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Autoimmune haemolytic anaemia (AIHA) is a rare immune-related adverse event and appears to be more common with anti-PD1/PDL1 than anti-CTLA4. Little is known about the safety of re-treating with anti-PD1/PDL1 or changing to anti-CTLA4. We present a case of grade 4 AIHA due to nivolumab (PD1-inhibitor) treatment in a patient with melanoma for adjuvant setting after surgery and the safeness of subsequent treatment with ipilimumab (anti-CTLA4). After the remission of AIHA with steroids, ipilimumab was started with the rationale of its different mechanism of action. Fortunately, AIHA did not recur. The mechanism by which checkpoint inhibitors cause AIHA is likely by augmenting or redirecting immune surveillance, especially by activating pre-existing red blood cell autoantibodies, but further studies must be done. To our knowledge, this is the first case published in the literature with the change of immunotherapy treatment to anti-CTLA4.

Sequential treatment of Panitumumab (Pb) plus Paclitaxel (Px) as induction treatment (IT) followed by concurrent bioradiotherapy (Bio–RT) with Pb may be an alternative for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in patients ineligible for high-dose cisplatin therapy. Phase II, single-arm, multicentre study, with two-stage design, in patients ≥ 18 years with stage III–IVa–b LA-SCCHN unfit for platinum. Patients received Px + Pb (9 weeks) as IT followed by Bio–RT + Pb. Primary endpoint: overall response rate (ORR) after IT, defined as: more than 70% of patients achieving complete response (CR) or partial response (PR) to IT. Secondary end-points: progression-free survival, organ preservation rate, safety profile. Study ended prematurely (51 patients) due to slow recruitment. ORR: 66.7% (95% CI: 53.7–79.6), 8 (15.7%) CR and 26 (51.0%) PR. 39 patients (76%) completed radiotherapy (RT). Pb and/or Px-related adverse events (AEs) grade 3–4: 56.9% during IT and 63.4% during the concomitant phase, of which most common were skin toxicity (33.3%). Five deaths occurred during treatment, two of them (3.9%) were Pb and/or Px-related. Although underpowered, ORR was higher than the pre-specified boundary for considering the treatment active. Although Px + Pb as IT provides some benefit, the safety profile is worse than expected. To consider Pb + Px as IT as an alternative for platinum-unsuitable LA-SCCHN, further research/investigation would be needed.

Introduction: Human papilloma virus (HPV)-related oropharyngeal carcinoma (OPC) can be considered a new subtype of cancer with different clinical characteristics and prognosis than that related to tobacco. Its incidence is increasing worldwide. Its epidemiology has been widely studied in areas such as North America and Northern Europe, but less is known in Southern Europe. Methods: We analyzed the epidemiology of OPC using the database from Girona’s population-based Cancer Registry, in the North-East of Spain, from 1994 to 2018. To analyze differences between neoplasms related to human papillomavirus or not, we determined the immunohistochemical expression of p16 in cases within four time periods: 1997–1999, 2003–2005, 2009–2011, and 2016–2018. Results: Oropharyngeal cancer incidence increased significantly from 2001 to 2018 with an Annual Percentage of Change (APC) of 4.1. OPC p16-positive cases increased with an APC of 11.1. In the most recent period, 2016–2018, 38.5% of OPC cases were p16-positive. European age-standardized incidence rate was 4.18 cases/100.000 inhabitants-year for OPC cancer and 1.58 for those p16-positive. Five-year observed survival was 66.3% for p16-positive OPC and 37.7% for p16-negative. Conclusions: Although with lower burden than in other regions, p16-positive oropharyngeal cancer is increasing in our area and has a better prognosis than p16-negative OPC.

Nasopharyngeal carcinoma (NPC) is distinct from other cancers of the head and neck in biology, epidemiology, histology, natural history, and response to treatment. Radiotherapy (RT) is the cornerstone of locoregional treatment of non-disseminated disease and the association of chemotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum/gemcitabine-based chemotherapy and patients may achieve a long survival time.

