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Bolnike z rakom glave in vratu v zelo dobrem splošnem stanju ob lokalni in/ali regionalni ali oddaljeni ponovitvi lahko zdravimo s kombinacijo citostatikov in tarčnega zdravila (cisplatin, 5-fluorouracil in cetuksimab) v tritenskih ciklusih. Bolnike v slabšem splošnem stanju zdravimo z monoterapijo, ponavadi z metotreksatom, s katerim dosežemo manj odgovorov na zdravljenje in krajše preživetje. Na Onkološkem inštitutu v Ljubljani smo pri bolnikih v slabšem splošnem stanju preizkusili zdravljenje s kombinacijo treh citostatikov (docetaksel 20 mg/m2, cisplatin 20 mg/m2 in 5-fluorouracil 350 mg/m2 intravensko) kot tedensko kemoterapijo. Rezultate smo analizirali retrospektivno. Zdravili smo 15 bolnikov, v starosti 45-78 let (srednja starost 60 let), srednje trajanje spremljanja je bilo 9,5 mesecev. Bolniki so prejeli povprečno 9 (4-15) tedenskih aplikacij kemoterapije. Sedeminosemdeset odstotkov bolnikov je imelo klinično korist zdravljenja (popolni odgovor - 2 bolnika, delni odgovor - 6 bolnikov, stagnacija bolezni - 5 bolnikov).

Vnetni rak dojke (VRD) je redka, vendar zelo agresivna oblika raka dojke. Pri več kot polovici bolnic so ob postavitvi diagnoze prisotni zasevki v pazdušnih bezgavkah, pri tretjini tudi oddaljeni zasevki. Izid VRD je kljub multimodalnemu zdravljenju, ki vključuje sistemsko zdravljenje, operacijo in obsevanje, slab. Bolnice skupine A so bile zdravljene s kemoterapijo po shemi CMF, skupine B z antraciklini (56%), kombinacijo antraciklinov in taksanov (36%) ali CMF (7%). Večina bolnic je imela operacijo (100 vs. 83%) in dopolnilno obsevanje (73 vs. 81% bolnic; skupina A vs. B). Dopolnilno HT je prejelo 7/27 bolnic skupine A oz. 28/31 bolnic skupine B s hormonsko odvisnim VRD (srednje trajanje 5 mes. v skupini A, 44 mes. v skupini B). Srednji čas do ponovitve je bil 16,9 (skupina A) in. 34,2 mes. (skupina B; p=0,01). Srednje celotno preživetje skupine A je bilo 33,8 mes., skupine B pa 56,6 mes. (p=0,06). Bolnice s hormonsko odvisnim VRD, zdravljene z dopolnilno HT, so imele najdaljši čas do ponovitve bolezni (89 mes.) in celotno preživetje (91 mes.). Preživetje brez ponovitve bolezni in celotno preživetje se je od obdobja 1983-87 do 2001-05 podaljšalo, najbolj pri bolnicah s hormonsko odvisnim VRD, ki so prejele dopolnilno HT.

In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.

Epidemiološki kazalci kažejo, daje rak v Sloveniji veliko javnozdravstveno breme. Rak je med vzroki smrti na prvem mestu pri moških in na drugem mestu pri ženskah. Za zagotavljanje primerne oskrbe bolnikov z rakom v bodoče je nujna primerna kadrovska zasedba, saj zadostni in primerno usposobljeni človeški viri predstavljajo osnovo za celostno izvajanje onkološke oskrbe v Sloveniji. V okviru Ciljnega raziskovalnega projekta Analiza stanja in ocena kadrovskih potreb za izvajanje zdravljenje raka v Republiki Sloveniji je bil razvit fleksibilen napovedovalni model za načrtovanje potrebnega zdravstvenega osebja za zdravljenje raka in paliativno oskrbo onkoloških bolnikov. Narejena je bila ocena kadrovskih potreb za kratkoročno obdobje do 2021 ter dolgoročno obdobje do leta 2030. V rezultatih so prikazane ocene kadrovskih potreb na podlagi podatkov o številu novih primerov raka za vse rake skupaj in za pogoste rake, to je rak debelega črevesa in danke, rak pljuč, rak dojke, rak prostate ter skupaj za ostale rake. Kadrovske ocene za izvajanje zdravljenje raka so bile izračunane za vsako navedeno lokacijo raka glede na vrsto zdravljenja ter po poklicnih skupinah v zdravstvu. Kadrovske potrebe za paliativno oskrbo so bile narejene na podlagi podatkov o umrljivosti za vse rake skupaj po nivojih paliativne oskrbe. Predstavljena metodologija omogoča različnim deležnikom v kratkoročnem 5-letnem obdobju hitre izračune letnih kadrovskih potreb le na podlagi podatkov o incidenci in umrljivosti, na daljša obdobja in v primeru večjih sprememb v zdravstvenem sistemu pa omogoča poglobljeno analizo kadrovskih potreb in testiranje različnih scenarijev., Onkologija : strokovno-znanstveni časopis za zdravnike, Vol 24 No 2 (2020)

