Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to ...resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS, and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors.
Roadmap: proton therapy physics and biology Paganetti, Harald; Beltran, Chris; Both, Stefan ...
Physics in medicine & biology,
02/2021, Letnik:
66, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton ...beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, 'improving efficiency', 'improving planning and delivery', 'improving imaging', and 'improving patient selection'.
Lymphedema: Time for an Update Shaitelman, Simona F
International journal of radiation oncology, biology, physics,
09/2018, Letnik:
102, Številka:
1
Journal Article
Neoadjuvant chemotherapy plus immunotherapy for triple-negative breast cancer (TNBC) is associated with improved but incomplete response. In this issue of Cancer Cell, Shiao et al. characterize ...longitudinal biopsies from a window of opportunity study with single-cell RNA sequencing (scRNA-seq) and spatial proteomic profiling and elucidate synergy between radiotherapy (RT) and pembrolizumab.
Neoadjuvant chemotherapy plus immunotherapy for triple-negative breast cancer (TNBC) is associated with improved but incomplete response. In this issue of Cancer Cell, Shiao et al. characterize longitudinal biopsies from a window of opportunity study with single-cell RNA sequencing (scRNA-seq) and spatial proteomic profiling and elucidate synergy between radiotherapy (RT) and pembrolizumab.
Purpose
New indications have been found for regional nodal irradiation (RNI) in breast cancer treatment, yet the relationship of RNI and lymphedema risk is uncertain. We sought to determine the ...association of RNI and lymphedema.
Methods
We searched MEDLINE, EMBASE, and Scopus for articles in English on humans published from 1995 to 2015, using search terms
breast neoplasm
,
treatment
, and
morbidity
. Two investigators independently selected articles and extracted information, including manuscripts reporting incidence of lymphedema by radiation targets. Meta-analyses, review papers, case–control studies, matched-pair studies, repetitive datasets, and retrospective studies were excluded. A total of 2399 abstracts were identified and 323 corresponding articles reviewed. Twenty-one studies met inclusion criteria. Data were pooled using a random effects mixed model. Network meta-analyses were performed to determine the association of radiation targets alone and radiation targets plus extent of axillary surgery on incidence of lymphedema.
Results
The addition of RNI to breast/CW irradiation was associated with an increased incidence of lymphedema (OR 2.85; 95% CI 1.24–6.55). In patients treated with sentinel lymph node biopsy or axillary sampling, there was no association of lymphedema with the addition of RNI to breast/CW irradiation (OR 1.58; 95% CI 0.54–4.66; pooled incidence 5.7 and 4.1%, respectively). Among patients treated with axillary lymph node dissection (ALND), treatment with RNI in addition to breast/CW radiation was associated with a significantly higher risk of lymphedema (OR 2.74; 95% CI 1.38–5.44; pooled incidence 18.2 and 9.4%, respectively).
Conclusions
RNI is associated with a significantly higher risk of lymphedema than irradiation of the breast/CW, particularly after ALND.
Background
Our group previously published data showing that patients could be stratified by constructed molecular subtype with respect to locoregional recurrence (LRR)-free survival after neoadjuvant ...chemotherapy and breast-conserving therapy (BCT). That study predated use of trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive patients. The current study was undertaken to determine the impact of subtype and response to therapy in a contemporary cohort.
Methods
Clinicopathologic data from 751 breast cancer patients who received neoadjuvant chemotherapy (with trastuzumab if HER2
+
) and BCT from 2005 to 2012 were identified. Hormone receptor (HR) and HER2 status were used to construct molecular subtypes: HR
+
/HER2
−
(
n
= 369), HR
+
/HER2
+
(
n
= 105), HR
−
/HER2
+
(
n
= 58), and HR
−
/HER2
−
(
n
= 219). Actuarial rates of LRR were determined by the Kaplan–Meier method and compared by the log-rank test. Multivariate analysis was performed to determine factors associated with LRR.
Results
The pathologic complete response (pCR) rates by subtype were as follows: 16.5 % (HR
+
/HER2
−
), 45.7 % (HR
+
/HER2
+
), 72.4 % (HR
−
/HER2
+
), and 42.0 % (HR
−
/HER2
−
) (
P
< 0.001). Median follow-up was 4.6 years. The 5-year LRR-free survival rate for all patients was 95.4 %. Five-year LRR-free survival rates by subtype were 97.2 % (HR
+
/HER2
−
), 96.1 % (HR
+
/HER2
+
), 94.4 % (HR
−
/HER2
+
), and 93.4 % (HR
−
/HER2
−
) (
P
= 0.44). For patients with HR
−
/HER2
+
disease, the LRR-free survival rates were 97.4 and 86.7 % for those who did and those who did not experience pCR, respectively. For patients with HR
−
/HER2
−
disease, the LRR-free survival rates were 98.6 % (pCR) versus 89.9 % (no pCR). On multivariate analysis, the HR
−
/HER2
−
subtype, clinical stage III disease, and failure to experience a pCR were associated with LRR.
Conclusions
Patients undergoing BCT after neoadjuvant chemotherapy have excellent rates of 5-year LRR-free survival that are affected by molecular subtype and by response to neoadjuvant chemotherapy.
Placing clips in nodes with biopsy-confirmed metastasis before initiating neoadjuvant therapy allows for evaluation of response in breast cancer. Our goal was to determine if pathologic changes in ...clipped nodes reflect the status of the nodal basin and if targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of clipped nodes, improves the false-negative rate (FNR) compared with SLND alone.
A prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the sampled node was performed. After neoadjuvant therapy, patients underwent axillary surgery and the pathology of the clipped node was compared with other nodes. Patients undergoing TAD had SLND and selective removal of the clipped node using iodine-125 seed localization. The FNR was determined in patients undergoing complete axillary lymphadenectomy (ALND).
Of 208 patients enrolled in this study, 191 underwent ALND, with residual disease identified in 120 (63%). The clipped node revealed metastases in 115 patients, resulting in an FNR of 4.2% (95% CI, 1.4 to 9.5) for the clipped node. In patients undergoing SLND and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2 to 19.8), which included seven false-negative events in 69 patients with residual disease. Adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03 to 7.3; P = .03). The clipped node was not retrieved as an SLN in 23% (31 of 134) of patients, including six with negative SLNs but metastasis in the clipped node. TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05 to 10.7).
Marking nodes with biopsy-confirmed metastatic disease allows for selective removal and improves pathologic evaluation for residual nodal disease after chemotherapy.
The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic ...variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxia-telangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.
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