Integrating 40-GEP Testing to Improve Clinical Recommendations for Adjuvant Radiation for Cutaneous Squamous Cell Carcinoma: Multidisciplinary Consensus Guidelines.

Early identification and intervention in patients with cutaneous squamous cell carcinoma (cSCC) who are at high risk for metastasis is important for optimal outcomes. Prognostic tools (e.g., American Joint Committee on Cancer, 8th edition [AJCC-8]) and management guidelines (National Comprehensive Cancer Network® [NCCN]) are useful in helping to identify high-risk patients with cSCC who might benefit from adjuvant therapies, such as radiation and/or immunotherapies; however, traditional staging and management guidelines rely on clinicopathologic risk factors to predict risk, which limits their prognostic accuracy. Gene expression profiling (GEP) is a clinically available, objective metric that can be used in conjunction with traditional clinicopathological staging to help clinicians stratify risk in patients with cSCC. The validated 40-GEP test can accurately classify patients with at least one high-risk feature as being at low (Class 1), higher (Class 2A), or highest (Class 2B) biological risk of nodal or distant metastasis within three years of diagnosis. A multidisciplinary panel comprising radiation oncologists and dermatologists/Mohs micrographic surgeons with expertise in cSCC management convened in June 2023 to discuss the utility of 40-GEP testing in cSCC clinical decision-making in regard to adjuvant radiation therapy (ART). The panel identified gaps in clinical practice in which 40-GEP testing has particular utility: in escalation of care for lower-stage patients with high-risk tumors; in de-escalation of care for patients for whom the risks of ART may outweigh the benefits; and in decision-making regarding elective radiation to the nodal basin. The expert panel developed a risk-based clinical workflow for ART in patients with cSCC, utilizing 40-GEP testing within NCCN management guidelines and AJCC-8 staging.

A phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases.

Stereotactic radiation therapy yields high rates of local control for brain metastases, but patients in rural or suburban areas face geographic and socioeconomic barriers to its access. We conducted a phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases in an integrated academic satellite network for patients 18 years of age or older with 4 or fewer brain metastases. Dose was based on gross tumor volume: less than 3.0 cm, 27 Gy in 3 fractions and 3.0 to 3.9 cm, 30 Gy in 5 fractions. Median follow-up was 10 months for 73 evaluable patients, with a median age of 68 years. Median intracranial progression-free survival was 7.1 months (95% confidence interval = 5.3 to not reached), and median survival was 7.2 months (95% confidence interval = 5.4 to not reached); there were no serious adverse events. Outcomes of this trial compare favorably with contemporary trials, and this treatment strategy provides opportunities to expand stereotactic radiation therapy access to underserved populations.

Optimizing Preventive Adjuvant Linac-Based (OPAL) Radiation: A Phase 2 Trial of Daily Partial Breast Irradiation.

PURPOSE: Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled. METHODS AND MATERIALS: We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost. RESULTS: All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P = .004), breast pain (P = .004), and physician-reported cosmesis (P < .001). CONCLUSIONS: Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation.

The effects of changes in glutathione levels through exogenous agents on intracellular cysteine content and protein adduct formation in chronic alcohol-treated VL17A cells.

Alcohol-mediated liver injury is associated with changes in the level of the major cellular antioxidant glutathione (GSH). It is interesting to investigate if the changes in intracellular GSH level through exogenous agents affect the intracellular cysteine content and the protein adduct formation indicative of oxidative insult in chronic alcohol treated liver cells. In VL-17A cells treated with 2 mM N-acetyl cysteine (NAC) or 0.1 mM ursodeoxycholic acid (UDCA) plus 100 mM ethanol, an increase in cysteine concentration which was accompanied by decreases in hydroxynonenal (HNE) and glutathionylated protein adducts were observed. Pretreatment of 100 mM ethanol treated VL-17A cells with 0.4 mM buthionine sulfoximine (BSO) or 1 mM diethyl maleate (DEM) had opposite effects. Thus, altered GSH level through exogenous agents may either potentiate or ameliorate chronic alcohol-mediated protein adduct formation and change the cysteine level in chronic alcohol treated VL-17A cells. The gene expression of non-treated and ethanol-treated hepatocytes in 2 microarray datasets was also compared to locate differentially expressed genes involved in cysteine metabolism. The study demonstrates that increased protein adducts formation and changes in cysteine concentration occur under chronic alcohol condition in liver cells which may increase alcohol-mediated oxidative injury.

CRCDA--Comprehensive resources for cancer NGS data analysis.