Despite professional recommendations malnutrition is not adequately addressed in cancer patients. Here, we explored whether nutritional status (NS) is associated with HRQoL in men with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Men with mCRPC enrolled into this prospective observational study were allocated to one of the four NS categories based on clinical, laboratory, and patient self-reported criteria: well-nourished (WN), nutritional risk without criteria for cachexia/sarcopenia (NR), sarcopenia, and cachexia. The HRQoL was evaluated by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Association between NS and self-reported HRQoL was sought by the linear regression model, which was adjusted for known prognostic variables and body mass index. Results: Over the period of two years, 141 patients were enrolled. Their median age was 74.1 years (IQR 68.6–79.4 years) and majority of them were minimally symptomatic. Fifty-nine patients (41.8%) were WN, followed by 24 (17%), 42 (29.8%), and 16 (11.4%) patients with NR, sarcopenia, and cachexia, respectively. As compared to WN patients, all three other NS categories were significant negative predictors of HRQoL (P

Background The aim of our study was to describe the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improvement made in different cancer types, population groups and prognostic factors. Materials and methods The principal data source was the population-based Slovenian Cancer Registry. The survival analysis included patients diagnosed with cancer in twenty years period from 1997 to 2016, which has been divided into four consecutive five-year periods. In addition, the analysis was stratified by cancer type, gender, age and stage. The survival was estimated using net survival calculated by the Pohar-Perme method and the complete approach has been applied. Results The survival of Slovenian cancer patients has been increasing over time. During the 20 years observed, five-year net survival increased by 11 percentage points. Significantly higher growth was observed in men. Age and stage at diagnosis are still crucial for the survival of cancer patients. Five-year net survival is lowest in those over 75 years of age at diagnosis but has also improved by seven percentage points over the past 20 years. The five-year net survival of patients in the localized stage increased by ten percentage points over the 20 years under observation. Survival of patients in the distant stage has not been improving. In both sexes, survival for melanoma, colorectal and lung cancers have increased significantly over the last 20 years. Progress has also been made in the two most common gender specific cancers: breast cancer in women and prostate cancer in men. Still, the significant progress in prostate cancer is probably mostly due to lead-time bias as during the study period, Slovenia used indiscriminate PSA testing, which probably artificially prolonged survival. Conclusions The survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improvements. To monitor the effectiveness of managing the cancer epidemic, the cancer burden needs to be monitored also in the future, using quality data and scientifically justified methodological approaches. In this process a well organised population-based cancer registries should play a key role.

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p&nbsp

Patients with recurrent or metastatic squamous cell head and neck cancer (R/M SCHNC) exhibit a poor prognosis with a median overall survival (OS) time of 2 infusion reaction to cetuximab and 27.3% had grade 3 skin rash. There were no differences in diarrhoea, hypomagnesaemia, infections and febrile neutropenia; however, the mortality on active treatment was high (13.4%). In conclusion, patients treated with PFE had similar PFS, but improved OS compared with patients treated with the PF protocol. The proportion of patients who died under treatment due to disease progression and toxicity was high in both treatment arms. A thorough selection of patients for this treatment is crucial.

Background: Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. Objectives: The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. Methods: In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). Results: 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. Conclusions: Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant. Resumo Fundamento: Cardiotoxicidade é um importante efeito colateral da terapia com trastuzumabe, recomendando-se vigilância cardíaca. Objetivos: Avaliar prospectivamente as características basais de pacientes, nível de fração N-terminal do pró-peptídeo natriurético cerebral (NT-proBNP) e parâmetros ecocardiográficos como possíveis preditores de disfunção cardíaca relacionada ao trastuzumabe. Métodos: Em um estudo clínico prospectivo de coorte, realizou-se avaliação ecocardiográfica e neuro-humoral basal, aos 4, 8 e 12 meses em pacientes com câncer de mama submetidas a terapia adjuvante com trastuzumabe após antraciclina (3-4 ciclos). Definiu-se disfunção cardíaca relacionada ao trastuzumabe como uma redução na fração de ejeção ventricular esquerda (FEVE) ≥ 10%. Resultados: Este estudo incluiu 92 pacientes (idade média, 53,6 ± 9,0 anos). Pacientes que desenvolveram redução na FEVE ≥ 10% (20,6%) relacionada ao trastuzumabe durante tratamento tinham FEVE basal significativamente maior (70,7 ± 4,4%) do que aqueles sem (64,8 ± 5,5%) (p = 0,0035). Todos os demais parâmetros basais medidos (idade, índice de massa corporal, hipertensão arterial, nível de NT-proBNP e outros parâmetros ecocardiográficos) não foram identificados como significativos. Conclusões: Nossos achados sugerem que as características basais das pacientes, nível de NT-proBNP e parâmetros ecocardiográficos, contanto que dentro da variação normal, não são ferramentas confiáveis para predição precoce de disfunção cardíaca relacionada ao trastuzumabe em pacientes submetidas a terapia adjuvante com trastuzumabe após baixa dose de antraciclina. Uma redução na FEVE em pacientes com FEVE basal alta-normal, ainda que estatisticamente significativa, não é clinicamente relevante.

Ni abstrakta.

Klasifikacija, diagnostika in zdravljenje stromalnih ter mezenhimskih neoplazem prebavil je v zadnjih 30 letih doživela obsežen napredek. Gastrointestinalni stromalni tumorji (GIST) predstavljajo manj kot 1 % vseh malignih tumorjev prebavil.Klinična slika je odvisna od mesta, velikosti in malignega potenciala GIST. Razsejani GIST predstavlja primer uspešnega zdravljenja s tarčno terapijo, saj se je z odkritjem KIT in PDGFR signalne poti ter tirozin kinaznih inhibitorjev, kot staimatinib mesilat in sunitinib, prognoza te bolezni pomembno izboljšala. Izhod zdravljenja slovenskih bolnikov z razsejanim GIST je primerljiv z izhodom zdravljenja bolnikov, ki so bili zdravljeni v pomembnih večjih mednarodnih kliničnih raziskavah, srednji čas do progresa bolezni pri naših bolnikih je 52 mesecev in srednje preživetje 72 mesecev. Uporabljali smo protokol sledenja, ki je poleg kontrastne računalniške tomografije trebuha vključeval tudi preiskavo trebuha z ultrazvokom. S tem smo ob primerljivem preživetju izboljšali kakovost življenja naših bolnikov in zmanjšali stroške zdravljenja. In the last 30 years, major progress has been made in the classification, diagnosis and treatment of gastrointestinal stromal and mesenchymal neoplasms. Gastrointestinal stromal tumours (GIST) represent less than 1% of all malignant gastrointestinal tumours. The clinical picture depends on the site, size and malignant potential of the GIST. Metastatic GIST is a case of successful treatment, as the detection of KIT- and PDGFR-signalling pathways and kinase inhibitors, such as imatinib, mesylate and sunitinib, has significantly improved the prognosis of this disease. The treatment outcome in Slovenian patients with metastatic GIST is comparable to the treatment outcome observed in patients treated in major international clinical trials. We used the follow-up protocol which, besides contrast computed tomography of the abdomen, also included ultrasound of the abdomen. By doing so, along with comparable survival rates, we improved the quality of life of our patients and reduced the treatment costs.

BACKGROUND/AIM It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). PATIENTS AND METHODS After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. RESULTS A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. CONCLUSION Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.