The diagnosis of a second primary cancer (SPC) is a major concern in the follow-up of survivors of a primary head and neck cancer (HNC), but the anatomic subsites in the head and neck area are close, making it difficult to distinguish a SPC of a recurrence and therefore register it correctly. We performed a retrospective cohort study using data from two population-based cancer registries in Catalonia, Spain: the Tarragona Cancer Registry and the Girona Cancer Registry. All patients diagnosed with HNC during the period 1994–2013 were registered and followed-up to collect cases of SPC. We analysed the standardized incidence ratio (SIR) and the excess absolute risk (EAR) to determine the risk of second malignancies following a prior HNC. 923 SPC were found in a cohort of 5646 patients diagnosed of a first head and neck cancer. Men had an increased risk of a SPC with a SIR of 2.22 and an EAR of 216.76. Women also had an increased risk with a SIR of 2.02 and an EAR of 95.70. We show the risk for different tumour sites and discuss the difficulties of the analysis. The risks of a SPC following a prior HNC in Tarragona and Girona are similar to those previously found in other similar cohorts. It would appear to be advisable to make a revision of the international rules of classification of multiple tumours, grouping the sites of head and neck area with new aetiological criteria to better determine and interpret the risks of SPC obtained in these studies.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer; Diagnòstic; Patologia Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cancer; Diagnóstico; Patologia Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cancer; Diagnosis; Pathology Introduction: The recent COVID-19 pandemic has compromised socio-health care, with consequences for the diagnosis and follow-up of other pathologies. The aim of this study was to evaluate the impact of COVID-19 on cancer diagnosis in Girona, Spain. Methodology: Observational study of samples received in two pathology laboratories during 2019-2020 (tertiary hospital in Girona and county hospital in Figueres). Date, sample type, and location and morphology were available. Samples were recoded to determine malignancy and grouped by location. Comparisons were made by calendar year and period of exposure to COVID-19. Results: 102,360 samples were included: 80,517 from Girona and 21,843 from Figueres. The reduction in activity in the pathology laboratories in 2020 compared to the previous year was 25.4% in Girona and 27.5% in Figueres. The reduction in cancer diagnoses in 2020 compared to 2019 was 6.8% in Girona and 21% in Figueres. In both laboratories, a decrease was observed in the diagnoses of neoplasms of the lip, oral cavity and pharynx, larynx, colon, rectum and anus, kidney and urinary system, melanoma, and central nervous system. A statistically significant higher probability of a sample received in the pathology laboratory displaying malignancy during COVID-19 was found (Girona: OR = 1.28, 95% CI: 1.23-1.34; Figueres: OR = 1.10, 95% CI: 1.01-1.20) with respect to the COVID-19-free period. Conclusions: The COVID-19 pandemic has resulted in a reduction in cancer diagnoses by pathology departments that varies according to tumor location and type of hospital. Despite this, the optimization of care resources and the recovery effort have partially reduced the impact of the pandemic in certain neoplasms. This work was partially funded by the Josep Carreras Leukaemia Research Institute (grant number: FIJC1100) and the Agency for Management of University and Research Grants, Government of Catalonia (grant number: 2017SGR00733)

The prevalence of BRAF mutation has been reported in between 38% and 48% of melanoma patients, based on mainly Stage III or metastatic melanoma, however, information based on population-based studies is scarce. We performed a population-based retrospective cohort study to determine the prevalence of the BRAF mutation in patients diagnosed with in situ and infiltrating cutaneous malignant melanoma in the province of Girona between 2009 and 2011. Using the database of the Girona Cancer Registry, we performed BRAF mutation analysis based on paraffin-embedded tissue. This data was then correlated with other known clinical and histological prognostic factors for survival. We found 286 incident cases of cutaneous melanoma in the Girona Cancer Registry database. Excluding missing cases, BRAF-mutated patients constituted 38.9% of "in situ" melanoma cases and 53.8% of invasive melanoma cases. Five-year relative survival was not statistically different between BRAF-mutated patients (93.6%; 95% CI: 87.1-100.5) and non-mutated patients (84.3%, 95% CI: 75.3-94.8). Only stage was significant as a prognostic factor for survival based on multivariate analysis. From our population-based study, we conclude that BRAF mutation is not an independent prognostic factor for melanoma survival.

Concurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT.This randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of lt; 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL).Between July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888-1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P =.0287; appetite loss, P =.0248; social contact, P =.0153).Noninferiority of cet+RT over cis+RT was not demonstrated.

Pediatric central nervous system tumors are one of the most frequent types of neoplasms in children but epidemiological data on these tumors have been sparsely reported in the medical literature. We analyze the epidemiology of this type of tumors performing a retrospective population-based study in pediatrics and adolescent age in the population of Girona and compare them with series from Spain, Europe and worldwide. Cases were registered using the International Classification of Disease for Oncology, third edition and grouping according the International Classification of Childhood Cancer, third edition (ICCC-3). For all the histologies and the whole population between 0 and 19 years old, ASRw was 41.8 cases per million person-years. In children population, meaning under 14 years old, we found 104 cases with ASRw of 45.6. Males were the most affected by CNS tumors with a 1.2 sex ratio between 0 and 14 years old, and 1.1 between 0 and 19 years old. The analysis of trends in incidence did not find any statistically significant increase or decrease. Five-year observed survival was 68%, both for patients under 19 and 14 years of age. The incidence in our area was among the highest in Spain and worldwide, while survival was comparable to others reported.

e18015 Background: PD-L1 is a biomarker of response to anti-PD1 in HNSCC. CA209-7HE trial (NCT04282109) is a randomized, open-label, multicenter, phase II trial including first line R/M HNSCC pts non-eligible for cisplatin-based chemotherapy. Pts were stratified according to Karnofsky performance status, HPV and tissue PD-L1 by Combined Positive Score (CPS). Subjects were randomized to either paclitaxel + nivolumab or paclitaxel + cetuximab. Primary objective was 2-year overall survival. We present the data on centrally determined PD-L1 patterns and its correlation with pt clinical characteristics. Methods: From 176 preliminary samples, only 141 were analyzed. 10 were excluded for not fulfilling quality requirements and 25 belonged to non-eligible pts. 74% (104) were paraffin blocks and 26% (37) tissue slides. 72.3% (102) were primary tumor biopsies, 12.7% (18) local soft tissue relapses, 9.2% (13) lymph node metastases and 5.6% (8) distant metastases. 46.6% (66) were collected from irradiated areas. Hematoxylin-eosin stain confirmed sample representativeness. At least 100 tumor cells/sample was required. Immunohistochemistry for PD-L1 was performed using DAKO PD-L1 IHC 22C3. Means and proportions were dropped for descriptive analyses. Multivariate logistic regresion was used to identify variables associated with higher CPS. Results: Clinical characteristics included 73% (103) males; 77% (108) were either former [56% (78)] or current smokers [21.2% (30)] and clinical stage was recurrent in 48.9% (69), metastatic alone in 29.8% (42) and both recurrent and metastatic in 21.3% (30). Diagnoses included 35.4% (51) oral cavity, 32.3% (45) oropharynx (only 2 pts HPV positive), 16.3% (23) larynx and 15.6% (22) hypopharynx. Mean time to CPS assessment was 5.25 days (CI 95% 4.95 – 5.55). CPS distribution was as follows: 21.7% (31) were CPS < 1, 42.8% (60) were CPS 1-20 and 35.4% (50) were CPS > 20. Multivariate model revealed that oral cavity tumors showed an increased likelihood of CPS > 20 (OR 2.35, 95%CI 1.46 - 3.78; p < 0.001) which was also seen among non-smokers (OR 3.37, 95% CI 1.16 - 9.73; p = 0.02) and pts with recurrent and metastatic disease (OR 2.75, 95% CI 1.03- 7.32; p = 0.04). Oropharyngeal tumors showed lower probability for CPS > 20 (OR 0.35, 95% CI 0.14 - 0.89; p = 0.03). Neither prior irradiation nor origin of the biopsy were associated with any significant variation in CPS. Conclusions: Central assessment of CPS is feasible with no significant treatment delay. HPV negative oropharyngeal tumors were not associated with higher CPS. We also found that oral cavity tumors, non-smokers and pts with recurrent and metastatic disease were independently associated with an increased probability of higher CPS. Future results will elucidate the promising role of combinatorial regimens with immunotherapy in these subpopulations. Clinical trial information: NCT04282109.