Next generation sequencing (NGS) innovations put a compelling landmark in life science and changed the direction of research in clinical oncology with its productivity to diagnose and treat cancer. The aim of our portal comprehensive resources for cancer NGS data analysis (CRCDA) is to provide a collection of different NGS tools and pipelines under diverse classes with cancer pathways and databases and furthermore, literature information from PubMed. The literature data was constrained to 18 most common cancer types such as breast cancer, colon cancer and other cancers that exhibit in worldwide population. NGS-cancer tools for the convenience have been categorized into cancer genomics, cancer transcriptomics, cancer epigenomics, quality control and visualization. Pipelines for variant detection, quality control and data analysis were listed to provide out-of-the box solution for NGS data analysis, which may help researchers to overcome challenges in selecting and configuring individual tools for analysing exome, whole genome and transcriptome data. An extensive search page was developed that can be queried by using (i) type of data [literature, gene data and sequence read archive (SRA) data] and (ii) type of cancer (selected based on global incidence and accessibility of data). For each category of analysis, variety of tools are available and the biggest challenge is in searching and using the right tool for the right application. The objective of the work is collecting tools in each category available at various places and arranging the tools and other data in a simple and user-friendly manner for biologists and oncologists to find information easier. To the best of our knowledge, we have collected and presented a comprehensive package of most of the resources available in cancer for NGS data analysis. Given these factors, we believe that this website will be an useful resource to the NGS research community working on cancer. Database URL: http://bioinfo.au-kbc.org.in/ngs/ngshome.html.

TaxKB: a knowledge base for new taxane-related drug discovery.

BACKGROUND: Taxanes are naturally occurring compounds which belong to a powerful group of chemotherapeutic drugs with anticancer properties. Their current use, clinical efficacy, and unique mechanism of action indicate their potentiality for cancer drug discovery and development thereby promising to reduce the high economy associated with cancer worldwide. Extensive research has been carried out on taxanes with the aim to combat issues of drug resistance, side effects, limited natural supply, and also to increase the therapeutic index of these molecules. These efforts have led to the isolation of many naturally occurring compounds belonging to this family (more than 350 different kinds), and the synthesis of semisynthetic analogs of the naturally existing molecules (>500), and has also led to the characterization of many (>1000) of them. A web-based database system on clinically exploitable taxanes, providing a link between the structure and the pharmacological property of these molecules could help to reduce the druggability gap for these molecules. RESULTS: Taxane knowledge base (TaxKB, http://bioinfo.au-kbc.org.in/taxane/Taxkb/), is an online multi-tier relational database that currently holds data on 42 parameters of 250 natural and 503 semisynthetic analogs of taxanes. This database provides researchers with much-needed information necessary for drug development. TaxKB enables the user to search data on the structure, drug-likeness, and physicochemical properties of both natural and synthetic taxanes with a "General Search" option in addition to a "Parameter Specific Search." It displays 2D structure and allows the user to download the 3D structure (a PDB file) of taxanes that can be viewed with any molecular visualization tool. The ultimate aim of TaxKB is to provide information on Absorption, Distribution, Metabolism, and Excretion/Toxicity (ADME/T) as well as data on bioavailability and target interaction properties of candidate anticancer taxanes, ahead of expensive clinical trials. CONCLUSION: This first web-based single-information portal will play a central role and help researchers to move forward in taxane-based cancer drug research.

A mycobacterial phosphoribosyltransferase promotes bacillary survival by inhibiting oxidative stress and autophagy pathways in macrophages and zebrafish.

Mycobacterium tuberculosis employs various strategies to modulate host immune responses to facilitate its persistence in macrophages. The M. tuberculosis cell wall contains numerous glycoproteins with unknown roles in pathogenesis. Here, by using Concanavalin A and LC-MS analysis, we identified a novel mannosylated glycoprotein phosphoribosyltransferase, encoded by Rv3242c from M. tuberculosis cell walls. Homology modeling, bioinformatic analyses, and an assay of phosphoribosyltransferase activity in Mycobacterium smegmatis expressing recombinant Rv3242c (MsmRv3242c) confirmed the mass spectrometry data. Using Mycobacterium marinum-zebrafish and the surrogate MsmRv3242c infection models, we proved that phosphoribosyltransferase is involved in mycobacterial virulence. Histological and infection assays showed that the M. marinum mimG mutant, an Rv3242c orthologue in a pathogenic M. marinum strain, was strongly attenuated in adult zebrafish and also survived less in macrophages. In contrast, infection with wild type and the complemented ΔmimG:Rv3242c M. marinum strains showed prominent pathological features, such as severe emaciation, skin lesions, hemorrhaging, and more zebrafish death. Similarly, recombinant MsmRv3242c bacteria showed increased invasion in non-phagocytic epithelial cells and longer intracellular survival in macrophages as compared with wild type and vector control M. smegmatis strains. Further mechanistic studies revealed that the Rv3242c- and mimG-mediated enhancement of intramacrophagic survival was due to inhibition of autophagy, reactive oxygen species, and reduced activities of superoxide dismutase and catalase enzymes. Infection with MsmRv3242c also activated the MAPK pathway, NF-κB, and inflammatory cytokines. In summary, we show that a novel mycobacterial mannosylated phosphoribosyltransferase acts as a virulence and immunomodulatory factor, suggesting that it may constitute a novel target for antimycobacterial drugs.

