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Checkpoint inhibitors are being added to standard-of-care chemotherapy in multiple clinical trials. Success has been reported in non–small and small cell lung carcinomas and urothelial, head and neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosuppressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemoimmunotherapy include neoadjuvant and adjuvant schemes.Significance: Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immunotherapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.

Background Anthracycline-based cancer chemotherapy (ACC) has been related to myocardial interstitial fibrosis (MIF), a lesion contributing to left ventricular dysfunction (LVD). We investigated whether biomarker-assessed MIF was associated with LVD in patients with breast cancer receiving ACC and in patients with ACC-induced heart failure (ACC-HF). Moreover, chemotherapy agent’s pro-fibrotic activity was evaluated in human cardiac fibroblasts (HCFs). Methods Echocardiography, serum biomarkers of collagen deposition (procollagen type-I C-terminal-propeptide [PICP]) and crosslinking (collagen type-I C-terminal-telopeptide/matrix metalloproteinase-1 ratio), and biomarkers of myocardial and vascular stress (galectin-3, sST2, amino-terminal pro-brain natriuretic peptide [NT-proBNP], hs-troponin-T and vascular cell adhesion molecule-1 [VCAM-1]) were assessed in 70 breast cancer patients at baseline, and during ACC at 3 and 6 months. Subclinical cardiotoxicity was defined as a global longitudinal strain (GLS) relative reduction>15%. In addition, PICP and NT-proBNP were determined in 347 patients with different HF etiologies, 37 with ACC-HF of whom 33 had 12-month-follow-up LVEF assessment. HCF activation was examined after incubation with chemotherapy agents for 24 hours. Results In breast cancer patients, six-months-ACC reduced GLS and upregulated PICP, hs-troponin-T, NT-proBNP and VCAM-1 (PP for interactionPrd tertile) but improved in the remaining patients (PConclusion These results indicate that increased levels of PICP, a biomarker related to MIF, are associated with early LVD in ACC-treated patients with breast cancer and with established LVD in ACC-HF patients, hindering LV functional improvement after 12 months. Chemotherapy can directly activate collagen metabolism and increase PICP extracellular presence in HCFs. Therefore, PICP emerges as a promising biomarker of ACC-induced cardiotoxicity.

Objectives This study examined whether palbociclib and cetuximab prolonged overall survival (OS) versus placebo and cetuximab. Materials and methods In this double-blind, randomized, phase 2 trial (PALATINUS), patients with platinum-resistant, cetuximab-naive, human papillomavirus-unrelated recurrent/metastatic head and neck squamous-cell carcinoma received cetuximab and either palbociclib (arm A) or placebo (arm B). The primary endpoint was OS; 120 patients were required to have ≥80% power to detect a hazard ratio (HR) of 0.6 (median OS of 10 months in arm A and 6 months in arm B) using a one-sided, log-rank test (P = 0.10). Results 125 patients were randomized (arm A: 65, arm B: 60). Median follow-up was 15.9 months (IQR, 11.3–22.7). Median OS was 9.7 months in arm A and 7.8 months in arm B (HR, 0.82; 95% CI, 0.54–1.25; P = 0.18). Median progression-free survival was 3.9 months in arm A and 4.6 months in arm B (HR, 1.00; 95% CI, 0.67–1.5; P = 0.50). The most common treatment-related adverse events in arm A were rash (39 patients, 60.9%) and neutropenia (26, 40.6%; three febrile) and in arm B was rash (32, 53.3%). Conclusion There was no significant difference in median OS with palbociclib and cetuximab versus placebo and cetuximab. Funding Pfizer Inc (NCT02499120).

Background The differential diagnosis between multiple primary lung cancer (MPLC) and advanced lung cancer has traditionally relied on conventional radiology and pathology. However, the outcomes of traditional diagnostic workup are often limited, and staging is uncertain. Increasing evidence suggests that next-generation sequencing (NGS) techniques offer the possibility of comparing multiple tumors on a genomic level. Objectives The objective of this study is to assess the clinical impact utility of targeted sequencing in patients presenting with multiple synchronous or metachronous lung tumors. Materials and methods We describe the diagnostic workup conducted in a patient with three lung tumors, where we used a targeted 50-gene DNA sequencing panel (Ion AmpliSeq TM Cancer Hotspot Panel v2) to assess clonality and establish an accurate lung adenocarcinoma stage. Positive results were confirmed by pyrosequencing or Sanger sequencing. Results Three surgically resected lung tumors were submitted for targeted sequencing. The tumor from the upper right lobe was positive for a TP53 c.659A > G mutation and native for KRAS. The tumor from the upper left lobe was positive for TP53 c.725G > T and KRAS c.35G > T mutations. The tumor from the lower left lobe was positive for TP53 c.1024C > T and KRAS C.34G > T mutations. Results and reviewed literature in the field support the diagnosis of MPLC instead of a single advanced lung cancer. Conclusion Targeted DNA sequencing significantly increases diagnostic accuracy in patients with multiple lung tumors. NGS panels should be available for patients presenting with multiple lung tumors.

