Survival Benefit of Stereotactic Radiotherapy in the Complex Management of Metastatic Melanoma.

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.

[Subcutaneous and intramuscular heterotopic calcification of the neck 42 years after radiotherapy]. / Subcutan és intramuscularis heterotop kalcifikáció a nyakon 42 évvel a sugárkezelést követoen.

Radiotherapy-induced heterotopic tissue calcification is an exceedingly rare complication in the head and neck region. We report a patient with extensive, radiotherapy-induced, combined subcutaneous and intramuscular, heterotopic calcification of the neck. An 80-year-old male presented with a 2-month history of severe dysphagia and a painful ulcer on the neck 42 years after salvage total laryngectomy following radiotherapy (total dose: 80 Gy) for a T3N0M0 glottic squamous cell carcinoma. We excluded recurrence or secondary malignancy by biopsy and performed computed tomography, which revealed subcutaneous and intramuscular calcification in the area of the skin ulcer and close to the hypopharyngeal wall, moreover, total occlusion of the common carotid and vertebral arteries bilaterally. Surgical correction involved removing the calcified lesions and closure using fasciocutaneous flap transposition. The patient has been asymptomatic for the past 48 months. Radiotherapy plays an essential role in the treatment of patients with head and neck squamous cell carcinoma. Distorted postoperative anatomy, excessive scar formation, radiotherapy-induced fibrosis as well as skin and subcutaneous tissue calcification can present as atypical findings. Orv Hetil. 2023; 164(10): 383-387.

Magnetic Resonance Imaging-Based Delineation of Organs at Risk in the Head and Neck Region.

Purpose: The aim of this article is to establish a comprehensive contouring guideline for treatment planning using only magnetic resonance images through an up-to-date set of organs at risk (OARs), recommended organ boundaries, and relevant suggestions for the magnetic resonance imaging (MRI)-based delineation of OARs in the head and neck (H&N) region. Methods and Materials: After a detailed review of the literature, MRI data were collected from the H&N region of healthy volunteers. OARs were delineated in the axial, coronal, and sagittal planes on T2-weighted sequences. Every contour defined was revised by 4 radiation oncologists and subsequently by 2 independent senior experts (H&N radiation oncologist and radiologist). After revision, the final structures were presented to the consortium partners. Results: A definitive consensus was reached after multi-institutional review. On that basis, we provided a detailed anatomic and functional description and specific MRI characteristics of the OARs. Conclusions: In the era of precision radiation therapy, the need for well-built, straightforward contouring guidelines is on the rise. Precise, uniform, delineation-based, automated OAR segmentation on MRI may lead to increased accuracy in terms of organ boundaries and analysis of dose-dependent sequelae for an adequate definition of normal tissue complication probability.

BC-Monitor: Towards a Routinely Accessible Circulating Tumor DNA-Based Tool for Real-Time Monitoring Breast Cancer Progression and Treatment Effectiveness.

Circulating tumor DNA (ctDNA) is increasingly employed in the screening, follow-up, and monitoring of the continuously evolving tumor; however, most ctDNA assays validated for clinical use cannot maintain the right balance between sensitivity, coverage, sample requirements, time, and cost. Here, we report our BC-monitor, a simple, well-balanced ctDNA diagnostic approach using a gene panel significant in breast cancer and an optimized multiplex PCR-based NGS protocol capable of identifying allele variant frequencies below 1% in cell-free plasma DNA. We monitored a cohort of 45 breast cancer patients prospectively enrolled into our study receiving neoadjuvant chemotherapy or endocrine therapy or palliative therapy for metastatic diseases. Their tumor mutation status was examined in the archived tumor samples and plasma samples collected before and continuously during therapy. Traceable mutations of the used 38-plex NGS assay were found in approximately two-thirds of the patients. Importantly, we detected new pathogenic variants in follow-up plasma samples that were not detected in the primary tumor and baseline plasma samples. We proved that the BC-monitor can pre-indicate disease progression four-six months earlier than conventional methods. Our study highlights the need for well-designed ctDNA monitoring during treatment and follow-up, integrated into a real-time treatment assessment, which could provide information on the active tumor DNA released into the blood.

Cognitive Functioning and Psychological Well-being in Breast Cancer Patients on Endocrine Therapy.

BACKGROUND/AIM: Anti-cancer therapies may deteriorate cognitive functioning, affective functioning and psychological well-being. MATERIALS AND METHODS: In this prospective longitudinal pilot study, premenopausal and postmenopausal patients received adjuvant endocrine therapy (ET) (tamoxifen with or without LHRH analog or aromatase inhibitor) or were observed only (control group). At baseline testing and 6, 12 and 24 months thereafter, cognitive, depression and anxiety tests and quality of life (QOL) measurements were performed. RESULTS: Overall, 46 cases were evaluated. None of the studied cognitive parameters differed between the subgroups or changed by time. No differences were found regarding anxiety, depression or QOL measures either. Baseline cognitive test and QOL results were in association with later anxiety and depression. CONCLUSION: No cognitive impairment was found during the two years of ET. Baseline cognitive scores and QOL dimensions proved good predictors of later anxiety and depression.

One-Year Neoadjuvant Endocrine Therapy in Breast Cancer.

The evaluation of the effects of 1-year endocrine therapy (NET) was aimed at. A retrospective analysis of 42 cases with 46 stage II-III invasive, hormone receptor-positive, HER2-negative breast cancers was performed. One-year NET was planned with letrozole (n = 33, postmenopausal group), or with goserelin plus letrozole (n = 7) or with goserelin plus tamoxifen (n = 2) (premenopausal group). Surgery was performed in accordance with the initial stage and the response to therapy. With regard to the tumor remaining in the surgical specimen, risk groups were constructed: Group 1: stage 0, pathological complete regression (pCR); Group 2: stages IA-IIA; Group 3: stages ≥ IIB + cases with clinical progression. Due to local progression, NET was replaced by neoadjuvant chemotherapy in three patients (four tumors). In two postmenopausal patients, letrozole was replaced by tamoxifen because of the insufficient treatment effect. In 19/42 cases, breast-conserving surgery was performed. Within Group 1, there was no cancer in four cases, while only DCIS remained in 2 (pCR: 13 %); Groups 2 and 3 comprised 25 and 15 cases, respectively. The likeliness of a good response (Groups 1 and 2 vs. Group 3) to NET was increased by 7 % for every 1 % increase of the expression of ER (OR = 1.070; 95 % CI: 1.007-1.138, p = 0.029). Progression-free survival differed according to treatment response (p = 0.001). The post-therapy Ki67 value of ≤ 15 % had only a marginal effect on survival. No other associations were detected between the tumor characteristics and the therapeutic response or survival. Long-duration NET is effective and safe in cases of hormone-sensitive breast cancer.

Different methods of pretreatment Ki-67 labeling index evaluation in core biopsies of breast cancer patients treated with neoadjuvant chemotherapy and their relation to response to therapy.

Increased proliferation activity of breast cancer cells evaluated by Ki-67 immunohistochemistry, i.e. a high Ki-67 labeling index (Ki-67 LI), may predict better tumor regression in case of neoadjuvant chemotherapy. Despite recommendations for the evaluation of Ki-67 LI, there are variations in methodology. We assessed the effect of different evaluation methods on the Ki-67 LI in patients with different response to neoadjuvant chemotherapy. Thirty pretreatment core-biopsy samples of patients receiving neoadjuvant docetaxel-epirubicin chemotherapy with or without capecitabine were evaluated for their Ki-67 LI. Pathologic regression was categorized as no regression, partial regression and complete regression, with 10 cases in each category. Three antibodies (MIB1, B56, SP6), 4 observers and 4 methods (counting or estimating on glass slides and counting or estimating on representative digital images) were compared. The Kruskal-Wallis test and analyses of variance were performed to investigate the differences in Ki-67 LIs between different clinical outcomes (tumor regression categories). Breast carcinomas with pathological complete regression had a higher mean Ki-67 LI than tumors not achieving complete regression with any methods, observers and antibodies investigated, although there was a variation between different evaluations in what may represent high proliferation. Estimating the Ki-67 LI on digital images representing the highest proliferation in the core biopsy seemed the best in separating complete responders from non-responders. High Ki-67 LI values were more likely associated with pathological complete regression independently of the method of evaluation used, although the definition of high proliferation is problematic. Estimating the Ki-67 LI may be an adequate method of evaluation.

The use of digital images improves reproducibility of the ki-67 labeling index as a proliferation marker in breast cancer.

The proportion of Ki-67 immunostained cells (Ki-67 labeling index, LI) is one of the most commonly used histology methods for estimating proliferation of breast carcinomas. Although the Ki-67 LI is used in treatment decision making, its reproducibility shows variation in different studies, and is generally less then optimal. The aim of the present study was to investigate how the use of a standardized, partially digitalized counting method could affect reproducibility of determining the Ki-67 LI. Thirty breast cancer core-biopsy samples were stained with B-56, SP-6 and MIB-1 monoclonal Ki-67 antibodies. Each sample was represented by a single digital photograph taken with a x20 objective. Four investigators determined the Ki-67 LI on these digital images by estimation, then by counting with the help of a grid overlaid on the same images. Altogether 720 evaluations were made by 4 independent pathologists. Good to excellent correlation was found between estimations and calculations of each observer. Kappa values >0.6 suggest substantial inter-observer agreement when classifying the cases into a 15 % and 30 % cut-off determined three-tiered or a 4-quarter-based four-tiered categorization, which is better than the fair reproducibility gained on the real slides in a previous study. The results also suggest that the type of the antibody may also impact on the consistency of both estimating and calculating the Ki-67 LIs. The results indicate that counting on digital images may significantly improve reproducibility of determining the KI-67 LI. Interestingly, estimation on the same images is not worse, but is obviously faster and more convenient.

