Determination of the optimal matching position for setup images and minimal setup margins in adjuvant radiotherapy of breast and lymph nodes treated in voluntary deep inhalation breath-hold

Background Adjuvant radiotherapy (RT) of left-sided breast cancer is increasingly performed in voluntary deep inspiration breath-hold (vDIBH). The aim of this study was to estimate the reproducibility of breath-hold level (BHL) and to find optimal bony landmarks for matching of orthogonal setup images to minimise setup margins. Methods 1067 sets of images with an orthogonal setup and tangential field from 67 patients were retrospectively analysed. Residual position errors were determined in the tangential treatment field images for different matches of the setup images. Variation of patient posture and BHL were analysed for position errors of the vertebrae, clavicula, ribs and sternum in the setup and tangential field images. The BHL was controlled with a Varian RPM® system. Setup margins were calculated using the van Herk’s formula. Patients who underwent lymph node irradiation were also investigated. Results For the breast alone, the midway compromise of the ribs and sternum was the best general choice for matching of the setup images. The required margins were 6.5 mm and 5.3 mm in superior-inferior (SI) and lateral/anterior-posterior (LAT/AP) directions, respectively. With the individually optimised image matching position also including the vertebrae, slightly smaller margins of 6.0 mm and 4.8 mm were achieved, respectively. With the individually optimised match, margins of 7.5 mm and 10.8 mm should be used in LAT and SI directions, respectively, for the lymph node regions. These margins were considered too large. The reproducibility of the BHL was within 5 mm in the AP direction for 75% of patients. Conclusions The smallest setup margins were obtained when the matching position of the setup images was individually optimised for each patient. Optimal match for the breast alone is not optimal for the lymph node region, and, therefore, a threshold of 5 mm was introduced for residual position errors of the sternum, upper vertebrae, clavicula and chest wall to retain minimal setup margins of 5 mm. Because random interfraction variation in patient posture was large, we recommend daily online image guidance. The BHL should be verified with image guidance.BioMed Central open acces

Troponin T-release associates with cardiac radiation doses during adjuvant left-sided breast cancer radiotherapy

Background Adjuvant radiotherapy (RT) for left-sided breast cancer increases cardiac morbidity and mortality. For the heart, no safe radiation threshold has been established. Troponin T is a sensitive marker of myocardial damage. Our aim was to evaluate the effect of left-sided breast cancer RT on serum high sensitivity troponin T (hscTnT) levels and its association with cardiac radiation doses and echocardiographic parameters. Methods A total of 58 patients with an early stage, left-sided breast cancer or ductal carcinoma in situ (DCIS) who received adjuvant breast RT without prior chemotherapy were included in this prospective, non-randomized study. Serum samples were taken before, during and after RT. An increase of hscTnT >30 % was predefined as significant. A comprehensive 2D echocardiograph and electrocardiogram (ECG) were performed before and after RT. Dose-volume histograms (DVHs) were generated for different cardiac structures. Results The hscTnT increased during RT from baseline in 12/58 patients (21 %). Patients with increased hscTnT values (group A, N = 12) had significantly higher radiation doses for the whole heart (p = 0.02) and left ventricle (p = 0.03) than patients without hscTnT increase (group B, N = 46). For the left anterior descending artery (LAD), differences between groups A and B were found in volumes receiving 15 Gy (p = 0.03) and 20 Gy (p = 0.03) Furthermore, after RT, the interventricular septum thickened (p = 0.01), and the deceleration time was prolonged (p = 0.008) more in group A than in group B. Conclusions The increase in hscTnT level during adjuvant RT was positively associated with the cardiac radiation doses for the whole heart and LV in chemotherapy-naive breast cancer patients. Whether these acute subclinical changes increase the risk of excessive long-term cardiovascular morbidity or mortality, will be addressed in the follow-up of our patients.BioMed Central open acces

Ihomelanooman onkologinen hoito päivittyi

Tiivistelmä Suomen Melanoomaryhmä ry päivitti suosituksensa ihomelanooman onkologisesta hoidosta. Vuoden kestävää liitännäislääkehoitoa PD-1-vasta-aineella eli immuuniaktivaation vapauttajalla (nivolumabi tai pembrolitsumabi) tai dabrafenibilla ja trametinibilla harkitaan leikatuille, levinneisyysasteen IIIB-IV melanoomapotilaille melanooman uusiutumisriskin pienentämiseksi. Päätös liitännäishoidosta tehdään yhdessä potilaan kanssa hyödyt ja haitat huomioiden. Levinneen melanooman ensilinjan hoitovaihtoehtona ovat PD-1-vasta-aineet, joiden lisäksi BRAFV600-mutaatiopositiivisille potilaille soveltuvat hoidot BRAF:n ja MEK:n estäjillä. Immunologista yhdistelmähoitoa CTLA-4- ja PD-1-vasta-aineilla (ipilimumabi ja nivolumabi) harkitaan huonoennusteisille hyväkuntoisille potilaille. Muita edenneen melanooman lääkehoitovaihtoehtoja ovat onkolyyttinen virushoito (TVEC) pinnallisen metastasoinnin ja isoloitu raajaperfuusio- eli ILP-hoito raajaan rajoittuvan metastasoinnin yhteydessä sekä solunsalpaajahoidot. Nopeasti kehittyvän hoidon vuoksi melanoomapotilaat pyritään rekrytoimaan kliinisiin hoitotutkimuksiin aina kun se on mahdollista

Systemic blockade of clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors:results from a phase I/II clinical trial

Abstract Purpose:: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell–targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8⁺ T-cell–mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1–targeting antibodies for cancer treatment. Patients and Methods:: In this study, we analyzed the mode of action of a humanized IgG4 anti–Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305–induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase–mediated endosomal acidification and improved the ability of macrophages to activate CD8⁺ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer