Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer. Methods: One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL. Results: When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Conclusions: Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.
Abstract Background Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes, but the clinical relevance of this triggered immune response is not known. We decided to investigate, whether treatment with various chemotherapeutic agents with significantly different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in the clinical setting. Methods 112 breast carcinoma cases treated with pre-operative chemotherapy were selected for the study. According to chemotherapy regimen 28/112 patients received platinum-based, 42/112 cyclophosphamide-based and 42/112 anthracycline-based chemotherapy. The percentage of stromal tumor-infiltrating lymphocytes (StrTIL) was evaluated on hematoxylineosin stained slides of pre-treatment core biopsy (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL), according to the most recent recommendation of International TILs Working Group. In survival analyses, TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL. Results Of the 112 cases, 58.0% (n=65) were hormone receptor (HR) positive and 42.0% (n=47) were HR negative. There was a trend of higher post-StrTIL compared to pre-StrTIL (median 6.25% vs. 3.00%; p<0.001). When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we experienced significant StrTIL increase independently of the treatment applied. Based on the results of survival analyses both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Each 1% increase in post-StrTIL reduced the hazard of distant metastases development by 2.6% (hazard ratio: 0.974; CI: 0.948-1.000; p=0.05) and for each 1% ΔStrTIL increment, the risk of distant metastases was reduced by 4.3% (hazard ratio: 0.957; CI: 0.932-0.983; p=0.001). The prognostic role of StrTIL in HR positive cases could not be proven. Conclusions StrTIL expression might be stimulated by highly (platinum), moderately (cyclophosphamide) and marginally (taxane, anthracycline) mutagenic chemotherapeutic agents. Increase in StrTIL in residual cancer compared to pre-treatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.
In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study.From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively.The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%.Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.
Background/Aim: Targeted therapy and immunotherapy, with additional stereotactic radiation therapy (SRT) have revolutionized the management of metastatic malignant melanoma (mMM). We aimed to analyze the effectiveness and safety of SRT and determine its role in the complex management of mMM. Patients and Methods: We treated 24 patients with solitary metastasis, 15 with oligometastatic disease and one with multiple metastases. The primary endpoint was to investigate the possible effect of stereotactic radiotherapy for metastatic lesions on patients' survival taking the systemic therapy into consideration. Results: The median overall survival (OS) for the entire group was 30.07 months; 50% of them received immunotherapy, 32% received targeted therapy. Complete remission of the irradiated lesions was observed in six patients, partial tumor response was achieved in 13, while stable disease was detected in 10; tumor progression occurred in four cases. Compartmental recurrence (recurrence in the brain in a not previously irradiated region) developed in seven patients. OS was significantly longer in those with extracranial metastases treated with stereotactic body radiotherapy in comparison to brain SRT. We found a strong correlation between tumor response and mean OS (42.5 months after complete or partial remission versus 11.8 months in those with stable or progressive disease). No OS difference was observed according to the number of irradiated lesions or type of systemic therapy before SRT (no therapy: 43.6 months, with therapy: 25.7 months). Significant OS advantage was shown when immunotherapy was administered post-SRT (mean OS: with immunotherapy: 39.6 months, no immunotherapy: 18.5 months). Conclusion: In the case of oligometastatic MM, SRT can be used safely and with good efficiency in addition to targeted therapy/anti-programmed cell death protein 1 therapy. Improved survival warrants including SRT in the complex management of mMM, however, further studies are needed for SRT optimization.
The presence of normal tissues in the irradiated volume limits dose escalation during pelvic radiotherapy (RT) for prostate cancer.Supine and prone positions on a belly board were compared by analyzing the exposure of organs at risk (OARs) using intensity modulated RT (IMRT).The prospective trial included 55 high risk, localized or locally advanced prostate cancer patients, receiving definitive image-guided RT.Computed tomography scanning for irradiation planning was carried out in both positions.Gross tumor volume, clinical and planning target volumes (PTV) and OARs were delineated, defining subprostatic and periprostatic rectal subsegments.At the height of the largest antero-posterior (AP) diameter of the prostate, rectal diameters and distance from the posterior prostate wall were measured.IMRT plans were generated.Normal tissue exposure and structure volumes were compared between supine and prone plans using paired t-test.In the volumes of the prostate, PTV, colon and small bowel, no significant differences were found.In prone position, all rectal volumes, diameters, and rectum-prostate distance were significantly higher, the irradiated colon and small bowel volume was lower in dose ranges of 20-40 Gy, and the exposure to all rectal segments was more favorable in 40-75 Gy dose ranges.No significant difference was found in the exposure of other OARs.Prone positioning on a belly board is an appropriate positioning method aiming rectum and bowel protection during pelvic IMRT of prostate cancer.The relative reduction in rectal exposure might be a consequence of the slight departure between the prostate and rectal wall.
Introduction: The excellent soft-tissue contrast of magnetic resonance imaging (MRI) is appealing for delineation of organs-at-risk (OARs) as it is required for radiation therapy planning (RTP). In the last decade there has been an increasing interest in using deep-learning (DL) techniques to shorten the labor-intensive manual work and increase reproducibility. This paper focuses on the automatic segmentation of 27 head-and-neck and 10 male pelvis OARs with deep-learning methods based on T2-weighted MR images. Method: The proposed method uses 2D U-Nets for localization and 3D U-Net for segmentation of the various structures. The models were trained using public and private datasets and evaluated on private datasets only. Results and discussion: Evaluation with ground-truth contours demonstrated that the proposed method can accurately segment the majority of OARs and indicated similar or superior performance to state-of-the-art models. Furthermore, the auto-contours were visually rated by clinicians using Likert score and on average, 81% of them was found clinically acceptable.
The aim of the current prospective pilot study exclusively for deep-seated soft tissue sarcomas (STS) was to evaluate efficacy and safety of bleomycin-based ECT using VEG (variable electrode geometry) electrodes. During a 2-year period, seven surgically inoperable STSs were treated at the University of Szeged, Department of Surgery in Hungary. Electrode placement was determined by software planning using preoperative imaging (CT/MRI) and intraoperative ultrasound. Intravenous bleomycin (15.000 IU/m2) was administered 8 min before first pulse generation which lasted up to 40 min. Tumour response was evaluated through CT/MRI 2 months after treatment as per RECIST v.1.1. Five male- and 2 female patients were treated with fibromyxoid sarcoma (n = 2), epitheloid sarcoma (n = 3), liposarcoma (n = 1) and myofibroblastic sarcoma (n = 1) with median age of 54 years (49-88). Median tumour diameter, tumour volume and tumour depth was 5.9 cm (3.7-22.5), 131.13 cm3 (35.6-2456.22) and 6.18 cm (3.74-18.18), respectively. Median operative time was 75 min (35-180), median hospital stay 2 days (2-20). Two month follow-up confirmed partial response in 5 patients, while stable disease in 1 patient, and progressive disease in 1 case as per RECIST v.1.1. Grade 2 ulceration was experienced in four cases, and a transient left musculus quadriceps femoris plegia occured in one patient. Local control of deep-seated STSs with BLM-based VEG ECT holds a promising perspective and our results may serve as a practical guide for further investigation and treatment planning.
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