580 Background: Papillary renal cell carcinoma type 1(PRCC1) is associated with MET alterations. Our phase II trial assessed the efficacy and safety of crizotinib in patients (pts) with advanced/metastatic PRCC1 with/without MET mutations( MET+, MET-). Methods: Eligible pts with reference pathology-confirmed PRCC1 received oral crizotinib 250mg twice-daily. Pts were attributed to MET+/ MET- sub-cohorts by sequencing of MET exons 16-19 in tumour tissue. Primary endpoint was objective response rate (ORR). If at least 2 of the first 12 eligible/evaluable MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were enrolled. Other endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and rate (PFSR), overall survival (OS) and safety. Results: 23 of 41 pts consenting were eligible, treated and evaluable. In 4 MET+ pts, 2 achieved a PR and 1 had stable disease (SD) (ORR 50%; 95% CI: 6.8-93.7%), DOR was 666 and 1138 days, 1-year PFSR was 75.0% (12.8-96.1%), 1-year OS: 75.0% (12.8-96.1%). Among 16 MET- pts, 1 achieved a PR lasting 302+ days and 11 had SD (ORR: 6.3%; 0.2-30.2%), 1-year PFSR: 27.3% (8.5-50.4%), 1-year OS: 71.8% (41.1-88.4%). Among 3 pts with unknown MET status ( MET?) due to technical failure, 1 achieved a PR lasting 211+ days and 1 had SD (ORR 33.3%, 0.8%-90.6%), 1-year PFSR: 66.7% (5.4-94.5%), 1-year OS: 100%. MET amplification was found post hoc in 1 MET+ (PR, DOR: 1138 days) and 1 MET- case (SD). Common treatment-related AEs were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%), and blurred vision (34.8%). Conclusions: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in pts with MET mutations or amplification. Sporadic, durable responses are also seen in MET-/ MET? cases, suggesting the presence of other alterations of MET or alternative pathways. Clinical trial information: NCT01524926.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. / Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET− sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. / Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET− patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET− cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. / Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. / Clinical trial number: EORTC 90101, NCT01524926

INTRODUCTION: Retroperitoneal sarcoma (RPS) is a rare disease accounting for 0.1%–0.2% of all malignancies. Management of RPS is complex and requires multidisciplinary, tailored treatment strategies at all stages, but especially in the context of metastatic or multifocal recurrent disease. Due to the rarity and heterogeneity of this family of diseases, the literature to guide management is limited. METHODS: The Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaboration of sarcoma experts from all disciplines convened in an effort to overcome these limitations. The TARPSWG has compiled the available evidence surrounding metastatic and multifocally recurrent RPS along with expert opinion in an iterative process to generate a consensus document regarding the complex management of this disease. The objective of this document is to guide sarcoma specialists from all disciplines in the diagnosis and treatment of multifocal recurrent or metastatic RPS. RESULTS: All aspects of patient assessment, diagnostic processes, local and systemic treatments, and palliation are reviewed in this document, and consensus recommendations provided accordingly. Recommendations were guided by available evidence, in conjunction with expert opinion where evidence was lacking. CONCLUSIONS: This consensus document combines the available literature regarding the management of multifocally recurrent or metastastic RPS with the practical expertise of high-volume sarcoma centers from multiple countries. It is designed as a tool for decision making in the complex multidisciplinary management of this condition and is expected to standardize management across centers, thereby ensuring that patients receive the highest quality care.

Background. The aim of the study was to investigate how the expression of tumor markers p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31 influenced the outcome of advanced inoperable oropharyngeal carcinoma patients, treated with concomitant radiochemotherapy. Patients and methods. The pretreatment biopsy specimens of 74 consecutive patients with inoperable stage IV oropharyngeal squamous cell carcinoma treated with concomitant radiochemotherapy were in retrospective study processed by immunochemistry for p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31. Disease-free survival (DFS) was assessed according to the expression of tumor markers. Results. Patients with a high expression of p21 (≥10%), p27 (>50%), Ki-67 (>50%), CD31 (>130 vessels/mm2) and low expression of p53 ( Conclusions. Statistical significance in survival between FL and UL emerged only for p27 and cyclin D1. The number of markers per tumor with UL of expression was an independent prognostic factor for an adverse outcome.

