Breast cancer, along with lung cancer and melanoma, is one of the most common origins of central nervous system metastases. Due to improvement of systemic therapy options for primary disease and consequential prolonged survival, treatment of brain metastasis (BM) is presenting an evolving challenge. While new systemic therapy approaches for breast cancer brain metastasis are focusing on overcoming the blood brain and blood tumor barrier, as well as targeted therapies, local therapy remains the primary line of treatment. The decision of which local therapies to use, depends upon the number and volume of BM, their localization, patient’s clinical status, previously used treatments, status of extracranial disease and patient’s prognosis. In cases when an active approach, including surgery and/or radiotherapy, does not bring benefit to the patient’s quality of life or overall survival, best supportive care is recommended.

Diffuse malignant peritoneal mesothelioma (DMPM) is generally an understudied disease, largely because most molecular and clinical studies of mesothelioma have been conducted in patients with the more common malignant pleural mesothelioma. We present the case of a 45-year-old male that initially presented with abdominal discomfort and ascites. Diagnostic workup revealed advanced DMPM. Bimodal treatment was stared with cytoreductive surgery and hyperthermic intraperitoneal perfusion with chemotherapy procedure, followed by pemetrexed systemic monotherapy. After the disease progression, and because of a very good previous treatment response to pemetrexed, we decided to rechallenge systemic pemetrexed, along with the introduction of cisplatin. Although the intent behind systemic treatment was at first solely palliative, overall survival after the initial diagnosis was 50 months. Treatment based on rechallenging pemetrexed with or without cisplatin in patients with advanced DMPM can result in a quite satisfactory disease control and symptom management.

Lung cancer is the most frequent cancer and the leading cause of cancer mortality. Lung cancer treatment results in terms of patients' long-term survival and cure are far from ideal. Radiotherapy as one of the lung cancer standard treatment modalities can be applied with curative or palliative intent. Radiotherapy treatment intent depends on tumor extent (disease stage), tumor location, patient’s performance status and comorbidities, availability of modern radiotherapy treatment machines and their technical and software capabilities.1-4 Radiotherapy with curative intent is indicated as an alternative to surgical treatment in patients having the early stage disease (generally stages I and II) or a locally more advanced disease (stage III). In early stage disease patients, which are the group with the best prognosis, radiotherapy can be applied as, for example, the sole treatment modality in the form of hypofractioned stereotactic ablative radiotherapy (SABR) for patients with lymph node-negative peripheral non-small cell lung cancer (NSCLC). For patients having inoperable locally advanced lung cancer (stage III) the five-year overall survival rate is at around 15-20%. Therefore, the two remaining standard treatment modalities, chemotherapy and radiotherapy with curative intent, are used and combined whenever possible. Concomitant chemoradiotherapy is the treatment of choice since it gives better results, but in practice a significant number of patients is not fit for this approach. Therefore, the alternative in unfit patients is sequential chemoradiotherapy or radiotherapy alone. In patients having concomitant chemoradiotherapy there are no results in favor of induction or consolidation chemotherapy. It might be that a novel immunotherapy approach with anti-PD-1 or anti-PD-L1 inhibition will in the future improve the survival rate of this group of patients and patients with the metastatic disease.1-4 The effectiveness of radiotherapy depends on the total radiation dose being delivered accurately. For most tumors there is a dose-response effect, i.e. the higher the dose, the higher the chance of local tumor control and cure. The first trial that in the case of lung cancer demonstrated this relationship was published by Perez et al (RTOG 71-01 trial).5 In this dose escalation trial, the dose of 60 Gy in comparison with the dose of 50 and 40 Gy was found, evaluated clinically, to have a lower incidence of local failures (33% versus 39% versus 44% to 49%). The survival of patients according to treatment regimen was not statistically significantly different. The one-year and two-year survival rates for all groups were, respectively, 45% and 25%. On the basis of this trial the dose of 60 Gy in 30 fractions (60 Gy/30x) or higher has since that time been the optimal standard radiotherapy treatment, although patient outcomes were objectively very poor. It should be mentioned that from today's perspective the radiotherapy techniques that were