6092 Background: Sinonasal cancers (SC) are heterogeneous diseases. Despite multimodality treatment, overall survival (OS) remains unsatisfactory. We aimed to identify prognostic factors (PFs) associated with patterns of failure and OS in non-metastatic SC (nmSC). Methods: We retrospectively reviewed a pooled dataset of nmSC from Princess Margaret (Canada) and Catalan Institute of Oncology (Spain) treated with definitive surgery ± postop radiotherapy (RT) or RT ± chemo according to institutional protocols between 2010-2019. In squamous cell carcinoma (SCC), HPV status was tested by p16 staining, and HPV DNA (ISH or PCR) if equivocal. The primary goal was to assess the association of tumor histology, stage (by 7th edition TNM), and other clinicopathological variables on locoregional control (LRC), distant control (DC) and OS. Actuarial rates were calculated with Kaplan–Meier (KM) method. Multivariable analysis (MVA) calculated hazard ratios (aHR) adjusted for histology type, T-/N-categories, and primary treatment. Results: Out of 342 pts, median age was 62 years (y) (range 21-96), Male:Female = 212:130, 95% had ECOG 0-1. Tumor histology types were: 192 (56%) SCC (p16+: 35; p16-/untested: 157), 40 (12%) adenocarcinoma (AD), 33 (10%) sinonasal undifferentiated carcinoma or sinonasal neuroendocrine tumors (SNUC/SNEC), 28 (8%) malignant melanoma (MM), 27 (8%) esthesioneuroblastoma (ES) and 22 (6%) adenoid cystic carcinoma (ACC). Median follow up was 3.6 y (range 0.1-11.3). Three-year actuarial rates for each endpoint are included in table. The PFs for LRC by MVA were: SNUC/SNEC (vs SCC) histology, T3-4 (vs T1-2: aHR 2.4, p = < 0.01) and N+ (vs N-: aHR 1.7, p = 0.02) diseases. The PFs for DC were: MM (vs SCC) and SNUC/SNEC (vs SCC) histology, and T3-4 (vs T1-2: aHR 6.0, p = 0.01) disease. The PFs for OS were: MM (vs SCC) histology, older age (aHR 1.0, p < 0.01), T3-4 (vs T1-2: aHR 5.6, p < 0.01), and N+ (vs N-: aHR 2.5, p < 0.01) disease. There was no difference in primary surgery vs RT in any outcome endpoint (all p > 0.05). p16+ SCC had a marginally higher LRC but similar DC and OS vs p16-/untested SCC (table). Conclusions: This large multicentre cohort of nmSC shows different patterns of relapse and survival with different tumor histologies. Our results suggest that individualization of treatment and follow-up strategies by histologic type is recommended to optimize outcomes in these orphan diseases. [Table: see text]

The aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI &gt, 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI &gt, 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky &lt, 80%, Non L-sarcomas and better response in the previous systemic line. The median GMI was 0.82 (0–69), with 198 patients (55%) with a GMI &lt, 1, 41 (11.5%) with a GMI 1–1.33 and 118 (33.1%) with a GMI &gt, 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.

Doege‐Potter syndrome is a rare hypoglycemic paraneoplastic disorder. This case describes that severe and symptomatic hypoglycemia can occasionally be due to a rare malignant neoplasm, and the differential diagnosis of malignancy should not be overlooked in this setting.

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients’ samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)—the main effector of muscular atrophy in cachexia—resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment., This project was funded by the 2014 SARC International Career Development Award (SARC Sarcoma Spore 1U54CA168512–01), Fundación Mari Paz Jiménez Casado, FERO Foundation, Spanish Society of Medical Oncology (SEOM), PERIS SLT006/17/221, ISCIII PI16/01371 and PI19/01271, all to C.S. ISCIII FI20/00275 (to DG-P), and a Ph.D. fellowship from the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT) (to DFP-J). AE-C is funded by ISCIII PT17/0009/0019 and co-funded by FEDER.