The combination of Pegylated Liposomal Doxorubicin (PLD) plus Gemcitabine (GEM) has been previously investigated in the treatment of metastatic breast cancer (MBC). PLD is a doxorubicin formulation with prolonged circulation time and better tissue distribution. GEM is a nucleoside analog with nonoverlapping toxicity compared to PLD. The aim of our study was to assess efficacy, toxicity, and long-term outcome of this combination. Patients with heavily treated MBC were retrospectively analyzed. Chemotherapy consisted of PLD 25 mg/m2 and GEM 800 mg/m2 day 1, on a three-week schedule. Cardiac function was evaluated baseline and during treatment. Radiological response was graded according to RECIST criteria v1.1. Toxicity was scored according to CTCAE v4.0. Progression-free survival (PFS) and overall survival (OS) were evaluated. From 2001 to 2014, 122 pts were included. Median age was 55 (range: 28-84). Median previous treatment schedules in the metastatic scenario were 3 (range: 1-15). Most patients received prior anthracyclines (85%). Median number of metastatic sites was 2 (range: 1-7). Median number of cycles delivered was 5 (range: 1-36). Overall response rate was 31% (5% complete responses; 26% partial responses). Stable and progressive diseases were observed in 32% and 26% of patients. Grade ≥3 neutropenia was observed in 29 patients (24%). Grade ≥3 hand-foot syndrome was detected in 17 patients (14%), mostly since cycle 3 (88%). Median cumulative PLD dose was 125 mg/m2 . At a median follow-up of 101 months, median PFS and OS were 7 and 22 months, respectively. PLD-GEM combination achieves remarkable long-term outcomes with an acceptable toxicity profile in patients with MBC.

Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro. Genetic loss of Id1 in the host tissue (Id1(-/-) mice) impaired liver colonization and increased survival of Id1 animals. Histologically, the presence of Idl in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1(+/+) mice and Idl(-/-) mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Idl significantly correlated with vimentin and other EMT-related proteins. Idl loss decreased the levels of vimentin, integrin beta 1, TGF beta 1 and snail, both in vitro and in vivo. Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis. (C) 2017 Elsevier B.V. All rights reserved.

Background Genomic alterations studies in cell-free DNA (cfDNA) have increasing clinical use in oncology. Next-generation sequencing (NGS) technology provides the most complete mutational analysis, but nowadays limited data are available related to the comparison of results reported by different platforms. Here we compare two NGS panels for cfDNA: Oncomine™ Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific), suitable for clinical laboratories, and Guardant360® (GuardantHealth), with more genes targeted but only available in an outsourcing laboratory. Methods Peripheral blood was obtained from 16 advanced cancer patients in which Guardant360® (G360) was requested as part of their clinical assistance. Blood samples were sent to be analyzed with G360 panel, and an additional blood sample was drawn to obtain and analyze cfDNA with Oncomine™ Pan-Cancer (OM) panel in an Ion GeneStudio S5™ System. Results cfDNA analysis globally rendered 101 mutations. Regarding the 55/101 mutations claimed to be included by manufacturers in both panels, 17 mutations were reported only by G360, 10 only by OM and 28 by both. In those coincident cases, there was a high correlation between the variant allele fractions (VAFs) calculated with each panel (r = 0.979, p Conclusions In summary, G360 and OM can produce different mutational profile in the same sample, even in genes included in both panels, which is especially important if these mutations are potentially druggable.

Nivolumab; Carcinoma cervical, vaginal o vulvar; Carcinoma metastàtic Nivolumab; Cervical, vaginal, or vulvar carcinoma; Metastatic carcinoma Nivolumab; Carcinoma de cuello uterino, vaginal o vulvar; Carcinoma metastático PURPOSE Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus–negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.

Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1–programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade. Ajona and colleagues report that short-term starvation synergizes with anti-PD-1 blockade to reduce lung tumor growth and metastasis. This antitumor effect is mediated through the reduction of plasma IGF-1 levels and IGF-1R levels on tumor cells.

Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median=11, IQR=9.5-13) to the best response (median=0, IQR=0-0, p<0.01), followed by a significant increase at progression (median=11, IQR=11-15, p<0.01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received.

Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors. We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR. Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p

Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software. Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software. E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043–0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed. E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence.