Background Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients. Methods A total of 66 osteosarcoma patients were genotyped for ERCC1 , ERCC2 , NBN , RAD51 , XRCC3 , and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression. Results Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) ( P =0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11–0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS ( P =0.005; HR=3.67; 95%CI=1.47–9.16; and P =0.004; HR=3.52; 95%CI=1.51–8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS ( P =0.001; HR=4.12; 95%CI=1.77–9.56). Conclusions Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization.

Cytotoxic activity of most chemotherapeutic agents is based on their ability to induce DNA damage. Interstrand crosslinks are among the most detrimental forms of DNA damage as both DNA strands are affected. As translesion polymerases participate in their repair, they may be important for response to chemotherapeutic agents that induce such lesions, including commonly used cisplatin. Altered expression of translesion polymerase genes REV1 and REV3L may modify sensitivity to cisplatin. As osteosarcoma patients are commonly treated with cisplatin-based chemotherapy, our aim was to investigate if REV1 and REV3L polymorphisms influence survival of osteosarcoma patients treated with cisplatin-based chemotherapy. We determined the genotypes of common functional tag REV1 and REV3L polymorphisms in 66 osteosarcoma patients. Cox regression was used for survival analysis. Carriers of at least one polymorphic REV1 rs3087403 allele had significantly shorter EFS and overall survival (OS) (p = 0.004; HR = 3.79; 95%CI = 1.53-9.35 and p0.001; HR = 4.44; 95%CI = 1.92-10.27, respectively). Combination of REV1 rs3087403 and REV3L rs462779 polymorphisms was also significantly associated with shorter OS (ptrend0.001) and shorter EFS (ptrend = 0.003). The results of this first study on polymorphisms in translesion polymerase genes in osteosarcoma suggest they could help predict outcome of cisplatin-based chemotherapy in osteosarcoma patients.

Purpose Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET−). Experimental design Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET− sub-cohorts by the sequencing of exons 16–19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety. Results Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8–93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8–96.1) and 1-year OS: 75.0% (95% CI: 12.8–96.1). Among 16 MET− patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2–30.2), 1-year PFSR: 27.3% (95% CI: 8.5–50.4) and 1-year OS: 71.8% (95% CI: 41.1–88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8–90.6), 1-year PFSR: 66.7% (95% CI: 5.4–94.5) and 1-year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET− case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%). Conclusion Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET− and MET? cases, suggesting the presence of other alterations of MET or alternative pathways.

Background The purpose of this study was to assess the efficacy and toxicity of docetaxel, cisplatin/5-fluorouracil (TPF) induction chemotherapy and concomitant immunochemoradiotherapy with cetuximab and cisplatin in unresectable head and neck carcinoma. Methods Treatment consisted of TPF induction chemotherapy (docetaxel 75 mg/m2 day 2; cisplatin, 75 mg/m2 day 2; and 5-fluorouracil 750 mg/m2 days 1–4; 4 cycles), followed by radiotherapy (RT) and concomitant weekly cetuximab, (250 mg/m2, after a loading dose of 400 mg/m2) and cisplatin (30 mg/m2). Results Twenty-five of 30 patients completed 4 cycles of induction chemotherapy. Six or more concomitant infusions of cisplatin and cetuximab were administered in 13 of 25 and 18 of 25 patients, respectively. The 2-year locoregional control, disease-free survival (DFS), and overall survival (OS) were 47%, 47%, and 50%, respectively. Patients with grade ≥2 skin reaction to cetuximab had a superior outcome. Conclusion The tested regimen was effective; however, cetuximab and low-dose cisplatin after induction TPF increased the treatment toxicity. A grade ≥2 skin rash correlated with improved efficacy. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1555–1561, 2014