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p, This research was funded by the health research program of the “Instituto de Salud Carlos III” (PI14/00071) co financed with FEDER founds and for the Health Regional Management of the Junta de Castilla y León (GRS1385/A/16). J. Fernández-Mateos was partially supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León and the European Social Fund to CC-B (EDU/1084/2012).

We conducted a population-based study on the Girona Cancer Registry (Spain) for the period 1994–2013 to determine patterns of change in the incidence of melanoma, which is increasing in many countries, and patient survival in our geographical area. Using the standard registration rules for cancer registries, we calculated crude and standardized incidence rates as well as their trends. We also analysed the observed survival, 1-year conditioned survival and relative survival at 3, 5 and 10 years. Our crude incidence rate was 9.13 cases/100,000 inhabitants for invasive and 2.59 for “in situ” melanomas. A statistically significant increase in incidence was found for melanomas of less than 1 mm in Breslow index and in males. 10-year observed and relative survival rates were 64.1 and 83.1%, respectively. We found an increasing trend in the incidence of low-risk melanoma and a survival rate similar to that reported elsewhere in Europe.

TPS6086 Background: Nivolumab is the standard of care for patients (pts) with R/M HNSCC in the platinum-refractory setting. Up to 20% of R/M HNSCC pts are ineligible for cisplatin-based CT due to poor performance status and/or comorbidities. ERBITAX (weekly cetuximab + paclitaxel) is a recommended regimen for this patient population according to the Spanish Society of Medical Oncology guidelines. Preclinical data suggests a role for paclitaxel as immuno-modulator, mainly by increasing tumor infiltrating CD8+ (Galluzzi L., et al 2015). NIVOTAX trial aims to evaluate efficacy and safety of nivolumab + paclitaxel vs ERBITAX as first-line treatment for R/M HNSCC pts with platinum-refractory disease or ineligible for platinum-based chemotherapy. Methods: NIVOTAX (NCT04282109) is a randomized, open-label, multicenter, phase II trial sponsored by the Spanish Group of Head and Neck Cancer Treatment (TTCC) including R/M HNSCC pts not amenable for curative-intent therapy, previously untreated for R/M disease and not candidates for cisplatin-based chemotherapy. Population is distributed in 3 Groups: 1= Platinum-refractory; 2=Platinum-sensitive but unable to receive cisplatin due to: Karnofsky performance status (KPS) 70% and/or major comorbidities (renal/heart failure, grade ≥2 hearing loss) and/or previous allergic reactions to platinum compounds; 3= Platinum-sensitive but cumulative cisplatin dose received ≥225 mg/m² for locally-advanced disease. Pt are stratified according to: KPS (70% vs 80-100%); PD-L1 by Combined Positive Score (CPS ≥1 vs < 1); and HPV positivity (HPV+ oropharynx vs HPV-/non-oropharyngeal). 141 Pt are being randomized 2:1 to NIVOTAX (nivolumab 240 mg q2 weeks + weekly paclitaxel at 80 mg/m2 up to 12 weeks followed by maintenance nivolumab 480 mg/ q4 weeks) or ERBITAX ( weekly 250 mg/m2 plus paclitaxel 80 mg/m2 up to 12 weeks followed by maintenance cetuximab 250 mg/m2 weekly). Both arms will be continued up to a maximum of 24 months. Primary end-point is to evaluate treatment efficacy in terms of 2-year overall survival (2-y OS). It is assumed that 2-y OS in the NIVOTAX arm will be at least 26% (10% gain when compared to the expected 16% 2-y OS rate in this pt population). Secondary objectives include progression free survival (PFS), overall response rate, disease control rate, duration of response, 6m PFS, 5y-OS and safety profile. Response endpoints will be assessed using RECIST 1.1 criteria. As of February 12, 2021, 64 pts have been randomized. Planned safety data review for the first 10 pts treated with NIVOTAX regimen did not show any unexpected AE. Clinical trial information: NCT04282109.