Hospitalized cancer patients are at high risk of venous thromboembolism (VTE). Despite current recommendations in clinical guidelines, thromboprophylaxis with low molecular weight heparin (LMWH) is underused. We performed an observational prospective study to analyse factors influencing prophylaxis use, VTE events and mortality in cancer-hospitalized patients. 1072 consecutive adult cancer patients were included in an University Hospital from April 2014 to February 2017, and followed-up for 30 days after discharge. The rate of LMWH prophylaxis was 67.6% (95% confidence interval [CI] 64.7% to 70.4%), with a 2.8% rate of VTE events (95% CI 1.9% to 3.9%) and 3.5% rate of major bleeding events (95% CI 2.5% to 4.8%). 80% of VTE events occurred despite appropriate thromboprophylaxis. Overall, 30-day mortality rate was 13.2% (95% CI 11.2% to 15.3%). Active chemotherapy treatment, hospital stay ≥ 4 days, and metastatic disease were associated with a higher use of LMWH. On the contrary, patients with hematologic malignancies, anemia or thrombocytopenia were less prone to receive thromboprophylaxis. The main reasons for not prescribing LMWH prophylaxis were thrombocytopenia (23.9%) and active/recent bleeding (21.8%). The PRETEMED score, used for VTE risk stratification, correlated with 30-day mortality. There is room for improvement in thromboprophylaxis use among hospitalized-cancer patients, especially among those with hematologic malignancies. A relevant number of VTE events occurred despite prophylaxis with LMWH. Therefore, identification of risk factors for thromboprophylaxis failure is needed.

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined = 5.66 × 10-5 ; ORcombined = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined = 1.02 × 10-4 ; ORcombined = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p

UNLABELLED Despite much investment and progress, oncology is still an area with significant unmet medical needs, with new therapies and more effective use of current therapies needed. The emergent field of pharmacometrics combines principles from pharmacology (pharmacokinetics [PK] and pharmacodynamics [PD]), statistics, and computational modeling to support drug development and optimize the use of already marketed drugs. Although it has gained a role within drug development, its use in clinical practice remains scarce. The aim of the present study was to review the principal pharmacometric concepts and provide some examples of its use in oncology. Integrated population PK/PD/disease progression models as part of the pharmacometrics platform provide a powerful tool to predict outcomes so that the right dose can be given to the right patient to maximize drug efficacy and reduce drug toxicity. Population models often can be developed with routinely collected medical record data; therefore, we encourage the application of such models in the clinical setting by generating close collaborations between physicians and pharmacometricians. IMPLICATIONS FOR PRACTICE The present review details how the emerging field of pharmacometrics can integrate medical record data with predictive pharmacological and statistical models of drug response to optimize and individualize therapies. In order to make this routine practice in the clinic, greater awareness of the potential benefits of the field is required among clinicians, together with closer collaboration between pharmacometricians and clinicians to ensure the requisite data are collected in a suitable format for pharmacometrics analysis.

Predictive biomarkers can play a key role in individualized disease monitoring. Unfortunately, the use of biomarkers in clinical settings has thus far been limited. We have previously shown that mechanism-based pharmacokinetic/pharmacodynamic modeling enables integration of nonvalidated biomarker data to provide predictive model-based biomarkers for response classification. The biomarker model we developed incorporates an underlying latent variable (disease) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment. Here, we show that by integrating CT scan data, the population model can be expanded to include patient outcome. Moreover, we show that in conjunction with routine medical monitoring data, the population model can support accurate individual predictions of outcome. Our combined model predicts that a change in disease of 29.2% (relative standard error 20%) between two consecutive CT scans (i.e., 6–8 weeks) gives a probability of disease progression of 50%. We apply this framework to an external dataset containing biomarker data from 22 small cell lung cancer patients (four patients progressing during follow-up). Using only data up until the end of treatment (a total of 137 lactate dehydrogenase and 77 neuron-specific enolase observations), the statistical framework prospectively identified 75% of the individuals as having a predictable outcome in follow-up visits. This included two of the four patients who eventually progressed. In all identified individuals, the model-predicted outcomes matched the observed outcomes. This framework allows at risk patients to be identified early and therapeutic intervention/monitoring to be adjusted individually, which may improve overall patient survival. Cancer Res; 75(12); 2416–25. ©2015 AACR.

Superior Vena Cava obstruction results in severe oedema of the upper thorax. Endovascular treatment allows a rapid restoration of the blood flow with a rapid resolution of symptoms. We retrospectively report a single institution's experience in stent placement for malignant Superior Vena Cava Syndrome (SVCS) caused by lung cancer.Thirty-three consecutive patients (23 men, 10 women; median age, 57.6 years; range 34-71 years) who underwent endovascular SVCS palliative treatment were enrolled between August 2002 and June 2015. All patients presented SVCS secondary to lung cancer. Signs and symptoms of SVCS were scored.All procedures were successfully completed (100% technical success rate). Twenty-eight patients showed a progressive clinical improvement after endovascular treatment of SVCS (84.8% clinical success rate) within 48 hours, there were five clinical failures which improved progressively with posterior radiotherapy. During follow-up, three patients (9%) suffered intra or post-procedural complications (1 cardiac arrhythmia, 2 stent thrombosis).Stent placement in malignant SVCS seems to be an effective and rapid treatment for the relief of symptoms and quality of life improvement with a relatively low complications rate with a rapid resolution of symptoms. Therefore, it should be seriously considered as the first option in the SVC obstruction treatment.

Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden. Experimental Design: IL8 levelsweremonitored by sandwich ELISAs incultured tumor cells supernatants, tumor-xenograftedmice serum, and in samples from126 patients with cancer. Wecorrelated IL8 serumlevels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis. Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract. Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Fil: Sanmamed, Miguel F.. Universidad de Navarra; España Fil: Carranza Rua, Omar. Universidad de Navarra; España Fil: Alfaro, Carlos. Universidad de Navarra; España Fil: Oñate, Carmen. Universidad de Navarra; España Fil: Martín Algarra, Salvador. Universidad de Navarra; España Fil: Perez, Guiomar. Universidad de Navarra; España Fil: Landazuri, Sara F.. Universidad de Navarra; España Fil: Gonzalez, Alvaro. Universidad de Navarra; España Fil: Gross, Stefanie. University Hospital Erlangen; Alemania Fil: Rodriguez, Inmaculada. Universidad de Navarra; España Fil: Muñoz Calleja, Cecilia. Universidad Autonoma de Madrid. Hospital Universitario de la Princesa; España Fil: Rodríguez Ruiz, María. Universidad de Navarra; España Fil: Sangro, Bruno. Universidad de Navarra; España Fil: López Picazo, José M.. Universidad de Navarra; España Fil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pascual, Juan I.. Universidad de Navarra; España Fil: Andueza, Maria Pilar. Universidad de Navarra; España Fil: Perez Gracia, Jose Luis. Universidad de Navarra; España Fil: Melero, Ignacio. Universidad de Navarra; España

Purpose The tumour molecular profile predicts the activity of epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). However, tissue availability and tumour heterogeneity limit its assessment. We evaluated whether [18F]FDG PET might help predict KRAS and EFGR mutation status in NSCLC.

Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α–primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15−/− and IL-7−/− recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2+ CD8 T cells with autologous dendritic cells loaded with MART126–35 peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.

The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone.From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test.Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group.The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.

Purpose: To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Patients and Methods: Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m 2 ) and cisplatin (100 mg/m 2 ) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m 2 ) and cisplatin (30 mg/m 2 ). Results: Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12―97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50―91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival. Conclusion: HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies·1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity).

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.

Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events.A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell's syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition.To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination.

Purpose Three-dimensional conformal radiation therapy (3D-CRT) represents an advance in the better delineation of the target contours and more accurate dose distributions. The purpose of this study was to identify local control prognostic factors in patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with 3D-CRT. Material and methods Between April 1995 and March 2002, 65 patients (NSCLC stage IIIA: 20%, IIIB: 77%) were treated with cisplatin-based induction and concurrent chemotherapy chemotherapy and hyperfractioned 3D-CRT (1.2Gy b.i.d.; median dose: 72.8 (range: 67–85.9). Clinical parameters (sex, age, performance status, stage, histology, tumor location), therapeutic factors (chemotherapy schedule, 3D-CRT dose, treatment response) and dosimetric factors (volume and dose of GTV, PTV-2, CTV and PTV-1) were evaluated. Local recurrences were divided into three dosimetric categories: those with more than 80% of their volume within high dose region (95% of prescription dose) were considered "central"; those between 20% and 80% were considered "marginal", and those with less than 20% of their volume within high dose region were considered "out-of-field". Local-failure free survival (LFFS) was obtained using the Kaplan–Meier method. Univariate and multivariate analyses were performed. Results There were 18 local failures (nine central, eight marginal and one out-of-field). The 2 and 5 year LFFS were 73% and 53%, respectively. In multivariate analysis, PTV-1>1146cc (HR=2.9, CI 95%: 1.1–7.5, p =0.026) was the only factor associated with worse LFFS. Conclusions This study shows that local control was independently related to PTV-1 size. The great majority of local recurrences were located in the high-dose region. Dosimetric parameters may contribute to improving radiotherapy results in multidisciplinary treatment for LA-NSCLC.

Radiation pneumonitis (RP) is a restricting complication of non-small-cell lung cancer irradiation. Three-dimensional conformal radiotherapy (3D-CRT) represents an advance because exposure of normal tissues is minimised. This study tries to identify prognostic factors associated with severe RP.Eighty patients with stage IIIA (20%) and IIIB (80%) NSCLC treated with cisplatin- based induction chemotherapy followed by concurrent chemotherapy and hyperfractionated 3D-CRT (median dose: 72.4 Gy, range: 54.1-85.9) were retrospectively evaluated. Acute and late RP were scored using RTOG glossary. Potential predictive factors evaluated included clinical, therapeutic and dosimetric factors. The lungs were defined as a whole organ. Univariate and multivariate analyses were performed.Early and late RP gradeor=3 were observed in two patients (2%) and 10 patients (12%), respectively. Five patients (6%) died of pulmonary toxicity, 3 of whom had pre-existing chronic obstructive pulmonary disease (COPD). Median time to occurrence of late RP was 4.5 months (range: 3-8). Multivariate analysis showed that COPD (OR=10.1, p=0.01) and NTCPkwa30% (OR=10.5, p=0.007) were independently associated with late gradeor=3 RP. Incidence of RPor=3 grade for patients with COPD and/or NTCPkwa30% was 25% vs. 4% for patients without COPD and NTCPkwa30% (p=0.01). Risk of severe RP was higher for patients with COPD and/or NTCPkwa30% (OR=7.3; CI 95%=1.4-37.3, p=0.016).COPD and NTCP are predictive of severe RP. Careful medical evaluation and meticulous treatment planning are of paramount importance to decrease the incidence of severe RP.

Introduction Current clinical practice guidelines do not recommend routine pharmacological thromboprophylaxis in cancer outpatients receiving chemotherapy. However, a high proportion of cancer-associated venous thromboembolism (VTE) events occur in this setting. There are scarce data on the use of thromboprophylaxis in ambulatory cancer patients in real clinical practice. Material and methods We conducted a single-center prospective study aimed to evaluate the use and factors influencing pharmacological prophylaxis in consecutive cancer patients receiving ambulatory chemotherapy. Patients were followed for 90 days after inclusion. Results A total of 1108 patients were included. According to the Khorana score, 45.8% patients were classified as low-risk, 47.4% intermediate-risk and 6.8% as high-risk. Outpatient pharmacological prophylaxis was administered at any time during follow-up to 157 patients (14.2%) with a median duration of 42 days (range 1–90). Main factors influencing thromboprophylaxis were: previous history of VTE (odds ratio [OR], 19.11; 95% CI, 9.61–37.98), intercurrent hospitalization (OR, 5.40; 95% CI, 3.57–8.16), and gastrointestinal or gynecologic cancer (OR, 1.76; 95% CI, 1.11–2.80 and OR, 2.34; 95% CI, 1.05–5.26, respectively). During follow-up 58 (5.2%) VTE events were observed. Independent predictors of VTE were the site of malignancy (OR, 3.04; 95%CI, 1.20–7.71 and OR, 2.47; 95%CI, 1.21–5.01 for pancreas and lung cancer, respectively) and previous VTE (OR, 4.23; 95%CI, 1.26–14.27). Outpatient prophylaxis was associated with a lower risk of VTE during follow-up (OR, 0.30; 95%CI, 0.10–0.95). Conclusions Although the type of malignancy appears as the most relevant variable for decision-making, additional efforts are required to identify patients at particular high thrombosis risk.

Purpose. To report our preliminary experience using intensity modulated radiation therapy (IMRT) in abdominopelvic tumors and to compare IMRT and three-dimensional conformal radiotherapy (3D-CRT) plans for various pelvic sites.

Activation of the ERK1/2 pathway is involved in malignant transformation both in vitro and in vivo. Little is known about the role of activated ERK1/2 in non-small cell lung cancer (NSCLC). The purpose of this study was to characterise the extent of the activation of ERK1/2 by immunohistochemistry in patients with NSCLC, and to determine the relationship of ERK1/2 activation with clinicopathological variables. Specimens from 111 patients with NSCLC (stages I-IV) were stained for P-ERK. Staining for epidermal growth factor receptor (EGFR) and Ki-67 was also performed. In all, 34% of the tumour specimens showed activation for ERK1/2, while normal lung epithelial tissue was consistently negative. There was a strong statistical correlation between nuclear and cytoplasmic P-ERK staining and advanced stages (P

Multidisciplinary treatment in high-risk breast cancer improves survival and local control. The feasibility and patterns of failure after several induction and high-dose consolidation regimens of chemotherapy were evaluated in this study. Between November 1990 and January 1997, 65 patients with histologically proven breast cancer American Joint Committee on Cancer stages II-III with four or more axillary lymph nodes positive or locally advanced breast cancer underwent high-dose chemotherapy (HDC) with peripheral stem cell support after surgery and induction chemotherapy. All patients were subsequently treated with radiotherapy (up to total doses of 50-60 Gy), which included the ipsilateral axilla and supraclavicular fossa and the chest wall or breast. A minimum follow-up period of 2 years from the completion of radiotherapy was required for analysis. Local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity were evaluated. With a median follow-up of 62 months (range: 32-107 months), LC was 89%, and 5-year OS and DFS were 78% and 63%, respectively. Symptomatic pneumonitis developed in six patients (9%); only one patient had her radiotherapy interrupted because of hematologic toxicity. No treatment-related mortality was observed. Radiation therapy after HDC provides excellent local control rates without excessive toxicity. Delaying the start of irradiation until recovery from HDC does not seem to increase local failure rates.

