Unraveling the Myth of Radiation Resistance in Soft Tissue Sarcomas.

There is a misconception that sarcomas are resistant to radiotherapy. This manuscript summarizes available (pre-) clinical data on the radiosensitivity of soft tissue sarcomas. Currently, clinical practice guidelines suggest irradiating sarcomas in 1.8-2 Gy once daily fractions. Careful observation of myxoid liposarcomas patients during preoperative radiotherapy led to the discovery of this subtype's remarkable radiosensitivity. It resulted subsequently in an international prospective clinical trial demonstrating the safety of a reduced total dose, yet still delivered with conventional 1.8-2 Gy fractions. In several areas of oncology, especially for tumors of epithelial origin where radiotherapy plays a curative role, the concurrent application of systemic compounds aiming for radiosensitization has been incorporated into routine clinical practice. This approach has also been investigated in sarcomas and is summarized in this manuscript. Observing relatively low α/ß ratios after preclinical cellular investigations, investigators have explored hypofractionation with daily doses ranging from 2.85-8.0 Gy per day in prospective clinical studies, and the data are presented. Finally, we summarize work with mouse models and genomic investigations to predict observed responses to radiotherapy in sarcoma patients. Taken together, these data indicate that sarcomas are not resistant to radiation therapy.

Transcutaneous electromyography as a tool to assess recovery of hemidiaphragmatic paresis: A case report.

In this case report, we describe two repeated transcutaneous electromyography of the diaphragm (dEMG) measurements in an infant with suspected paresis of the right hemidiaphragm after cardiac surgery. The first measurement, performed at the time of diagnosis, showed a lower electrical activity of the right side of the diaphragm in comparison with the left side. The second measurement, performed after a period of expectative management, showed that electrical activity of the affected side had increased and was similar to the activity of the left diaphragm. This finding was accompanied by an improvement in the clinical condition. In conclusion, repeated measurement of diaphragmatic activity using transcutaneous dEMG enables the observation and quantification of spontaneous recovery over time. This information may assist the clinician in identifying patients not responding to expectative management and in determining the optimal timing of diaphragmatic surgery.

Added value of repeat sentinel lymph node biopsy in FDG-PET/CT node-negative patients with ipsilateral breast cancer recurrence.

PURPOSE: Repeat sentinel lymph node biopsy (rSLNB) has been suggested for axillary staging in clinically node-negative (cN0) patients with ipsilateral breast tumor recurrence (IBTR). Although rSLNB is technically feasible in this group of patients, the clinical value has not been established. We aimed to assess the added value of rSLNB in cN0 patients with IBTR who underwent optimal clinical staging with FDG-PET/CT. METHODS: This retrospective single-center cohort study included 119 patients with IBTR-staged cT1-4N0M0 with FDG-PET/CT who underwent rSLNB between 2006 and 2020. Overall recurrence-free survival (RFS) and overall survival (OS) were calculated for subgroups with tumor-positive, tumor negative, and unsuccessful rSLNB. RESULTS: rSLNB was successful in 79 (66%) of the 119 included patients, of whom 70 (59%) had a tumor negative and 9 (8%) a tumor-positive rSLNB; rSLNB was unsuccessful in the remaining 40 (34%) patients. Patients with a tumor-positive rSLNB had poorer overall 5-year RFS compared to patients with a tumor negative or unsuccessful rSLNB (44% vs. 86% vs. 90%, p = 0.004). Although patients with a tumor-positive rSLNB had worse RFS, the 10-year OS was comparable to a tumor negative or unsuccessful rSLNB (89% vs. 89% vs. 95%, p = 0.701). CONCLUSION: The incidence of a tumor-positive rSLNB in patients with a negative FDG-PET/CT is low and does not change survival. Therefore, in cN0 patients with IBTR who underwent optimal clinical staging with FDG-PET/CT, we support a patient- and tumor-tailored treatment strategy in which rSLNB may be omitted.

Cellular Radiosensitivity of Soft Tissue Sarcoma.

Currently, all soft tissue sarcomas (STS) are irradiated by the same regimen, disregarding possible subtype-specific radiosensitivities. To gain further insight, cellular radiosensitivity was investigated in a panel of sarcoma cell lines. Fourteen sarcoma cell lines, derived from synovial sarcoma, leiomyosarcoma, fibrosarcoma and liposarcoma origin, were submitted to clonogenic survival assays. Cells were irradiated with single doses from 1-8 Gy and surviving fraction (SF) was calculated from the resulting response data. Alpha/beta (α/ß) ratios were inferred from radiation-response curves using the linear-quadratic (LQ)-model. Cellular radiosensitivities varied largely in this panel, indicating a considerable degree of heterogeneity. Surviving fraction after 2 Gy (SF2) ranged from 0.27 to 0.76 with evidence of a particular radiosensitive phenotype in only few cell lines. D37% on the mean data was 3.4 Gy and the median SF2 was 0.52. The median α/ß was 4.9 Gy and in six cell lines the α/ß was below 4 Gy. A fairly homogeneous radiation response was observed in myxoid liposarcoma cell lines with SF2 between 0.64 and 0.67. Further comparing sarcomas of different origin, synovial sarcomas, as a group, showed the lowest SF2 values (mean 0.35) and was significantly more radiosensitive than myxoid liposarcomas and leiomyosarcomas (P = 0.0084 and 0.024, respectively). This study demonstrates a broad spectrum of radiosensitivities across STS cell lines and reveals subtype-specific radiation responses. The particular cellular radiosensitivity of synovial sarcoma cells supports consideration of the different sarcoma entities in clinical studies that aim to optimize sarcoma radiotherapy.

Management of meningeal solitary fibrous tumors/hemangiopericytoma; surgery alone or surgery plus postoperative radiotherapy?

INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

Preoperative breast radiation therapy: Indications and perspectives.

Preoperative breast radiation therapy (RT) is not a new concept, but older studies failed to change practice. More recently, there has been interest in revisiting preoperative RT using modern techniques. This current perspective discusses the indications, summarises the published literature and then highlights current clinical trials, with particular attention to combining with novel drugs and optimising associated translational research.

Offering a tailored return to work program to cancer survivors with job loss: a process evaluation.

BACKGROUND: In Europe, 1.7 million persons of working age are diagnosed with cancer each year. During or after treatment, cancer survivors (CSs) are vulnerable for job loss, and many CSs struggle with return to work (RTW). When offering RTW interventions to CSs, it is important to conduct a process evaluation to assess such factors as the population reached and implementation problems. Recently, we developed an innovative RTW program, tailored specifically to the needs of CSs with job loss in the Netherlands. The aim of this study was to evaluate the likelihood of theory and implementation failure, as well as to evaluate procedures for recruitment, execution and implementation of the tailored RTW program for CSs with job loss. METHODS: Six components were evaluated in the RTW program: Recruitment, Reach, Dosage, Implementation, Satisfaction, and Experienced Barriers. Data were provided by logbooks and questionnaires from participating CSs, occupational health care (OHC) professionals, and re-integration coaches and job hunting officers who delivered the RTW program. SPSS and Excel were used to conduct the analyses. RESULTS: 85 CSs received the tailored RTW program. Their mean age was 47.9 years (SD 8.5). The majority were female (72 %), married (52 %), and of Dutch nationality (91 %). The program reached 88.2 % of the target population and 52 % of participants who started the program received the adequate dosage. The program implementation score was 45.9 %. Participants' mean overall program duration remained within the protocol boundaries. Re-integration coaches were more satisfied with the program than job hunting officers or OHC professionals. Likewise, participants were more satisfied with the program delivery by the re-integration coaches than with the delivery by the job hunting officers. Reported barriers within the RTW program were a lack of communication, high program intensity and short program duration, and, with regard to the job hunting officers, a lack of experience with cancer-related RTW problems. CONCLUSIONS: Participants, OHC professionals, re-integration coaches and job hunting officers generally had positive experiences with the innovative tailored RTW program. Facilitating communication between the delivering parties, and engaging usual care during program delivery, could be key elements to improved program implementation. TRIAL REGISTRATION: Dutch Trial Register, registration number NTR3562 , registered 07-08-2012.

