Metastatic Research Articles

RADT-50. CLINICAL OUTCOME OF DAILY 5-FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES

Abstract INTRODUCTION With the introduction of the Gamma Knife Icon, hypo-fractionated Gamma Knife radiosurgery (GKRS) for large brain metastases (LBMs) is beginning to be performed. This study aimed to assess the clinical outcome and risk of the daily 5-fractionated GKRS for LBMs. METHODS A total of 100 patients who underwent 5-fractionated GKRS for LBMs (> 14cm3) were enrolled. Forty-six were male patients, and the median age was 60 years. Most common primary cancer sites were lung (41 non-small cell cancers), breast (24), and kidney (14). The median tumor volume was 22cm3 (14 – 69cm3) and marginal dose was 35Gy (50% isodose line) in 5 fractions. Median follow-up duration was 18 months (3 – 72 months). RESULTS The last follow-up showed local tumor control in 74 cases. The cumulative 1, 2, and 3-year local tumor control rates were 73, 65, and 60%, respectively. Eighty-six tumors showed best MRI response in a year, and median tumor volume decrease rate was 80% (22 – 100%). Thirty patients experienced dramatically tumor volume decrease (> 95%). Median progression free and overall survival were 7 and 16 months, respectively. Radiation necrosis occurred in 24 patients, of which only 9 had neurological symptoms and treated with steroid and bevacizumab. CONCLUSIONS The daily 5-fractionated GKRS for very LBMs showed favorable local tumor control and acceptable radiation necrosis, but questionable survival benefit. In the future, prospective multi-center study is needed.

EPID-23. HISTORY OF TYPE III IMMUNE HYPERSENSITIVITY IMPROVES SURVIVAL IN GLIOBLASTOMA

Abstract Preexisting atopy, particularly allergic rhinitis, is consistently associated with decreased risk of glioma, and there is evidence that preexisting autoimmune conditions may also decrease risk. Glioblastoma is both locally and systemically immunosuppressive and, unlike many other forms of cancer, its initiation is not strongly linked with chronic inflammation. Therefore, history of immune hypersensitivity could be associated with improved anti-glioma immunosurveillance. We leveraged Surveillance, Epidemiology and End Results (SEER) data combined with Medicare claims to investigate the effect of preexisting immune hypersensitivities on overall survival of glioblastoma patients receiving resection, radiation, and temozolomide (standard of care, or SOC) from 2008-2019. Patients <66 years of age, enrolled in Medicare Advantage, not continuously enrolled in Medicare Part A/B, missing follow-up, reported by autopsy/death certificate only, or who did not receive surgery were excluded. Prior history of immune hypersensitivity (≥6 months prior to primary cancer diagnosis) was identified by ICD-9/ICD-10 codes. Treatment pattern was determined using ICD-9/ICD-10 and HCPCS/CPT codes. Conditions were classified into broad immune hypersensitivity types: type I (IgE-mediated, including atopy), type II (IgG- or IgM-mediated), type III (immune complex-mediated, including lupus and rheumatoid arthritis), and type IV (cell-mediated). Survival comparisons were made using Cox proportional hazard models adjusted for demographics, extent of resection, and Charlson comorbidity score (excluding immune conditions) to estimate hazard ratios, 95% confidence intervals, and p-values. Overall, 44% of 3,426 glioblastoma patients who received SOC had an immune hypersensitivity (type I: 33%, type II: 4%, type III: 8%, and type IV: 15%). These conditions were significantly more common in females (47% vs 41%, p<0.001). After adjustment, only type III immune sensitivity was associated with improved OS (HR=0.81, 95% CI:0.71-0.92, p=0.002). These results suggest that underlying immune-complex mediated hypersensitivity may improve treatment response and prognosis in glioblastoma, and that these pathways could potentially be exploited for therapy.