5504 Background: Treatment options for cervical, vaginal, and vulvar (GYN) cancers are limited after first-line therapy. Human papillomavirus (HPV) infection is associated with squamous cell carcinomas of the cervix (≥90%) and vulva/vagina (40–70%), and may elicit an immune reaction. Programmed death (PD)-1 and its major ligand PD-L1 are expressed in GYN cancers and inhibit immune responses. Nivolumab disrupts PD-1–mediated signaling, restoring antitumor immunity. Methods: In CheckMate 358 (NCT02488759), an ongoing multicohort study of 5 virus-associated cancers, PD-L1–unselected adults with R/M GYN cancers, ECOG PS 0–1, and ≤2 prior systemic therapies for R/M disease were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated patients (pts), 19 had cervical and 5 had vaginal or vulvar cancer; median age was 51 y. At a median follow-up of 31 wks (range: 6–38), ORR was 20.8% (Table), and disease control rate (ORR + SD) was 70.8%. All responses were in pts with cervical cancer (ORR, 26.3%) and were observed regardless of PD-L1 or HPV status or number of prior R/M therapies. Median PFS was 5.5 mo (95% CI: 3.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated encouraging clinical activity in pts with cervical cancer and a manageable safety profile in virus-associated GYN cancers, supporting further evaluation in these pts. Updated clinical and biomarker data to be presented. Clinical trial information: NCT02488759. [Table: see text]

e20553 Background: NSCLC therapeutic paradigm has changed with immune checkpoint blockers. Biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT. Methods: We retrospectively analyzed 26 consecutive patients with stage IV NSCLC treated with IT at Clínica Universidad de Navarra (Spain) during 2016. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC ( < 1,000 vs > 1,000) and ANC ( < 4,000 vs > 4,000) after 2 cycles and response to IT. TTF-1 expression was correlated with treatment response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC. Results: An ALC increase after 2 cycles was significantly associated with DCR compared to progression (192 vs -155; p = 0.043). ALC > 1,000 after 2 cycles was more frequent among patients experiencing DCR compared to progression (87% vs 50%; p = 0.07). ALC > 1,000 after 2 cycles was more frequently observed among patients with TTF1+ tumors (93% vs 55%; p = 0.03). Patients with ANC < 4,000 showed a longer median OS (NR vs 19.25 months; p = 0.03). TTF1 expression in adenocarcinoma (n = 18) was associated with response to IT (83% vs 16%, p = 0.01). Conclusions: Despite this retrospective small series’ limitations, our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger prospective series.

Dysphagia is a common symptom in neuromuscular junction disorders, but it rarely occurs in isolation or is the presenting feature. We describe a patient presenting with isolated dysphagia to liquids. Electrophysiological studies, such as repetitive nerve stimulation and single-fiber electromyography, were normal. Serum anti-P/Q-type voltage-gated calcium-channel (anti-P/Q-type VGCC) and anti-acetylcholine receptor (AChR ab) antibodies were above the normal range. A computed tomography scan showed a mediastinal mass corresponding to a thymic carcinoma. After chemotherapy, surgical removal of the thymic carcinoma and radiotherapy, the patient no longer complained of dysphagia, AChR ab titers were reduced and anti-P/Q-type VGCC antibodies became negative. To the best of our knowledge, no previous reports of a paraneoplastic myasthenic syndrome related to thymic carcinoma with both anti-P/Q-type VGCC and AChR antibodies have been described.

The development of individualized therapies poses a major challenge in oncology. Significant hurdles to overcome include better disease monitoring and early prediction of clinical outcome. Current clinical practice consists of using Response Evaluation Criteria in Solid Tumors (RECIST) to categorize response to treatment. However, the utility of RECIST is restricted due to limitations on the frequency of measurement and its categorical rather than continuous nature. We propose a population modeling framework that relates circulating biomarkers in plasma, easily obtained from patients, to tumor progression levels assessed by imaging scans (i.e., RECIST categories). We successfully applied this framework to data regarding lactate dehydrogenase (LDH) and neuron specific enolase (NSE) concentrations in patients diagnosed with small cell lung cancer (SCLC). LDH and NSE have been proposed as independent prognostic factors for SCLC. However, their prognostic and predictive value has not been demonstrated in the context of standard clinical practice. Our model incorporates an underlying latent variable (“disease level”) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment; these assumptions are in agreement with the known physiology of SCLC and these biomarkers. Our model predictions of unobserved disease level are strongly correlated with disease progression measured by RECIST criteria. In conclusion, the proposed framework enables prediction of treatment outcome based on circulating biomarkers and therefore can be a powerful tool to help clinicians monitor disease in SCLC.