Isolated port-site metastases after minimally invasive hysterectomy for endometrial cancer: outcomes of patients treated with radiotherapy.

OBJECTIVE: The management and prognosis of isolated port-site metastases after laparoscopic surgery for endometrial cancer is poorly understood and rarely described in the literature. We report a series of cases treated with radiotherapy to better characterize outcomes in these patients. METHODS: We retrospectively reviewed medical records of patients with endometrial cancer who developed isolated port-site metastases and were treated with radiation therapy at MD Anderson Cancer Center from 1996 to 2013. Seven patients met these criteria for whom treatment and outcome data were collected. RESULTS: The median interval from initial surgery to port-site recurrence was 15 months. Recurrent tumor size varied from 0.5 to 9 cm as measured on axial imaging. Six of the 7 patients underwent surgical resection of the recurrence. All received radiotherapy to a dose of 45 to 66 Gy. At a median follow-up of 2 years from the time of the port-site recurrence, the rate of disease-free survival at 1 and 2 years after the recurrence was 100% and 44%, respectively. The rate of local control and overall survival at 2 years was 100%. CONCLUSIONS: Isolated port-site metastases in the setting of endometrial cancer are associated with high rates of local control when treated with multimodality therapy including radiotherapy. Long-term disease-free outcomes in some patients suggest the potential for cure and justify aggressive local therapy. The optimal integration of surgery, chemotherapy, and radiation is unknown.

NGS meta data analysis for identification of SNP and INDEL patterns in human airway transcriptome: A preliminary indicator for lung cancer.

High-throughput sequencing of RNA (RNA-Seq) was developed primarily to analyze global gene expression in different tissues. It is also an efficient way to discover coding SNPs and when multiple individuals with different genetic backgrounds were used, RNA-Seq is very effective for the identification of SNPs. The objective of this study was to perform SNP and INDEL discoveries in human airway transcriptome of healthy never smokers, healthy current smokers, smokers without lung cancer and smokers with lung cancer. By preliminary comparative analysis of these four data sets, it is expected to get SNP and INDEL patterns responsible for lung cancer. A total of 85,028 SNPs and 5738 INDELs in healthy never smokers, 32,671 SNPs and 1561 INDELs in healthy current smokers, 50,205 SNPs and 3008 INDELs in smokers without lung cancer and 51,299 SNPs and 3138 INDELs in smokers with lung cancer were identified. The analysis of the SNPs and INDELs in genes that were reported earlier as differentially expressed was also performed. It has been found that a smoking person has SNPs at position 62,186,542 and 62,190,293 in SCGB1A1 gene and 180,017,251, 180,017,252, and 180,017,597 in SCGB3A1 gene and INDELs at position 35,871,168 in NFKBIA gene and 180,017,797 in SCGB3A1 gene. The SNPs identified in this study provides a resource for genetic studies in smokers and shall contribute to the development of a personalized medicine. This study is only a preliminary kind and more vigorous data analysis and wet lab validation are required.

ACR Appropriateness Criteria® on Induction and Adjuvant Therapy for Stage N2 Non-Small-Cell Lung Cancer: expert panel on radiation oncology-lung.

"The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document."

BCDB - A database for breast cancer research and information.

UNLABELLED: In pursuit of a better updated source including 'omics' information for breast cancer, Breast Cancer Database (BCDB) has been developed to provide the researcher with the quick overview of the Breast cancer disease and other relevant information. This database comprises of myriad of information about genes involved in breast cancer, its functions and drug molecules which are currently being used in the treatment of breast cancer. The data available in BCDB is retrieved from the biomedical research literature. It facilitates the user to search information on gene, its location in chromosome, functions and its importance in cancer diseases. Broadly, this can be queried by giving gene name, protein name and drug name. This database is platform independent, user friendly and freely accessible through internet. The data present in BCDB is directly linked to other on-line resources such as NCBI, PDB and PubMed. Hence, it can act as a complete web resource comprising gene sequences, drug structures and literature information related to breast cancer, which is not available in any other breast cancer database. AVAILABILITY: The database is freely available at http://122.165.25.137/bioinfo/breastcancerdb/

A novel strategy for mechanism based computational drug discovery.