then used (2D radiotherapy planning and relatively large tumor/target volumes) are not recommendable nowadays in radiotherapy treatments with curative intent.3,4 The objectively unsatisfactory clinical outcomes in terms of local tumor control, progression free survival (PFS) and overall survival (OS) after radiotherapy +/- chemotherapy treatments are probably the consequence of the inadequate radiation dose to the tumor tissue. However, the usage of higher doses is limited by the radiation tolerance of surrounding normal tissues and organs.3,4 In clinical radiotherapy, the radiation tolerance of normal tissues and organs surrounding the tumor limits the radiotherapy dose that can be given safely. As the dose is increased, the incidence and severity of normal tissue damage rises. When severe, normal tissue damage can produce life threatening morbidities. Multiple parameters such as total radiation dose, fraction size, overall treatment time, volume and type of normal tissues to be irradiated, definition of target volume, and quality control of radiotherapy techniques should be taken into account. A reduction of radiotherapy-related toxicity is fundamental to the improvement of clinical results in lung cancer as well as other types of cancers. Organs at risk of lung cancer radiotherapy include the lungs, heart, spinal cord, and esophagus. Present knowledge of radiation toxicity is derived from conventional and newer 3D-conformal radiotherapy (3D-CRT) data. The QUANTEC project 6 produced data that are currently used to predict the side effects of radiotherapy and the plausibility of evaluated treatment plans. Before being approved all radiotherapy treatment plans have to be evaluated for the probability of organ-specific radiation toxicity.3,4 Thanks to the evolving radiation imaging and computer technology, a number of innovations in radiotherapy have been introduced in radiotherapy practice within the several past decades. Conventional 2D treatment simulation has been replaced with computer tomography (CT) planning, with volumes delineated according to the International Commission on Radiation Units and Measurements (ICRU) report and ICRU supplements. This CT-based planning together with the possible implementation of other imaging methods such as PET/CT and MRI have enabled more precise target borders and volume determination with the consequence of radiotherapy treatment plans having better tumor dose conformity and sparing the surrounding normal tissues.3,4 Due to a better delineation of tumor margins and reduced rates of radiation-associated toxicity, the current standard radiation treatments based on the implementation of these various technical and technological advances in radiation planning and delivery have allowed the design of clinical studies with radiotherapy dose escalations and modified fractionation schemes. The goal of radiation treatment is to improve clinical outcomes while reducing the damage to the normal tissues. Newer radiotherapy equipment, techniques and treatment planning software can, due to a better delineation of tumor margins and reduced rates of radiation-associated toxicity, allow tumor dose escalation to improve local control and possible tumor cure. Improvements in radiotherapy technique are achieved by using functional images for target definition (PET/CT), 4D-computed tomography (4D-CT), intensity modulated radiation therapy (IMRT) and adaptive radiotherapy.3,4 Several studies have shown a better response with dose escalation in NSCLC. Doses of up to 74 Gy can be delivered when normal tissue constraints are considered. The phase I/II RTOG 9311 trial reported the outcome of a dose-escalated 3D conformal radiotherapy in stage I-III NSCLCs stratified at escalation dose level according to parameters V20 Gy (percentage of the total lung volume that received > 20 Gy). The results of this trial showed that radiation dose escalation was considered safe when using 3D conformal techniques to 83.8 Gy in patients with a V20 < 25% and 77.4 Gy in patients with V20 between 25 and 36%.7 In the RTOG 0617 trial two schedules were compared: 60 Gy (in 6 weeks) versus 74 Gy (in 7.5 weeks) in a 2×2 design where patients were also randomized to receive or not receive cetuximab. Surprisingly, the higher dose arm was not associated with improved survival at 1 year but, rather, showed a contrary trend. The trial showed an OS of 28.7 months for patients who received standard dose radiotherapy compared with 20.3 months for those who received high dose radiotherapy. Median survival in patients who received cetuximab was 21.3 months compared to 24.0 months in those who did not receive cetuximab (p = .29).8 The use of IMRT allows clinicians to obtain better radiotherapy planning parameters such as V20 and mean lung dose and to reduce the probability of development of lung toxicity - radiation pneumonitis. As reported in literature, V20 values of 35–37% and the MLD value of 20–23 Gy