PURPOSE: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. METHODS: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. RESULTS: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. CONCLUSIONS: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.

Resultados finales de tolerancia, control local y supervivencia de un estudio fase II con quimioterapia y radioterapia radical en el tratamiento del carcinoma nasofaringeo localmente avanzado. Entre septiembre de 1986 y mayo de 1996 fueron tratados 45 pacientes. El tratamiento consistio en lomustina y ciclofosfamida simultanea con radioterapia sobre cavum y areas ganglionares locorregionales (60-70 Gy) y posteriormente cada 4 semanas durante 1 ano. Cuarenta y tres pacientes (95%) finalizaron radioterapia. La mediana de ciclos por paciente fue 7. Se obtuvieron 29 respuestas completas (64%), 7 parciales (16%) y 4 progresiones (9%). Desarrollaron leucopenia grado III-IV 26 pacientes (57%) y xerostomia cronica 30 pacientes (67%). El fallo fue: locorregional, 12 pacientes (30%); mixto, 2 (5%), y a distancia, 7 (17%). Con una mediana de seguimiento de 102 meses, la supervivencia actuarial a 5 y 10 anos fue del 39% y 23%, respectivamente, y la supervivencia actuarial libre de eventos a 5 y 10 anos fue del 39% y 22%, respectivamente. Al cierre del estudio, 14 pacientes (31%) viven sin enfermedad. Nuestros resultados reproducen los publicados en la literatura. La incidencia de recidivas locales y complicaciones tardias empleando tecnicas convencionales es elevada. Se necesitan protocolos que disminuyan la morbilidad y mejoren la tasa de curacion actual. The final results of tolerance, local control and survival from a phase II study in patients with locoregio nally advanced carcinoma who received concurrent chemo-radiotherapy followed by adjuvant chemotherapy are shown. Between September 1986 and May 1996, 45 patients were enrolled in a trial of cyclophosphamide and lomustine concurrent with radiotherapy over the primary lesion and cervical-supraclavicular areas (60-70 Gy), followed by the same chemotherapy every four weeks during one year. Forty three patients (95%) completed the radiotherapy. The median number of chemotherapy cycles was 7. There were 29 (64%) complete responses, 7 (16%) partial responses and 3 (9%) progressions. Twentysix (57%) patients had grade III-IV leucopenia and 30 patients (67%) developed permanent xerostomia. Patterns of first failure were as follows: locoregional in 12 patients (30%), distant relapse in 7 patients (17%) and both locoregional and distant failure in 2 patients (5%). The median of follow-up was 102 months. The survival at 5 and 10 year was 39% and 23% respectively and the event-free-survival at 5 and 10 year was 39% and 22% respectively. At the end of the study, 14 patients (31%) are alive. Our results are acceptable, but the local relapses and the incidences of long-term complications using conventional techniques are important. Improved radiotherapeutic techniques coupled with effective systemic therapy should further improve the prognosis of patients with nasopharyngeal carcinoma and decrease the acute and long-term morbidity.

Pemetrexed is a multitargeted antifolate approved for the second-line treatment of locally advanced or metastatic non-small cell lung cancer. The combination of pemetrexed with gemcitabine has been studied in several clinical trials showing a promising antitumor activity with a mild toxicity profile. We present the case of a patient who experienced fever, arthralgia, skin rash and high serum ferritin levels after first cycle of this chemotherapy combination, compatible with an adult onset Still's disease. This adverse event has not been previously reported.

This study evaluated tolerance, local control, and short-term survival in patients with locally advanced non-small-cell lung carcinoma treated with induction chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy. Thirty-one patients with stage IIIa (N2) or IIIb tumors were treated with cis-platinum-based induction chemotherapy for 1 to 4 courses followed by radical hyperfractionated radiotherapy (69.6 Gy) with concurrent chemotherapy given at the beginning and end of radiotherapy. Induction chemotherapy produced no complete responses and 18 (58%) partial responses. After completion of radiotherapy, 4 patients had complete response (13%) and 23 patients (74%) partial response. The patterns of failure were as follows: intrathoracic, 6 patients (22%); intrathoracic + distant metastasis, 6 patients (22%); distant metastasis without thoracic failure, 5 patients (19%). Six patients of the 12 with intrathoracic failure experienced in-field radiotherapy pure local failure. At the time of this analysis, 10 patients were alive and well (4 complete and 6 partial responders). Actuarial survival projected at 39 months is 35%. No benefit was observed for those patients responding to induction chemotherapy. Toxicity was as follows: grade III neutropenic fever in 4 patients (13%), grade IV neutropenia in 13 patients (42%), pneumonia in 6 patients (19%), grade III esophagitis in 4 patients (13%) and severe clinical pneumonitis in 1 patient (3%). Induction chemotherapy followed by chemoradiotherapy is feasible, and the preliminary results are encouraging. Complete response after radiotherapy appeared to be related to short-term disease-free survival, and decisions based on the response to chemotherapy may be equivocal.

