2023 Radiation oncology highlights.

Radiation oncology plays an important role in the local treatment of cancers. Understanding recent advances in the application of radiation therapy to solid tumors is important for all disciplines. The radiation oncology section editors for this journal have selected the following articles for their overall significance, relevance to surgical oncologists, and to illustrate important concepts within the practice of radiation oncology.

Sulfamethoxazole is Metabolized and Mineralized at Extremely Low Concentrations.

The presence of organic micropollutants in water and sediments motivates investigation of their biotransformation at environmentally low concentrations, usually in the range of µg L-1. Many are biotransformed by cometabolic mechanisms; however, there is scarce information concerning their direct metabolization in this concentration range. Threshold concentrations for microbial assimilation have been reported in both pure and mixed cultures from different origins. The literature suggests a range value for bacterial growth of 1-100 µg L-1 for isolated aerobic heterotrophs in the presence of a single substrate. We aimed to investigate, as a model case, the threshold level for sulfamethoxazole (SMX) metabolization in pure cultures of Microbacterium strain BR1. Previous research with this strain has covered the milligram L-1 range. In this study, acclimated cultures were exposed to concentrations from 0.1 to 25 µg L-1 of 14C-labeled SMX, and the 14C-CO2 produced was trapped and quantified over 24 h. Interestingly, SMX removal was rapid, with 98% removed within 2 h. In contrast, mineralization was slower, with a consistent percentage of 60.0 ± 0.7% found at all concentrations. Mineralization rates increased with rising concentrations. Therefore, this study shows that bacteria are capable of the direct metabolization of organic micropollutants at extremely low concentrations (sub µg L-1).

Extrapolation of cytotoxic masked effects in planar in vitro assays.

The masking of specific effects in in vitro assays by cytotoxicity is a commonly known phenomenon. This may result in a partial or complete loss of effect signals. For common in vitro assays, approaches for identifying and quantifying cytotoxic masking are partly available. However, a quantification of cytotoxicity-affected signals is not possible. As an alternative, planar bioassays that combine high-performance thin layer chromatography with in vitro assays, such as the planar yeast estrogen screen (p-YES), might allow for a quantification of cytotoxically affected signals. Affected signals form a typical ring structure with a supressed or completely lacking centre that results in a double peak chromatogram. This study investigates whether these double peaks can be used for fitting a peak function to extrapolate the theoretical, unaffected signals. The precision of the modelling was evaluated for four individual peak functions, using 42 ideal, undistorted peaks from estrogenic model compounds in the p-YES. Modelled ED50-values from bisphenol A (BPA) experiments with cytotoxically disturbed signals were 13 times higher than for the apparent data without compensation for cytotoxicity (320 ± 63 ng versus 24 ± 17 ng). This finding has a high relevance for the modelling of mixture effects according to concentration addition that requires unaffected, complete dose-response relationships. Finally, we applied the approach to results of a p-YES assay on leachate samples of an elastomer material used in water engineering. In summary, the fitting approach enables the quantitative evaluation of cytotoxically affected signals in planar in vitro assays and also has applications for other fields of chemical analysis like distorted chromatography signals.

Machine learning denoising of high-resolution X-ray nanotomography data.

High-resolution X-ray nanotomography is a quantitative tool for investigating specimens from a wide range of research areas. However, the quality of the reconstructed tomogram is often obscured by noise and therefore not suitable for automatic segmentation. Filtering methods are often required for a detailed quantitative analysis. However, most filters induce blurring in the reconstructed tomograms. Here, machine learning (ML) techniques offer a powerful alternative to conventional filtering methods. In this article, we verify that a self-supervised denoising ML technique can be used in a very efficient way for eliminating noise from nanotomography data. The technique presented is applied to high-resolution nanotomography data and compared to conventional filters, such as a median filter and a nonlocal means filter, optimized for tomographic data sets. The ML approach proves to be a very powerful tool that outperforms conventional filters by eliminating noise without blurring relevant structural features, thus enabling efficient quantitative analysis in different scientific fields.

Role of Radiation Therapy in Retroperitoneal Sarcoma.

Retroperitoneal sarcoma comprises a small subset of all soft tissue sarcoma and includes various histopathologic subtypes, each with unique patterns of behavior and differential risks for local recurrence and hematogenous metastatic spread. The primary treatment modality is surgery, although even with complete macroscopic resection, recurrence is common. The rationale for the addition of radiotherapy to resection is to improve local control; however, the use of radiation therapy for retroperitoneal sarcoma is controversial, and existing data are suboptimal to guide management. Treatment decisions should be determined with multidisciplinary input and shared decision-making. When used in selected patients, radiation therapy should be delivered preoperatively; postoperative treatment is not recommended.