have been considered safe but 10–15% of patients can still develop a severe radiation pneumonitis when lower doses are delivered.9 The concomitant use of chemotherapy with radiotherapy can achieve a better overall response, albeit with an increased number of treatment related toxicities – esophagitis and pneumonitis in 10 to 40% of patients.7-9 The use of radiotherapy after chemotherapy with delivered escalated doses of 74 Gy and 86 Gy is associated with a higher incidence of bronchial stenosis (4% and 25%, respectively) and can increase when radiotherapy is used concurrently with chemotherapy. For patients with a locally advanced NSCLC stereotactic ablative radiation treatment (SABR) can be used as a boost to the primary parenchymal lesion. SABR treatment was added after the conventional chemo-radiation (60 Gy/ 30 fractions) treatment: the prescription dose varied from 10 Gy in 2 fractions in peripheral lesion to 6.5 Gy in 3 fractions in the central tumors. After a median follow-up of 13 months local control was 82.9% and there were no patients with a radiation pneumonitis grade 4 or 5.10 Proton therapy is a new potential therapeutic approach to the treatment of NSCLC. Protons have the potential role of reducing the dose to the normal tissue, in particular to the lung and the heart. Initial studies have demonstrated that in patients receiving a concomitant treatment of chemo-radiotherapy the overall survival is influenced by the mean dose to the heart and the lung.3,4,11 As previously described, the univariate and multivariate analysis of RTOG 0617 demonstrated that lung V5, heart V5 and heart V30 were considered predictors of OS. Intraluminal (IL) high-dose rate (HDR) brachytherapy, as the exclusive conformal brachytherapy technique, avoids the previously mentioned dose constraints and could be applied in highly selective cases with significant predominantly endobronchial or endotracheal tumors as a “boost” of 10-15 Gy after external beam radiation therapy (EBRT) (60 Gy/30 fractions) or in a palliative setting in recurrent tumors after EBRT in various fractionation schemes according to the American Brachytherapy Society (ABS): 10-15 Gy in one fraction or IL high-dose rate (HDR) alone 22,5 Gy/3 fractions, 24Gy/4 fractions, 30 Gy/6 fractions. Brachytherapy is recommended if there is a collapsed lung at the first presentation because of improved re-expansion rates using IL HDR over EBRT.4,12,13 In conclusion, remarkable technological advances in the planning and delivery of radiotherapy allows us to do more, which raises hopes that this will be translated into improved clinical outcomes for patients having lung cancer. 1. Non-Small Cell Lung Cancer Treatment (PDQ®) - Health Professional Version. Available from https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq 2. Small Cell Lung Cancer Treatment (PDQ®) - Health Professional Version. Available from https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq 3. Baker S et al. Radiat Oncol. 2016;11:115. http://dx.doi.org/10.1186/s13014-016-0693-8. 4. Giaj-Levra N et al. Cancer Invest. 2016;34:80-93. http://dx.doi.org/10.3109/07357907.2015.1114121. 5. Perez CA et al. Cancer. 1980;45:2744-53. 6. Marks LB et al. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S70-6. http://dx.doi.org/10.1016/j.ijrobp.2009.06.091. 7. Bradley J et al. Int J Radiat Oncol Biol Phys 2005;61:318–28. 8. Bradley JD et al. Lancet Oncol. 2015;16:187-99. http://dx.doi.org/10.1016/S1470-2045(1471207-0). 9. Graham MV et al. Int J Radiat Oncol Biol Phys 1999;45:323–9. 10. Feddock J et al. Int J Radiat Oncol Biol Phys 2013;8:1325–31. 11. Oshiro Y et al. J Radiat Res 2014;55:959–65. 12. Stewart A et al. Brachytherapy, 2016:15:1-11. 13. Langendijk H et al. Radiother Oncol 2001;58:257–68. Radiotherapy, Radiotherapy dose escalation, Radiation dosimetric parameters of toxicity, lung cancer

The recent successful results of several relatively new immunotherapeutic anti-cancer strategies such as the blockade of immune inhibitory pathways by monoclonal antibodies against checkpoint molecules can be considered as a medical breakthrough in clinical cancer immunotherapy. This paper presents a basic overview of cancer immunoediting and the clinical application of monoclonal antibodies against checkpoint molecules in cancer patients. Interactions between the immune system and the malignancy are complex, but the results obtained by using the above mentioned therapeutic approaches indicate acceptable clinical utility, efficacy and safety against several types of cancer. Clinical application of monoclonal antibodies against checkpoint molecules CTLA-4, PD-1, and PD-L1, depending on which tumors these antibodies are tested and applied against, ranges from their already usage having been approved by regulatory agencies for patients with particular metastatic tumors to their testing in clinical studies with the aim of demonstrating their efficiency and consequently obtaining approval.