Cosmetic outcome 1-5 years after breast conservative surgery, irradiation and systemic therapy.

The late side-effects of the local therapy of early breast cancer depend on many patient- and therapy-related parameters. We aimed at investigating the factors that influence the cosmetic and functional outcomes among our breast cancer patients after breast-conserving surgery and conformal radiotherapy, with or without adjuvant systemic therapy. A study was made of the association of the cosmetic outcome after a median follow-up time of 2.4 years and the clinical data on 198 patients extracted from a prospectively compiled database. Breast tenderness occurred more frequently among patients ≤50 years old (p < 0.05). Long-term side effects were related to radiotherapy-related factors the most, while no effect of the systemic therapy could be detected. The risk of hyperpigmentation, breast edema and breast fibrosis increased by 18%, 23% and 7%, respectively for every 100 cm(3) increase in the irradiated breast volume, while that of breast edema and breast fibrosis increased by 21% and 12%, respectively for every 10 cm(3) increase in the boost volume. Patients who received a photon boost were significantly more likely to develop breast edema and fibrosis than those who received electrons (p < 0.005). Dose inhomogeneity was related to the volume of the irradiated breast (p = 0.037). Dyspigmentation developed more often among patients older than 50 years, while smoking favoured both dyspigmentation and teleangiectasia. Breast edema was related to dyspigmentation (p = 0.003), fibrosis (p < 0.001) and breast asymmetry (p = 0.032), whereas none of these abnormalities were associated with teleangiectasia. Body image changes were more frequent at a younger age (p < 0.005), while the need to change clothing habits occurred more often at an older age (p < 0.05). Radiotherapy-related parameters appear to exert the greatest effect on the overall cosmetic outcome after breast-conserving surgery and postoperative radiotherapy.

Role of systemic therapy in the development of lung sequelae after conformal radiotherapy in breast cancer patients.

PURPOSE: To analyze the risk of radiogenic lung damage in breast cancer patients after conformal radiotherapy and different forms of systemic treatment. METHODS AND MATERIALS: In 328 patients receiving sequential taxane-based chemotherapy, concomitant hormone therapy (tamoxifen or aromatase inhibitors), or no adjuvant systemic therapy, symptomatic and asymptomatic lung sequelae were prospectively evaluated via the detection of visible CT abnormalities, 3 months or 1 year after the completion of the radiotherapy. RESULTS: Significant positive associations were detected between the development of both pneumonitis and fibrosis of Grade 1 and patient age, ipsilateral mean lung dose, volume of the ipsilateral lung receiving 20 Gy, and irradiation of the regional lymph nodes. In multivariate analysis, age and mean lung dose proved to be independent predictors of early (odds ratio [OR] = 1.035, 95% confidence interval [CI] 1.011-1.061 and OR = 1.113, 95% CI 1.049-1.181, respectively) and late (OR = 1.074, 95% CI 1.042-1.107 and OR = 1.207, 95% CI 1.124-1.295, respectively) radiogenic lung damage, whereas the role of systemic therapy was significant in the development of Grade 1 lung fibrosis (p = 0.01). Among the various forms of systemic therapy, tamoxifen increased the risk of late lung sequelae (OR = 2.442, 95% CI 1.120-5.326, p = 0.025). No interaction was demonstrated between the administration of systemic therapy and the other above-mentioned parameters as regards the risk of radiogenic lung damage. CONCLUSIONS: Our analyses demonstrate the independent role of concomitant tamoxifen therapy in the development of radiogenic lung fibrosis but do not suggest such an effect for the other modes of systemic treatment.

Estrogen receptor negative and progesterone receptor positive breast carcinomas-how frequent are they?