Passive Sampling and Dosing of Aquatic Organic Contaminant Mixtures for Ecotoxicological Analyses.

Toxicity results from exposure to mixtures of organic contaminants. Assessing this using ecotoxicity bioassays involves sampling of the environmental mixture and then introducing this into the test. The first step is accounting for the bioavailable levels of all mixture constituents. Passive sampling specifically targets these bioavailable fractions but the sampler-accumulated mixture varies with the compound and sampler properties as well as time. The second step involves reproducing and maintaining the sampled mixture constituents in the bioassay. Passive sampler extraction and spiking always leads to a skewed mixture profile in the test. Alternatively, the recovered passive samplers might be directly used in passive dosing mode. Here, the reproduced contaminant mixture depends on whether kinetic or equilibrium sampling applies. These concepts were tested for determining the combined toxicity of laboratory and field mixtures of aquatic contaminants in the Microtox and ER-Calux bioassays. Aqueous sample extraction and spiking, passive sampler extraction and spiking, and passive sampling and dosing were compared for first sampling and then introducing mixtures in toxicity bioassays. The analytical and toxicity results show that the correct way to first sample the bioavailable mixture profile, and then to reproduce and maintain this in the toxicity test, is by combining equilibrium passive sampling and dosing.

Kinetic Passive Sampling: In Situ Calibration Using the Contaminant Mass Measured in Parallel Samplers with Different Thicknesses.

The use of single-phase passive samplers is a common method for sampling bioavailable concentrations of hydrophobic aquatic pollutants. Often such samplers are used in the kinetic stage, and in situ calibration is necessary. Most commonly, exchange kinetics are derived from the release rates of performance reference compounds (PRCs). In this study, a complementary calibration approach was developed, in which measuring the contaminant mass ratio (CMR) from two samplers with different thicknesses allows the dissolved concentrations to be determined. This new CMR calibration was tested (1) in a laboratory experiment with defined and constant concentrations and (2) in the field, at a storm water retention site. Silicone passive samplers with different thicknesses were used to sample a range of dissolved polycyclic aromatic hydrocarbons. In the laboratory study, the concentrations derived from the CMR calibration were compared with those from water extraction and passive dosing and differences below a factor 2 were found. In the field study, CMR-derived concentrations were compared to those from PRC calibration. Here, differences ranged by only a factor 1 to 3 between both methods. These findings indicate that the CMR calibration can be applied as a stand-alone or complementary calibration method for kinetic passive sampling.

Directed OmniChange Evolution Converts P450 BM3 into an Alkyltrimethylammonium Hydroxylase.

Cetyl-trimethylammonium bromide (CTAB) is a widely used cationic surfactant that is biodegradable in nature. CTAB biodegradation requires hydroxylation in the first step, which is rate-limiting and crucial for solubility in water. In this study, the OmniChange multi-site mutagenesis method was applied to reengineer the P450 BM3 substrate specificity towards the hydroxylation of CTAB by simultaneous mutagenesis of four previously reported positions (R47, Y51, F87, and L188). 1740 clones from the P450 BM3 OmniChange library were screened with the NADPH depletion assay. A total of 696 clones were rescreened with the NADPH depletion and an Ampliflu™ Red/ horseradish peroxidase based H2 O2 detection assay. Several improved P450 BM3 variants were identified and finally four were kinetically characterized with respect to CTAB hydroxylation, based on both performance and coupling efficiency. Based on NADPH consumption, the P450 BM3 variant P3A8 (R47E/Y51M/F87V/L188E) displayed an initial activity (64.9±4.8 s-1 , 13.5-fold increased activity compared with wild-type P450 BM3), which nearly matches the specific activity for its natural fatty acid substrate (palmitic acid (32-122 s-1 )). Variant P3A8 showed high coupling efficiency (92.5 %), whereas wild-type P450 BM3 displayed a low coupling efficiency (0.5 %). HPLC-MS/MS detection confirmed that P3A8 and P2E7 (R47D/Y51L/F87V/L188A) form 13 and 35 times more 2-hydroxylated CTAB than P450 BM3. In addition, di-hydroxylated CTAB products were detected for all four investigated P450 BM3 variants (up to a yield of 77 %; P3A8). Di-hydroxylated quaternary amines are highly interesting bolaform surfactants with a high hydrophilicity (surface contact angle: θ=16.7°).

Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

PURPOSE: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer.

