation.

The INK4a/ARF locus encodes two tumour suppressor proteins, p16INK4a and p14ARF, which act in the two main cell-cycle control pathways, p16-Rb and p14-p53 respectively. The present study examined the mRNA expression of these genes by reverse transcription-polymerase chain reaction (RT-PCR), and the inactivation mechanisms that alter these levels, in 100 primary breast carcinomas. Furthermore, the interdependence of these mechanisms was examined, since it has been reported that p14ARF is altered in most tumours in concordance with p16INK4a. The results show that promoter hypermethylation, tested by methylation-specific PCR (MSP), was the major mechanism of inactivation of these genes and was present in 31 (31%) and 50 (50%) of the tumours that showed decreased p16INK4a and p14ARF expression, respectively. Hemizygous deletion was the second cause of down-regulation. Homozygous deletion was rare and mutation was absent. In most tumours overexpressing p16INK4a or p14ARF, no detectable inactivation mechanisms were observed. Finally, the results indicate that these proteins are often co-altered in primary breast tumours and that p16INK4a and p14ARF had non-independent behaviour, since they were silenced or overexpressed concomitantly with a significant correlation (p < 0.05).

The treatment of choice for patients with early stage Hodgkin's disease (HD) has been extended field or subtotal nodal irradiation. Remission rates of over 95% have been obtained, however, about 5% of stage I and II patients will suffer from progressive disease while on therapy and an additional 15-20% will relapse. Chemotherapy (Ch) alone has not been adequately tested in early-stage HD. In this study, all HD stage I and II patients treated with Ch alone in the University Hospital "Clínica Puerta de Hierro" between 1980 and 1997 were reviewed. Thirty-five patients were treated between 04/80 and 12/97. All patients achieved complete remission. The median follow-up was 119 months (range 21-240 months), no patients were lost at follow-up. Overall survival (OS) was 97% (IC 95%, 92-100) at 5 years and 88% (IC 95%, 75-100) at 10 years. Failure free survival (FFS) was 93% (IC 95%, 83-100) at 5 years and 66% (IC 95%, 47-86) at 10 years. Three (8.5%) patients died: two due to a second tumour (non-Hodgkin's lymphoma and myeloid acute leukaemia) and the other due to sepsis post-Ch. Univariate and multivariate analysis only associated histology subtype relative risk (RR) 4.0 nodular sclerosis (95% IC, 1.0-5.5; p:0.02) with higher relapse. Other prognostic factors did not reveal significant differences with respect to failure free or OS. In conclusion, we believe that death from HD in early-stage patients is unusual and mortality from causes other than HD occurs many years later. Outside clinical trials due to the lack of clear prognostic factors, with the exception of specific situations, patients should be informed of all the possible alternatives as well as the consequences of the treatments employed. In our experience, it appears that using Ch alone in the initial stages does not jeopardize overall patient survival, with similar results being achieved.