Less increase of CT-based calcium scores of the coronary arteries : Effect three years after breast-conserving radiotherapy using breath-hold.

PURPOSE: The aim of this prospective longitudinal study was to compare coronary artery calcium (CAC) scores determined before the start of whole breast irradiation with those determined 3 years afterwards. PATIENTS AND METHODS: Changes in CAC scores were analysed in 99 breast cancer patients. Three groups were compared: patients receiving left- and right-sided radiotherapy, and those receiving left-sided radiotherapy with breath-hold. We analysed overall CAC scores and left anterior descending (LAD) and right coronary artery (RCA) CAC scores. Between the three groups, changes of the value of the LAD minus the RCA CAC scores of each individual patient were also compared. RESULTS: Three years after breath-hold-based whole breast irradiation, a less pronounced increase of CAC scores was noted. Furthermore, LAD minus RCA scores in patients treated for left-sided breast cancer without breath-hold were higher when compared to LAD minus RCA scores of patients with right-sided breast cancers and those with left-sided breast cancer treated with breath-hold. CONCLUSION: Breath-hold in breast-conserving radiotherapy leads to a less pronounced increase of CT-based CAC scores. Therefore, breath-hold probably prevents the development of radiation-induced coronary artery disease. However, the sample size of this study is limited and the follow-up period relatively short.

Professionals' opinion on follow-up in breast cancer patients; perceived purpose and influence of patients' risk factors.

AIM: To provide insight into professionals' opinions on breast cancer follow-up to facilitate implementation of new follow-up strategies. The study focuses on current practice, purpose and perceived effects, and preferred frequency and duration of follow-up. DESIGN: A 29-item questionnaire on professionals' demographics, current practice, opinion on the current guideline, preferences in frequency and duration of tailored follow-up, and the purpose and perceived effects of follow-up was sent to 633 Dutch professionals. RESULTS: The current national guideline is followed by 81% of respondents. All different specialists are involved in follow-up. Sixty-nine percent of respondents' report nurse practitioners to be involved in follow-up. When asked for tailored follow-up, professionals indicate more factors for increased follow-up (age<40 years, pT3-4 tumour, pN2-3, treatment related morbidity, and psychosocial support), than for reduced schedules (age >70 years and DCIS histology). Alternative forms of follow-up are not endorsed by >90% of respondents. Detection of a new primary tumour of the breast is considered the most important purpose of follow-up (98%), 57% still indicates detecting metastases as a goal. CONCLUSIONS: Professionals tend towards longer and more intensive follow-up than the current guideline for a large group of patients. Limitations and developments in follow-up need to be considered to facilitate alternative follow-up strategies.

Multicenter cohort study on treatment results and risk factors in stage II endometrial carcinoma.

The aim of this study was to report outcome data and prognostic factors from a large cohort of pathologic stage II endometrioid type endometrial carcinoma. One hundred forty-two stage IIA-B patients were included. A central histopathologic review was performed. Follow-up ranged from 2 to 217 months with a median of 61 months. End points of the study were local and locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS), and disease-specific survival (DSS). The local failure rate was 5.1% for stage IIA patients and 10.8% for stage IIB patients. Grade was the only significant prognostic factor for local failure. With respect to DMFS, DFS, and DSS, grade 3 showed to be the most prominent prognostic factor in multivariate analyses. Lymphvascular space involvement combined with grades 3 and 2 and myometrial invasion greater than 0.5 also showed to be significant for DMFS and DFS. Our study showed grade 3 to be the most important single independent predictive factor for locoregional and distant recurrences in endometrial carcinoma stage II.