BACKGROUND. Reference centers (RCs) are a key point for improving the survival of patients with soft‐tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of patients with STS, comparing results between RC and local hospitals (LHs). MATERIALS AND METHODS. Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed. RESULTS. A total of 622 sarcomas were analyzed, with a median follow‐up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p = .006). The provenance of the biopsy (RC vs. LH) significantly affected relapse‐free survival (RFS; 3‐year RFS 66% vs. 46%, respectively; p = .019). Likewise, 3‐year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p < .001). Patients managed by RCs had a better 3‐year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p = .003). Perioperative chemotherapy in high‐risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3‐year RFS (66% vs. 44%; p = .011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p = .036). CONCLUSION. Our series indicate that selected quality‐of‐care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS. IMPLICATIONS FOR PRACTICE. This prospective study in patients diagnosed with soft‐tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers.

Background Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20-24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. Methods We analyzed clinical, pathological, and molecular characteristics and long-term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for >= 5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. Results Sixty-four imatinib long-term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0-1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression-free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long-term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after >= 5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. Conclusion GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. Implications for Practice This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first-line imatinib therapy. Patients reaching >= 5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.

Population-based cancer registry data from three Spanish areas were used to assess the patterns of care and adherence to guidelines for cutaneous malignant melanoma. We included 934 cases diagnosed in 2009-2013. Completeness of the pathology reports, imaging for detecting distant metastasis and the use of sentinel lymph node biopsy (SLNB) were analysed. The proportion of pathology reports that mentioned the essential pathological features required for T staging was 93%, ranging across geographic areas from 81% to 98% (p 0.001). The percentage of low-risk patients who underwent no imaging studies, as proposed by guidelines, or only chest imaging ranged among areas from 0.6% to 84% (p 0.001). Of the patients with clinically node-negative melanoma1 mm thick and no distant metastases, 68% underwent SLNB, varying by area from 61% to 78% (p = 0.017). This study revealed wide geographic variation in different aspects of melanoma care. The use of a standardised structured pathology report could strengthen the completeness of reporting. Improvement strategies should also include efforts to reduce overuse of imaging in low-risk patients and to increase the adherence to guidelines recommendations on the use of SLNB.

Cetuximab is a monoclonal antibody against epidermal growth factor receptor useful in the treatment of patients with Head and Neck Squamous Cell Carcinoma combined with radiotherapy or chemotherapy. Its pharmacokinetics are not influenced by hepatic status and there are no specific warnings concerning its indication in patients with impaired hepatic function. Patients with a previous liver transplant are at risk for hepatic toxicity and use immunosupressants to avoid rejection that can interact with other drugs. We present two cases of patients with a previous liver transplant in which cetuximab was administered to treat head and neck cancer.

[Introduction] There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients., [Methods] KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test., [Results] Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014)., [Conclusions] We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors., The project was funded by the Instituto de Salud Carlos III (ISCIII) - Fondo Europeo de Desarrollo Regional (FEDER), through a public competitive call (project reference PI15/01254; principal Investigator Javier Martín Broto), and the Spanish Group for Research on Sarcoma (GEIS).

Introduction We present an epidemiological study focused on Non-melanoma skin cancers (NMSC), including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFS) and adnexal and skin appendages neoplasm (ASAN), a neoplasm understudied in cancer registries. Material and methods We analyze trends of incidence and survival of NMSC registered with the Cancer Registry of Girona, Spain. Results We found 14389 cases of NMSC, accounting 3,474 SCC, 10729 BCC, 33 MCC, 61 DFSP and 71 ASAN. Incidence increased significantly in SCC and BCC with annual percentage of change of 1.6 and 1.5, respectively, but not in MCC, DFS or ASAN. Five-year relative survival for both sexes was 90.1% in SCC, 99.8% in BCC, 44.2% in MCC, 93.7% in DFS and 84% in ASAN. Conclusions Our study confirms the increasing incidence and good survival of SCC and BCC and enhances knowledge on the epidemiology of the less incidental NMSC.