Background Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. Patients and Methods Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0–24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA). Results From October 2009 to July 2010, 25 evaluable patients were included. AUC0–24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p = 0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69–168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. Conclusions Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy. Trial Registration ClinicalTrials.gov NCT01046240

Purpose: Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. Methods: Patients received cetuximab 250 mg/m(2) (loading dose: 400 mg/m(2)) days 1, 8 and 15; pemetrexed 500 mg/m(2) + cisplatin 75 mg/m(2) on day 1, q3w up to six cycles and folic acid, vitamin B-12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. Results: Sixty-six patients received >= 1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. Conclusions: Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected. (C) 2013 Elsevier Ltd. All rights reserved.

e20653Background: Inhibitor of differentiation 1 (Id1) and 3 (Id3) genes confer poor prognosis being involved in LA spreading to the liver. KM may constitute a poor prognosis and a pro-metastatic f...

Within an oncology setting, certain chemotherapy drugs, such as cisplatin, may lead to magnesium loss causing nephropathy. Neurological and cardiovascular symptoms caused by hypomagnesaemia are well known. The relationship between serious hypomagnesemia and severe pain is not well documented but nevertheless, when faced with unexplained episodes of pain which do not respond to powerful analgesics, it is important to review blood magnesium levels. We present two cases of opioid-refractory pain attacks. Patients received drugs which have been linked to hypomagnesemia. In both cases, endovenous magnesium replacement led to a drastic improvement in pain management.

Purpose: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we examined the role of SF2/ASF in human non–small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in SF2/ASF-related carcinogenesis. Experimental Design: SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry. SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to identify the association between the expression of the proteins and time to progression. Results: Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex 1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore, combined expression of these proteins was associated with prognosis. Conclusion: This study provides novel data on the mTORC1- and survivin-dependent mechanisms of SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in NSCLC progression. Clin Cancer Res; 16(16); 4113–25. ©2010 AACR.

BACKGROUND: Optimal management of SST is still controversial several years after the proposal of a multidisciplinary approach including neoadjuvant chemotherapy and external radiation. Our objective is to report our experience of this multidisciplinary approach from the surgical point of view. PATIENTS AND METHODS: From January 1997 to January 2008, 24 patients were treated surgically (18 with induction chemotherapy and 15 with radiotherapy). The surgical approach was thoracic (14 cases, 1 with a spinal approach) or cervical (10 patients, 2 thoracotomies). Pulmonary surgery performed consisted of 11 wedge resections, 10 lobectomies, 1 pneumonectomy and 2 cases without lung resection (1 exploratory thoracotomy and 1 local progression after a previously resected tumor). Intraoperative radiotherapy (IORT) was given in 7 cases. Partial vertebral body resection was performed in 5 cases. A pathologically complete response (pT0) was found in 7 cases (29 %). RESULTS: Surgery-related morbidity was mainly due to respiratory distress (5 patients). Two patients died in the first month after surgery (mortality: 8 %). The surgical approach (cervical vs. thoracic) did not influence postoperative morbidity ( P = NS). Overall 5-year survival was 56.6 % according to the Kaplan-Meier method. No influence on survival was observed with regard to the approach (cervical vs. thoracic), the use of IORT, or the performance of spinal surgery. Patients with a complete pathological response had a better 5-year survival, but this did not reach statistical significance. CONCLUSION: Surgery has a role in the multidisciplinary approach, especially when we consider long-term survival. A multidisciplinary approach using neoadjuvant chemo and radiotherapy has a high rate of complete pathological response. It is also associated with a high incidence of postoperative distress syndrome. The 5-year survival is acceptable.

Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by the presence of IgG autoantibodies against Dsg3. Our aim was to investigate the molecular events implicated in the development and localization of apoptosis and acantholysis in PV. We used a passive transfer mouse model together with immunohistochemical (IHC) techniques and the TUNEL assay, with quantification analysis in the basal layer of the epidermis. The activated signalling molecules analysed and apoptotic cells detected showed an identical localization. Herein, we found for the first time in vivo an increased expression of activated HER receptor isoforms in the basal layer in PV lesions. Besides, we observed the almost total lack of activated Akt compared with a higher level of activated mTOR within the basal cells of the epidermis. Our observations strongly support that the restriction of acantholysis to the basal layer may be due, at least in part, to the selective and increased presence of activated HER receptor isoforms in these cells. After phosphorylation of HER receptor isoforms, intracellular signalling pathways are activated in the basal layer. In addition, the imbalance in Akt/mTOR that takes place in the basal cells may provide intracellular signals necessary for the development of apoptosis and acantholysis.