Combined E-cadherin, alpha-catenin, and beta-catenin expression is a favorable prognostic factor in endometrial carcinoma.

Cell adhesion molecules, such as epithelial cadherin (E-cadherin), might be involved in the processes of tumor invasion and differentiation. The aim of this study was to investigate the expression of E-cadherin, alpha-catenin, and beta-catenin in endometrial carcinoma and to determine the prognostic value of these factors. We have investigated the expression of E-cadherin, alpha-catenin, and beta-catenin by immunohistochemistry in 225 endometrial carcinomas. The correlation between the E-cadherin and the catenins and their correlation with several histologic and clinical parameters were analyzed. Negative E-cadherin, alpha-catenin, and beta-catenin expression was observed in 44%, 47%, and 33% of endometrial carcinomas, respectively, and was correlated with histologic FIGO grade 3 (P < 0.001). Negative E-cadherin expression was more often observed in nonendometrioid endometrial carcinomas (NEECs) than in endometrioid carcinomas (75% versus 43%; P= 0.04). Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was an independent positive prognostic factor for survival in patients with grade 1-2 carcinomas (P= 0.02). Negative E-cadherin expression was found to be associated with histologic grade 3 and with NEEC. Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was a significant prognostic factor.

Unipolar cardiac pacemakers in electromagnetic fields of high voltage overhead lines.

Experimental studies have shown that both electric and magnetic extremely low frequency fields are able to disturb a cardiac pacemaker (CPM) at certain field strengths. However, the simultaneous influence of multiphase electric and magnetic fields beneath high voltage overhead lines (HVOLs) has not yet been investigated. Therefore, the distribution of the electric and the magnetic field as well as the phase angle between both components for an exemplary HVOL was numerically calculated. The calculations show that the phase difference of the capacitive and the inductive induced voltage on the input of an implanted cardiac pacemaker is position-dependent. Based on these and our earlier results a worst-case-scenario for two virtual patients beneath an exemplary HVOL was derived. It turned out that although the interference of CPMs by the electromagnetic fields (EMFs) of HVOLs cannot be ruled out, the life-threatening interference condition 'inhibition by EMF' is unlikely. Due to various factors depending on technical parameters and the individual patient a definite answer about the disturbance of an implanted CPM beneath HVOLs can be given by studies with real CPM patients only.

Nuclear beta-catenin is a molecular feature of type I endometrial carcinoma.

Two types of endometrial carcinoma can be distinguished: type I tumours, which are oestrogen-related and are typically low-grade endometrioid carcinomas; and type II tumours, which are unrelated to oestrogen stimulation and are often non-endometrioid carcinomas. The molecular abnormalities involved in carcinogenesis appear to be different for these tumour types. The aim of this study was to test the hypothesis that an abnormality in the Wnt/beta-catenin signalling pathway is a molecular feature of type I endometrial carcinoma. This study investigated nuclear beta-catenin by immunohistochemistry in 233 endometrial carcinomas and analysed its correlation with several immunohistochemical, histological, and clinical parameters, such as proliferation rate (Ki-67), expression of oestrogen and progesterone receptors, and survival. Nuclear beta-catenin expression was observed in 39 cases (16%). All tumours expressing nuclear beta-catenin were endometrioid adenocarcinomas, were significantly better differentiated, and were more often hormone receptor-positive than tumours without nuclear beta-catenin. No correlation with proliferation rate was found. It was found that several features of type I endometrial carcinoma occur significantly more often in tumours expressing nuclear beta-catenin, suggesting that an abnormality in the Wnt/beta-catenin signalling pathway, resulting in nuclear beta-catenin immunopositivity, is a molecular feature of a subset of type I endometrial carcinomas.

Hypofractionated radiotherapy for invasive bladder cancer.