Estrogen receptor (ER) testing has become an important part of breast cancer reporting as the ER status is a predictor of hormonal treatment efficacy. Progesteron receptors (PR) are often tested in parallel, and the best response to hormonal manipulations can be expected in tumors positive for both receptors. The existence of breast cancers with an ER negative and PR positive phenotype is controversial. A series of cases with this phenotype were reevaluated to clarify the existence and the frequency of this entity. A total of 205/6587 (3.1%; range of the rate per department: 0.3-7.1%.) cases reported to have the ER-negative and PR-positive status by immunohistochemistry were collected from 9 Hungarian departments. After careful reevaluation of the tumor slides and control tissues with a 1% cut-off for positivity and restaining of the questionable cases, all but 1 of the reevaluable 182 cases changed their original phenotype. Most cases converted to dual positives (n = 124) or dual negatives (n = 31) or unassessable / questionable. ER-negative and PR-positive breast cancers are very rare if existing. Such a phenotype should prompt reassessment.

Breast cancer under 40 years of age: increasing number and worse prognosis.

Breast cancer at a relatively young age with a poor prognosis is currently exhibiting an increasing incidence. In a retrospective cohort analysis of early breast cancer cases after surgery from our institutional patient registry, 141 patients aged ≤ 40 years constituted the younger group, with 300 randomly selected patients aged >40 years as controls. A significant and steady increase was found in the relative number of younger cases during the years 2004-2009. The histological type and grade and the lymph node status of the cancers differed significantly between the two groups, with more aggressive biological behaviour, a more advanced stage and a worse prognosis in the younger group. Half of the cancers in the younger cohort were ER-negative, while two-thirds in the control group were ER-positive. Comparatively more tumours were PR-positive and HER2-negative in the control group than in the younger group. The rates of triple-negative cases were 25% and 13% in the younger age and the control group, respectively (p = 0.026). Significantly higher mastectomy and axillary block dissection rates were observed in the younger age group, and more chemotherapy was administered than in the control group. Our findings demonstrate the significance of breast cancer in cases aged <40 years, and draw attention to the need for appropriate care in these cases.

Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer.

OBJECTIVES: To perform a protocol-specified analysis of the dose-dense adriamycin-paclitaxel-cyclophosphamide (ddATC) study. METHODS: Survival and late toxicity were analyzed in 55 patients enrolled to receive 4 x adriamycin 60 mg/m(2), 4 x paclitaxel 200 mg/m(2), 4 x cyclophosphamide 800 mg/m(2), every 2 weeks, with cardioxane and filgrastim support. Kaplan-Meier curves were used to analyze relapse-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). Survival analyses were performed according to the presence of casting-type calcifications on the mammogram. RESULTS: After a median follow-up time of 78.5 (64.3-100.0) months, 29 (52.7%) patients were free of relapse (local, regional, distant or contralateral breast cancer), 34 (61.8%) patients were free of distant metastases, and 36 patients (65.5%) survived. The median times of RFS, DDFS and OS were not yet reached at 100.0 months. The median RFS, DDFS and OS times among breast cancer patients with tumors not associated with casting-type calcifications were >100.0 months, the corresponding parameters among patients with tumors accompanied by casting calcifications were 11.5 (p < 0.001), 11.5 (p < 0.001) and 29.6 months (p = 0.035), respectively. None of the patients developed myelodysplastic syndrome or leukemia. No cardiac failure occurred during the follow-up period. CONCLUSIONS: Our results indicate that adjuvant sequential ddATC is an efficient and less toxic chemotherapy regimen in high-risk breast cancer. The presence of casting-type calcifications on the mammogram points to a special biologic nature with very poor prognosis.

Tumor characteristics in screen-detected and symptomatic breast cancers.

The natural course of early breast cancer has changed as a result of the introduction of mammographic screening. The present aim was a prospective analysis of screen-detected and symptomatic operable breast cancers in the era of mammographic service screening. The mode of detection (screen-detected, symptomatic or interval cancer), the type of mammographic image and other characteristics (the invasive tumor size, histological tumor type, grade, nodal, hormone receptor and HER2 status and the presence of lymphovascular invasion) of 569 invasive breast cancers were studied. Screen-detected cancers were significantly more frequently of grade I, < 10 mm of size and node-negative (p < 0.001, respectively). Symptomatic/interval cancers were significantly more frequently of grade 3, >20 mm of size (p < 0.001), and exhibited lymphovascular invasion (p = 0.001). Screening-detection of the tumor favored breast-conserving surgery, sentinel lymph node biopsy and the avoidance of chemotherapy (p < 0.001). Cancers associated with casting-type calcifications on the mammogram were typically of ductal type (p = 0.043), of grade 2-3, estrogen receptor and progesterone receptor-negative and HER2-positive (p < 0.001). Interval cancers occurred significantly more often at a younger age and remained mammographically occult as compared with other cancers. Mammographic screen-detected cancers demonstrate more favorable prognostic features, and need less extensive treatment than symptomatic or interval cancers. The mammographic appearance of the tumor reflects its biological behavior, and this should be considered in the management optimization.