Glioma, the common brain tumor, which arises from the glial cells, offers worse prognosis and therapy than any other tumors. Despite the genetic and pathological diversities of malignant gliomas, common signaling pathways that drive cellular proliferation, survival, invasion and angiogenesis have been identified. Very often, various tyrosine kinase receptors are inappropriately activated in human brain tumors and contribute to tumor malignancy. During such tumourous states where multiple pathways are involved, a few of them are responsbile for cell differentiation, proliferation and anti-apoptosis. Computational simulation studies of normal EGFR signaling in glioma together with the mutant EGFR mediated signaling and the MAPK signaling in glioma were carried out. There were no significant cross talks observed between the mutant EGFR and the MAPK pathways and thus from the simulation results, we propose a novel concept of 'multiple-targeting' that combines EGFR and Ras targeted therapy thereby providing a better therapeutic value against glioma. Diallyl Disulfide (DADS) that has been commonly used for Ras inhibition in glioma was taken for analyses and the effect of inhibiting the EGFR downstream signaling protein with this DADS was analyzed using the simulation and docking studies.

CanGeneBase (CGB)--a database on cancer related genes.

UNLABELLED: The advent of genomic and proteomic technologies in this post-genomic era has urged the researchers to develop novel research strategies against cancer by targeting the human genes that would greatly facilitate to identify more promising treatment and to develop accurate early diagnosis for cancer. To harness the power of cancer genetic information towards better treatment we have developed a cancer gene database called CanGeneBase (CGB). It is a comprehensive data collection of cancer-related genes with the intention of helping the researchers to stay on a single platform to gain exclusive information on the genes of their interest. According to the Cancer Gene Data Curation Project, about 4,700 genes have been identified as being related to cancer. The present CanGeneBase covers about 12 different types of cancer which includes 190 unique gene entries. Each entry encompasses about 33 useful parameters to provide detailed information about specific gene. CanGeneBase is made in such a way that it can be easily accessed by either gene symbol or by the type of cancer. AVAILABILITY: The database is freely available at http://122.165.25.137/bioinfo/cancerdb/

ACR appropriateness criteria on nonsurgical treatment for non-small-cell lung cancer: poor performance status or palliative intent.

Radiation therapy (RT) plays a major role in the definitive treatment of patients with non-small-cell lung cancer who are unable to tolerate surgery. Radiation therapy alone is used primarily for early-stage (stages I and II) patients. Higher doses of RT (>65 Gy) seem to improve outcomes, and modern techniques such as stereotactic body RT have been very promising. For patients with locally advanced disease (stages IIIA and IIIB), concurrent chemotherapy and RT remains the standard of care. However, many patients cannot tolerate the regimen because of its toxicity. Sequential chemotherapy followed by RT is used in these situations. Radiation therapy alone is used for the rare patient who cannot tolerate the use of any chemotherapy because of comorbid conditions. Palliative external-beam RT is useful for patients with metastatic disease, causing symptoms such as dyspnea, cough, hemoptysis, postobstructive pneumonia, and pain. Hypofractionation has been attempted as a means to provide more rapid and convenient symptom relief, but results from clinical trials are conflicting on whether it is an improvement over standard palliative fractionation. Endobronchial brachytherapy provides relief for patients with endobronchial lesions causing obstruction or hemoptysis. Palliative chemotherapy improves survival and quality of life in patients with metastatic disease compared with best supportive care. Chemotherapy also improves outcomes as a second-line and third-line treatment for patients in whom previous regimens have failed. Biologic therapies such as erlotinib and bevacizumab have been incorporated into every phase of chemotherapy with good results.

Assessment for the identification of better HDAC inhibitor class through binding energy calculations and descriptor analysis.