Fin dalle sue origini, con la nascita nel 1962 del primo Sistema d’Informazione Geografica (SIG) – il Sistema d’Informazione Geografica del Canada (CGIS) –, l’evoluzione vissuta da questi sistemi è stata formidabile e i loro ambiti di applicazione ogni volta più numerosi, con la progressiva copertura di un ampio spettro di discipline che hanno tratto profitto dal loro potenziale. Sono ancora molte, tuttavia, le funzionalità da valorizzare.Ed è precisamente in questo contesto, nell’utilizzo cioè dei SIG nell’ambito di campi del sapere non strettamente collegati alla geografia quantitativa attuale, che si misura maggiormente il valore aggiunto che tali sistemi possono apportare anche negli studi e nelle analisi dei processi storici, come dimostra il caso della tesi El éxodo catalán de 1936 a través de los Pirineos. De la derrota a la victoria qui discussa. Born in 1962 with the Canadian Geographical Information System (CGIS), the GIS knew a spectacular development and broaden its applications, touching various disciplines that made its potential come out. Nonetheless, many functions have not been exploited yet. And it is precisely in domains other than the most usual, such as the quantitative geography, that we can appreciate the value of this tool, as this historical research El éxodo catalán de 1936 a través de los Pirineos. De la derrota a la victoria demonstrates. Desde sus orígenes, con la aparición en 1962 del primer Sistema de Información Geográfica (SIG) – el Sistema de Información Geográfica de Canadá (CGIS) –, la evolución que han experimentado estos sistemas ha sido espectacular y sus ámbitos de aplicación cada vez mayores, abarcando un amplio espectro de disciplinas que han sacado provecho a su potencial. Siguen existiendo, sin embargo, muchas funcionalidades que explotar.Y es precisamente en este contexto, en el uso de los SIG por parte de campos de conocimiento no directamente vinculados a la geografía cuantitativa actual, en el que se constata el valor añadido que estos pueden tener también en estudios e investigaciones de procesos históricos como el correspondiente a la tesis El éxodo catalán de 1936 a través de los Pirineos. De la derrota a la victoria.

Purpose To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. Patients and Methods Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1,800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1,200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. Results From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. Conclusion The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.

6007Background: Severe Oral Mucositis (SOM) is one of the most significant adverse events (AE) in H&N cancer patients undergoing concurrent chemo/bio-radiotherapy. The objective of the trial is to ...

Summary Background Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC). Methods Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m 2 (days 1 and 8), oral capecitabine 500 mg/m 2 twice a day (final dose after adjustment, days 1–14), and oral sorafenib 400 mg twice a day (days 1–21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov, number NCT00496301. Findings 44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11·1 months (95% CI 7·9–17·1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand–foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug. Interpretation PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration. Funding Spanish Oncology Genitourinary Group (SOGUG).

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain., Novartis have provided funding for this observational study.

Purpose To assess the progression-free survival (PFS) and antitumor response to standard-dose doxorubicin compared with sequential dose-dense doxorubicin and ifosfamide in first-line treatment of advanced soft tissue sarcoma. Patients and Methods Patients with measurable advanced soft tissue sarcoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2, between the ages 18 and 65 years, and with adequate bone marrow, liver, and renal function were entered in the study. The stratifications were: ECOG PS (0 v 1), location of metastases, and potentially resectable disease. Patients were randomly assigned to either doxorubicin 75 mg/m2 given as a bolus injection every 3 weeks for 6 cycles (arm A) or doxorubicin at 30 mg/m2 per day for 3 consecutive days once every 2 weeks for 3 cycles followed by ifosfamide at 12.5 g/m2 delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles with filgastrim or pegfilgastrim support (arm B). Results Between December 2003 and September 2007, 132 patients were entered onto the study. Febrile neutropenia, asthenia, and mucositis were more frequent in the arm B. The interim preplanned analysis for futility allowed the premature closure. Objective responses were observed in 23.4% of assessable patients in arm A and 24.1% in arm B. PFS was 26 weeks in the arm A and 24 weeks in arm B (P = .88). Overall survival did not differ between the two therapeutic arms (P = .14). Conclusion Single-agent doxorubicin remains the standard treatment in fit patients with advanced soft tissue sarcoma.