In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, among adjuvant radiotherapy options for whole-breast irradiation after breast-conserving surgery, hypofractionation is preferred. For the use of accelerated partial-breast irradiation, the NCCN Guidelines have adopted the updated definition of "suitability" used by the American Society for Radiation Oncology. Regional nodal irradiation is indicated-either in the setting of breast-conserving surgery or after mastectomy-for women with ≥4 positive nodes and should be strongly considered for 1 to 3 positive lymph nodes and select patients with node-negative disease deemed at high risk for recurrence.

NCCN Guidelines Insights: Breast Cancer, Version 1.2017.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

NCCN Guidelines Update: Breast Cancer.

The updates to management of early invasive breast cancer in 2016 are minor but have important treatment implications for patients. The NCCN Guidelines Panel for Breast Cancer has added endocrine therapy to its recommendations for the neoadjuvant treatment of patients with ER-rich tumors. For women who are premenopausal at diagnosis, the NCCN Guidelines suggest tamoxifen for 5 years, with or without ovarian suppression, or an aromatase inhibitor for 5 years combined with ovarian suppression or ablation. For HER2-positive patients, neoadjuvant pertuzumab is acceptable, and in advanced estrogen receptor-positive disease, palbociclib can be given with endocrine therapy. Hypofractionation is now the preferred approach for whole-breast irradiation after breast-conserving therapy. Regional nodal irradiation should be strongly considered for women with 1 to 3 positive lymph nodes and is indicated for those with 4 or more positive nodes.

Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at NCCN.org.

Retroperitoneal sarcoma (RPS) high risk gross tumor volume boost (HR GTV boost) contour delineation agreement among NRG sarcoma radiation and surgical oncologists.

PURPOSE: Curative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering "boost doses" of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams. METHODS: Radiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. RESULTS: HRGTV boost volume contour agreement between the seven teams was "substantial" or "moderate" for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection. CONCLUSIONS: Agreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for "individualized" target delineation on the basis of areas deemed at risk and planned resection.

Breast Cancer Version 2.2015.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.

NCCN Guidelines Insights Breast Cancer, Version 1.2016.

These NCCN Guideline Insights highlight the important updates to the systemic therapy recommendations in the 2016 NCCN Guidelines for Breast Cancer. In the most recent version of these guidelines, the NCCN Breast Cancer Panel included a new section on the principles of preoperative systemic therapy. In addition, based on new evidence, the panel updated systemic therapy recommendations for women with hormone receptor-positive breast cancer in the adjuvant and metastatic disease settings and for patients with HER2-positive metastatic breast cancer. This report summarizes these recent updates and discusses the rationale behind them.

Neoadjuvant chemotherapy for primary cutaneous/soft tissue angiosarcoma: Determining tumor behavior prior to surgical resection.

BACKGROUND: Given the propensity for hematogenous metastases, neoadjuvant chemotherapy (NAC) could treat occult metastatic disease early, potentially improving survival and better defining which primary angiosarcomas (AS) benefit from surgical resection. METHODS: A retrospective comparison was performed of 23 patients with resectable, localized cutaneous/soft tissue primary AS treated with surgery alone (S, n = 13) or NAC followed by surgery (NAC-S, n = 12). RESULTS: Primary sites included breast/chest (n = 9), head/neck (n = 9), extremity (n = 3), and other (n = 2). 23% S versus 40% NAC-S had prior radiation (RT). NAC regimens were paclitaxel (n = 6) or gemcitabine/docetaxel (n = 4). Seventy percent were high grade. Distant metastases were found in 17% after NAC. Non-primary wound closure was required in 54 %S versus 30%NAC-S (P = 0.4). R0 resections were achieved in 85% S versus 80% NAC-S (30% had a complete pathologic response). Two-year local recurrence (LR)-free, disease-free, and overall survivals were 67.1, 38.5, and 61.5% for S versus 68.6, 54.9, and 68.6% for NAC-S (P = 0.52, 0.67, and 0.58). The mean number of surgical resections/patient to maintain local control was 1.8 S versus 1.3 NAC-S (P = 0.06). CONCLUSIONS: NAC for primary AS was well tolerated. Although there was no statistically significant survival benefit, NAC helped define who would benefit from surgical resection.

Breast cancer version 3.2014.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.

Hypofractionated Preoperative Radiation Should Not Yet Be Used as Standard of Care for Extremity and Truncal Soft Tissue Sarcoma.

Hypofractionated radiation therapy regimens should not be used as standard of care for localized soft tissue sarcoma.