Histone Deacetylase (HDAC) inhibitors represent a budding class of targeted anti-cancer agents. This structurally diverse group of molecules can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. Of the different classes of HDAC the class I and Class II are considered the main targets for cancer. For the two classes of HDAC, only a few compounds have emerged as preferential inhibitors and even fewer are able to discriminate efficiently among HDACs in the same class. This limitation has diminutive relevance to the use of HDAC inhibitors as potential anti-tumor drugs. Hence, the four HDACs of class I was modeled and about twelve known inhibitors which are currently under the phase I/II trials were docked using an efficient shape-based search algorithm and the AScore scoring function, to each of the class I HDAC members in order to identify the inhibitor or group with better pharmacological action. The molecular descriptors study and the drug score, drug likeness prediction helped in the identification of potential compounds targeting specific enzymes of HDAC family. The ranking of various groups of ligands helped in the identification of potential groups and better compound that can better target class I HDAC in an effective way.

Pulmonary toxicity associated with the treatment of non-small cell lung cancer and the effects of cytoprotective strategies.

Concurrent chemoradiation regimens for the treatment of non-small cell lung cancer have resulted in improved treatment outcomes. However, they are also more toxic. Acute esophagitis and pneumonitis are experienced by a large number of treated patients. Cytoprotective agents are used to reduce treatment-related toxicity. The cytoprotectant amifostine has been shown to reduce some of the toxicity associated with concurrent chemoradiation. Clinical studies of its role in reducing esophagitis and radiation pneumonitis are discussed. Lung irradiation also leads to a reduction in lung diffusion capacity (DLCO). The magnitude of this reduction is related to the volume of lung irradiated as well as to the use and timing of chemotherapy. Concurrent chemoradiation regimens result in a larger reduction in DLCO than radiation alone. Small changes in DLCO can be detected with sensitive pulmonary function tests, but are subclinical. Larger reductions in DLCO correlate with significant clinical symptoms. Preliminary data show that amifostine can significantly decrease the treatment-related reduction in DLCO associated with concurrent chemoradiation (42% v 24%; P = .004). Additional studies are being designed to verify these results and to further define the evolving role of cytoprotection in cancer care.

Non-small cell lung cancer: the role of cytoprotection in treating therapy-related toxicity.

Concurrent radiochemotherapy improves outcomes in patients with stage III non-small cell lung cancer but produces greater toxicity, especially esophagitis and pneumonitis. Preliminary evidence suggests that cytoprotection might decrease the incidence and severity of therapy-related toxicity in these patients. In radiation-related pneumonitis, the protective effect of amifostine appears to be partly the result of a reduction in the accumulation of macrophages and a decrease in plasma and tissue tumor growth factor-beta levels.

The relationship between local dose and loss of function for irradiated lung.

PURPOSE: To determine the relationship between the local radiation dose and the decrease in lung function associated with thoracic irradiation. PATIENTS AND METHODS: Twenty-six patients treated with thoracic irradiation for lung cancer, for whom three-dimensional CT-based dosimetry was used in treatment planning, were evaluated with before and after treatment pulmonary function tests. Six patients were treated with radiotherapy alone (2.15 Gy daily fractions), and 20 patients with concurrent chemotherapy (cisplatin, etoposide) with hyperfractionated (HF) radiation therapy (1.2 Gy in twice-daily fractions). Eleven patients treated with concurrent HF chemoradiation also received the radioprotector amifostine. The normalized decrease in the diffusing capacity for carbon monoxide (DL(CO)) was used as an objective measure of the change in lung function. The dose-volume histogram (DVH) data were used to estimate the local dose-response relationship for loss of DL(CO). In each subvolume of lung, the loss in normalized DL(CO) was assumed to be a sigmoid function of dose, ranging from no loss at low doses to total loss at high doses. The whole-lung decrease in DL(CO) was modeled as the sum of the local declines in DL(CO) over all subvolumes. Nonlinear regression analysis was used to estimate the parameters of the local dose-response function. RESULTS: The data are most consistent with a pronounced decrease in DL(CO) when the local dose (for radiotherapy alone or HF concurrent chemoradiation) exceeds 13 Gy (95% CI, 11-15 Gy). In patients who received amifostine in addition to HF radiotherapy with concurrent chemotherapy, this stepwise loss of DL(CO) occurred above 36 Gy (95% CI, 25-48 Gy). Grade 2 or higher pulmonary symptoms were associated with a DL(CO) loss of >30% (p = 0.003). CONCLUSIONS: The decrease in pulmonary diffusion capacity correlates with the local dose to irradiated lung. Amifostine significantly reduces the loss in DL(CO). A local dose-loss relationship for normalized DL(CO) can be extracted from DVH data. This relationship allows an estimate of the loss of function associated with a radiation treatment plan. Different plans can thus be compared without resort to an empiric DVH reduction algorithm. The very low (13 Gy) threshold for deterioration of DL(CO) suggests that it is better to treat a little normal lung to a high dose than to treat a lot to a low dose.