BACKGROUND AND PURPOSE: The policy of the Radiotherapy Department of St. Thomas' Hospital in London for patients with invasive bladder cancer, used to be treatment with hypofractionated radiotherapy. The advantages of this fractionation scheme included reduction of the number of treatment sessions and better use of limited resources. Our results after hypofractionation were compared to series with more conventional radiotherapy. MATERIAL AND METHODS: Between 1975 and 1985, 123 patients with a T2-T3 transitional cell carcinoma of the bladder were treated by a radical course of hypofractionated radiotherapy. Local control, survival and morbidity rates were analysed retrospectively. RESULTS: The actuarial local control rates at 5 and 10 years were 31 and 29%, respectively. The actuarial cancer-specific 5- and 10-year survival rates were 48 and 39%, respectively. Acute side effects were observed in 87% of patients. The actuarial overall and severe late complication rates at 5 years were 33 and 9%, respectively. The local control, survival and early side effect rates we found, were in the same range as those reported in literature. Late radiation side effects however, were more common after hypofractionated radiotherapy compared to conventional radiotherapy schedules. CONCLUSIONS: We conclude that the potential advantage of a reduced number of treatment sessions may be lost in the long term, because of the higher incidence of late morbidity after hypofractionated radiotherapy. Hypofractionation however, remains a valuable technique for palliation and deserves further investigation for radical treatment where access to equipment is difficult or resources are limited.

[Electron beam irradiation is effective in the treatment of skin carcinomas; a comparison with superficial roentgen therapy]. / Elektronenbestraling effectief bij de behandeling van huidcarcinomen; een vergelijking met röntgencontacttherapie.

OBJECTIVE: To compare recurrence rates and cosmetic results after electron beam therapy versus superficial X-ray therapy for basal cell and squamous cell carcinomas of the skin. SETTING: Department of Radiotherapy, University Hospital Leiden, the Netherlands. DESIGN: Retrospective. METHODS: A retrospective analysis was performed of 389 histologically confirmed basal cell and squamous cell carcinomas of the skin (1980-1990), treated with either superficial X-rays or electron beam therapy, with regard to local recurrence rates and cosmetics scored with an arbitrary three point scale. RESULTS: Of 389 patients 19 developed a local recurrence (4.9%). For small tumours (irradiated surfaces < or = 10 cm2) a local recurrence rate of 2.2% was observed, both after electron beam therapy and after superficial X-ray therapy. Large tumours (irradiated surface > 50 cm2, treated with electron beam) had a higher recurrence rate (13.8%) as had tumours which had been treated before. The cosmetic results with electron beam treatment were better, because smaller fractions were used compared with superficial X-ray treatment. CONCLUSION: In our hands electron beam treatment was not inferior to superficial X-ray treatment, cosmetically even better and also applicable in case of larger tumours. The inferior results of electron beam therapy reported in literature may be due to technical factors.

Electron beam therapy is not inferior to superficial x-ray therapy in the treatment of skin carcinoma.

PURPOSE: To compare recurrence rates and cosmetic results after electron beam therapy vs. superficial x-ray therapy for nonmelanoma skin carcinoma. METHODS AND MATERIALS: A retrospective analysis was performed on 389 histologically confirmed basal cell and squamous cell carcinomas of the skin, treated with either superficial x-rays or electron beam therapy, with regard to local control rates and cosmetics, as scored with an arbitrary three-point scale. RESULTS: The overall local recurrence rate was 4.9% (19 out of 389). For small tumors (irradiated surfaces < or = 10 cm2) a local recurrence rate of 2.2% was observed, both after electron beam therapy and after superficial x-ray therapy. Tumor size and previous treatment proved to be important prognostic factors with regard to control rate. The well-fractionated electron beam therapy yielded better cosmetic results than the large fraction superficial x-ray therapy. CONCLUSION: Electron beam treatment is not inferior to superficial x-ray treatment and even better for larger tumors. The inferior results of electron beam therapy reported in literature might be due to technical factors, which are discussed.