This phase II clinical trial evaluated the antitumour response of Kahalalide F (KF) 650 microg/m(2) given as a 1-h weekly infusion in advanced malignant melanoma patients, both untreated and those who relapsed or progressed after one line of systemic therapy. Of 24 enrolled patients (median age, 55 years; range, 28-89), 14 patients had been previously treated with chemotherapy or biological therapy. No RECIST responses occurred; five chemotherapy-naive patients with cutaneous melanoma had disease stabilisation for > or = 3 months; median progression-free survival was 1.7 months (95% CI, 1.2-1.9 months); and median overall survival was 10.8 months (95% CI, 5.0-upper limit not reached). The most common laboratory toxicities were non-cumulative increase of transaminases (ALT/AST) and gamma-glutamyltransferase (GGT). No patients experienced leukopenia and thrombocytopenia during the study. KF was a well-tolerated and safe chemotherapy regimen. Despite a favourable safety profile, this trial was closed after the first stage because of the lack of objective response in patients with malignant melanoma.

Introduction Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain. Patients and methods An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments. Results In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups. Conclusions Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior.

Recurrent, metastatic, and locally advanced gastrointestinal stromal tumors (GISTs) can be treated successfully with imatinib mesylate. Surgery for residual disease has been suggested for nonrefractory metastatic GISTs to reduce the probability of resistant recurrent clones, although no randomized Phase III trial has been performed to answer the question about its benefit. We carried out an analysis of the outcome of patients with recurrent unresectable locally advanced or metastatic imatinib-sensitive priamary GIST in 14 institutions in Spain. We compared two cohorts: treated or not treated with surgery after partial response or stabilization by imatinib. Data were obtained from the online GIST registry of the Spanish Group for Research in Sarcomas. Selected patients were then divided into two groups: group A, treated initially only with imatinib, and group B, treated additionally with metastasectomy. Baseline characteristics between groups were compared, and univariate and multivariate analysis for progression-free survival and overall survival (OS) were performed. Analysis was undertaken in 171 patients considered nonrefractory to imatinib. The median follow-up time was 56.6 months. Focusing on OS, the Eastern Cooperative Oncology Group performance status different than 0, extent of disease limited to one metastatic organ, and comparison between groups A or B achieved statistical difference in the multivariate analysis. Median survival was 59.9 months in group A and 87.6 months in group B. Based in its benefit in OS, our study supports surgery of metastatic disease in GIST patients who respond to imatinib therapy.

11070 Background: The GMI is a marker of drug activity and represents an intra-patient comparison of successive time to progression (TTP), defined as the TTP ratio between the second (or later) line (TTPn) of therapy divided by the prior line (TTPn−1). Defining a clinical profile of pts with GMI >1.33 could help to identify pts who can gain greater benefit from T. Methods: We retrospectively evaluated the concordance between the GMI and the efficacy outcomes and clinical profiles of 198 pts with ASTS treated with trabectedin 1.5 mg/m² (24-h infusion q3w) as a 2nd or further-line treatment from Jan 2007 to Jun 2016. Results: After a median follow-up of 58 months (m; range: 18-172) median overall survival from ASTS diagnosis (MOS) and from T (MT-OS) were 27.5 m (23-32.1) and 10.8 m (8.9-12.7), respectively, while median TTP from T (MT-TTP) and T-1 were 3.4 m (2.8-4) and 3.5 m (2.8-4.2). Overall, 106 pts (53%) had a GMI 1.33. A high GMI (1.33) correlated with favorable efficacy outcomes: MT-OS: 23 vs 36 m (p 8.1 m (2.24, 95%CI 1.19-4.18) and Karnofsky >80 (2.3, 95%CI 1.00-5.28) as factors independently associated to GMI> 1.33. Based on these 3 variables we defined a new GEISTRA score assigning 1 point for each adversely affected variable: non L-Sarcoma, MFI

Cochlear implantation is a surgical procedure that can restore the hearing capabilities to patients with severe or complete functional loss. However, the level of restoration varies highly between subjects and depends on patient-specific factors. This paper presents a software application for planning cochlear implantation procedures that includes patient-specific anatomy estimation using high resolution models, implant optimization for patient-specific implant selection, simulation of mechanical and electrical properties of the implant as well as clinical reporting.