Background Guidance on cardiac surveillance during adjuvant trastuzumab therapy remains elusive. The recommended methods are two-dimensional echocardiography (2D-ECHO) and electrocardiography gated equilibrium radionuclide ventriculography (RNV). We assessed the correlation and possible specific merits of these two methods. Methods In a prospective cohort study in patients undergoing post-anthracycline adjuvant trastuzumab therapy, clinical assessment, 2D-ECHO and RNV were performed at baseline, 4, 8 and 12 months. The correlation between used methods was estimated with Pearson's correlation coefficient and Bland-Altman analysis. Results Ninety-two patients (mean age 53.6±9.0 years) were included. The correlation of LVEF measured by ECHO and RNV at each time point was statistically insignificant. Values obtained by ECHO were on average higher (3.7% to 4.5%). A decline in LVEF of ≥10% from baseline was noticed in 19 (24.4%) and 13 (14.9%) patients with ECHO and RNV, respectively, however in only one patient by both methods simultaneously. A decline in LVEF of ≥10% to below 50% was found in three and none patients according to RNV and ECHO measurements, respectively. Conclusions There is a weak correlation of ECHO and RNV measurements in individual patient, the results obtained by the methods are not interchangeable. LVEF values determined by 2D-ECHO were on average higher compared to RNV determined ones. When in an asymptomatic patient a decline in LVEF requiring treatment interruption is detected by RNV ECHO re-evaluation and referral to a cardiologist is advised.

11540Background: ASPS is an orphan disease associated with rearrangement of transcription factor E3 (TFE3), leading to abnormal MET expression. We assessed crizotinib in pts with ASPS (NCT01524926)...

In this paper, we describe the first practical application of two methods, which bridge the gap between the non-expert user and machine learning models. The first is a method for explaining classifiers’ predictions, which provides the user with additional information about the decision-making process of a classifier. The second is a reliability estimation methodology for regression predictions, which helps the users to decide to what extent to trust a particular prediction. Both methods are successfully applied to a novel breast cancer recurrence prediction data set and the results are evaluated by expert oncologists.

Study Design. A case report is of a giant dumbbell-shaped synovial sarcoma of the thoracolumbar spine is presented. Objective. To report a case of a rare dumbbell-shaped tumor treated by multimodal approach. Surgical procedures, adjuvant treatment, and outcome were discussed. Summary of Background Data. Synovial sarcomas of the spine are very rare tumors. Radical surgical resection is the goal, but is often not feasible. Dumbbell-shaped spinal synovial sarcoma with a giant extraspinal extension has not yet been reported. The rationale for 2-step surgical procedure and adjuvant therapy is discussed in light of the clinical picture, preoperative imaging and extension of the disease. Methods. A 32-year-old male patient presented with signs of quickly progressive paraparesis. A dumbbell-shaped tumor at the level Th12–L1 was found with a giant retroperitoneal extension. Tumor was nonradically excised in a 2-step operation: first through a dorsal approach with laminectomy and removal of the intraspinal extradural part, and later through a laparotomy with removal of the retroperitoneal part. Histologic examination revealed highly malignant synovial sarcoma. Patient was treated with chemotherapy and radiotherapy after surgery. Results. Patient was in remission and symptom free for 1 year after surgery; he then developed a local recurrence and died soon afterwards. Conclusion. A good treatment result was achieved initially. A combined approach in cases like this is warranted, with as radical surgery as possible in order to avoid local recurrence, a common cause of treatment failure in sarcomas.

Purpose To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck. Patients and Methods Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m 2 IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m 2 /d IV, applied during the last 10 fractions of irradiation ("chemoboost"). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m 2 /d up to the maximum tolerated dose (MTD) or at the most 14 mg/m 2 /d (Phase I study), which was tested in the subsequent Phase II study. Results All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m 2 /d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m 2 /d, the corresponding rates were 40%, 20%, and 22%, respectively. Conclusion Concomitant chemoradiotherapy with mitomycin C and cisplatin "chemoboost" at 14 mg/m 2 /d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.

Objectives Osteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients. Patients and methods In total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels. Results Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles [P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07-0.94; and P=0.034, HR=0.20, 95% CI=0.05-0.89, respectively]. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10-0.72). Conclusion We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.

As compared to tamoxifen aromatase inhibitors (AIs) may increase the risk of heart disease. Here we explored the association between the use of AIs and coronary artery disease (CAD) in a population-based observational study. In a small and heterogeneous population of 74 women with early breast cancer who received adjuvant hormonal therapy and subsequently underwent cardiac angiography, AIs significantly increased the hazard for CAD (HR 3.23, 95% confidence intervals [CI] 1.26–8.25, p = .01) compared to tamoxifen. Our results suggest that therapy with AIs may increase the risk for CAD.