Uvod: Opis jezgara u ekstirpiranom tumoru neizostavni je dio patohistoloske analize bioptata/ekstirpata raka dojke. Ovisno o velicini, obliku i drugim znacajkama ustanovljenim mikroskopskim pregledom jezgara tumorskog tkiva, rezultat se izražava u tri stupnja. Dobiveni nuklearni gradus predstavlja nezavisnu varijablu prognosticke važnosti. Premda utjece na histoloski gradus (nuklearni gradus je jedna od komponenti skale za histolosko gradiranje tumorskog tkiva), proucava se i izražava neovisno, posto se ne poklapa u potpunosti sa histoloskim gradusom. Histoloski i nuklearni gradus služe procjeni i semi-kvantitativnom izražavanju diferenciranosti tumora (slicnost s normalnim, ishodisnim tkivom). Pri tome nuklearni gradus ima siru primjenjivost jer se može izraziti i kod neinvazivnih lezija (za izražavanje histoloskog gradusa nužna je invazivna komponenta tumora, odnosno sklonost formiranju tubulima-slicnih formacija). Ki-67 (ne-histonski jezgreni protein) kao marker proliferacije (izražen kao proliferacijski indeks – udio pozitivnih stanica, ‘cut-off’ vrijednosti 14%) također ima nezavisni prognosticki znacaj. Nasuprot spomenutom gradiranju, određivanje Ki-67 imunohistokemijskim tehnikama uz brojanje obojanih stanica, nacelno je kvantitativna metoda, manje ovisna o subjektivnoj procjeni analiticara. Podaci o uzorcima hrvatske populacije bolesnica s primarno operabilnim rakom dojke relativno se rijetko objavljuju te stoga želimo prikazati svoje rezultate određivanja nuklearnog gradusa i cimbenika Ki-67 u kohorti bolesnica lijecenih tijekom 2002.-03. u nasem centru, ciji je medijan pracenja oko 10 godina. Materijali i metode: Ukupni broj pracenih bolesnica je 209. Od toga 135 žena bilo je u menopauzi kod dijagnoze. Prevladavale su bolesnice s ranim stadijem bolesti (stadij I i IIa N=130). Nakon operacije i standardne patohistoloske i imunohistokemijske analize primijenjena je adjuvantna terapija prema tada važecim smjernicama, uz iznimku trastuzumaba koji u to doba nije bio dostupan na pozitivnoj listi osiguravatelja. Za pozitivni Ki-67 izražaj uzeta je ‘cut-off’ vrijednost od 14% (postotak obojanih jezgri na sto tumorskih stanica). Kaplan-Meierove krivulje s log-rank testom te Kruskal-Wallisov i Mann-Whitneyev test s Bonferronijevom korekcijom koristeni su za procjenu statisticke znacajnosti razlika među pojedinim skupinama. Rezultati: Nuklearni gradus utjece na ukupno preživljenje (OS, engl. overall survival): nakon 10 godina procjenjeni OS bolesnica s nuklearnim gradusom I iznosi 88, 8%, s nuklearnim gradusom II 80, 8%, a s gradusom III 56%. (Log Rank χ² = 13, 873, P = 0, 001). Preživljenje bez znakova bolesti (DFS, engl. disease free survival) pokazuje trend produljenja kod manjeg nuklearnog gradusa, no nije doseglo statisticku znacajnost (gradus I 84, 2%, gradus II 70, 5%, gradus III 63, 8%, Log Rank χ² = 4, 417, P = 0, 110) Proliferacijski indeks (udio Ki-67 pozitivnih stanica) je veci kod tumora veceg nuklearnog gradusa, premda razlika

Prikazana je problematika lijecenja lokoregionalnog recidiva raka dojke nakon adjuvantnog lijecenja postedno operiranog raka dojke. Dan je prikaz ogranicenja ponavljanja kako sistemne terapije tako radioterapije.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)