RADT-22. EFFICACY AND SAFETY OF CYBERKNIFE STEREOTACTIC RADIOSURGERY FOR OCCIPITAL CONDYLE METASTASIS

Abstract BACKGROUND Occipital condyle metastasis (OCM) is a rare condition characterized by severe occipital pain and neurological symptoms due to lower cranial nerve deficits, stemming from its anatomical location. Despite the widespread use of stereotactic radiosurgery (SRS) for cranial metastases, its specific impact on OCM remains underexplored. OBJECTIVE This study evaluates the efficacy and safety of CyberKnife SRS in treating OCM, focusing on symptom control and local tumor control. METHOD We retrospectively analyzed cases of OCM treated with SRS at our institute from 2012 to 2023, evaluating patient demographics, presenting symptoms, treatment parameters, and outcomes. Key measures included occipital pain, dysfunctions of cranial nerves IX, X, and XII, and local tumor control. RESULTS Eighteen patients (10 females) with a median age of 64 years (range: 40-79) were treated. Common presentations included occipital pain (44%) and lower cranial nerve deficits (28%). The median target volume was 6.95 cc (range: 0.95-72.7), and the median margin dose was 20 Gy (range: 16-40). The median follow-up period was 7 months (range: 1-44). Notably, only one patient experienced tumor recurrence and subsequently died from primary cancer progression five months after treatment. SRS achieved a 93.8% local tumor control rate over three years, with a median overall survival of 13 months. Among those presenting with symptoms, 87.5% reported pain relief, and 80% observed improvements in cranial nerve function. The only patient without clinical symptom improvement also had tumor recurrence. CONCLUSION CyberKnife SRS is a promising treatment for OCM, offering significant pain relief and improvement in neurological symptoms with excellent local control rates. This non-invasive therapy provides a valuable alternative to surgery, potentially enhancing the quality of life for patients with limited treatment options due to this challenging condition.

Exploration of the pattern of lymph node metastasis in esophageal cancer based on membrane anatomy theory

AbstractObjectiveTo analyze the pattern of lymph node metastasis in esophageal cancer based on the theory of membrane anatomy.MethodsA retrospective analysis was conducted on 143 patients who underwent esophageal surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences from March 2021 to March 2022. Lymph node metastasis was observed and categorized according to postoperative T staging. The characteristics and patterns of lymph node metastasis in different regions were observed, and the lymph node metastasis patterns in patients with clinical T3 esophageal cancer were analyzed using membrane anatomy theory.ResultsAmong the 143 patients with esophageal squamous cell carcinoma, 21 were treated with surgery alone, while the rest received preoperative adjuvant therapy. A total of 5456 lymph nodes were cleared from the 143 patients, with 204 positive lymph nodes, resulting in a positive rate of 3.74%. In the thoracic lymph node dissection, the metastatic rates exceeded 5% for the following regions: 106recR (17.36%), 106recL (12.5%), 107 (10.42%), and 108 (5.56%) station. When analyzing the abdominal lymph node metastasis, the metastatic rates exceeded 5% for regions 7 (13.19%), 3a (7.64%), 2 (6.94%), and 1 (6.25%) station. Group analysis of patients with esophageal squamous cell carcinoma before postoperative pathological T3 stage revealed an increasing trend in tumor lymph node metastasis rate with later T staging. Lymph node metastasis in region 106recR can occur early, with a metastasis rate of 18.37% in T1 tumors. Analysis of lymph node metastasis characteristics in 103 patients clinically staged as T3 showed that 3966 lymph nodes were cleared, with 186 positive nodes, resulting in a positive rate of 4.69%. Lymph node metastasis rates were higher in regions 106recL, 106recR, 107, 108, 110, 1, 2, 3a, and 7, all exceeding 5%.ConclusionThe theory of membrane anatomy can effectively explain the pattern of lymph node metastasis in esophageal cancer.

Stroma‐and Tumor‐Associated Predictive Features in Salivary Gland Adenoid Cystic Carcinoma of the Head and Neck

ABSTRACTBackgroundThere is lack of knowledge on the utility of prognostic histopathologic characteristics in adenoid cystic carcinoma (ACC) of the head and neck. We evaluated the prognostic value of tumor and stroma‐related histopathologic features in ACC.Materials and MethodsA total of 65 cases of ACC from minor and major salivary glands were included in this study. We evaluated tumor budding, tumor‐infiltrating lymphocytes (TILs), and tumor‐stroma ratio (TSR) in hematoxylin and eosin (HE) stained sections.ResultsStroma‐rich ACCs recurred more frequently (p = 0.029) during follow‐up and associated with distant metastasis (p = 0.038). In multivariable analysis, stroma‐rich tumors associated with poorer disease‐specific survival with a hazard ratio of 3.76 (95% CI 1.10–12.83, p = 0.034). ACCs commonly showed a low infiltration of TILs as 89% of the tumors was characterized by an immune desert pattern. Low infiltration of TILs associated significantly with increased tumor budding (p = 0.039).ConclusionAdverse features of TSR and tumor budding are widely expressed in ACC, and stroma‐rich tumors are associated with poor prognosis. Low number of TILs in ACC tissue indicates a weak immune response by the host and illustrates the nature of ACC as a relentless malignancy.

Cyproheptadine inhibits in vitro and in vivo lung metastasis and drives metabolic rewiring

BackgroundNon-small cell lung cancer (NSCLC) accounts for 81% of lung cancer cases, among which over 47% presented with distant metastasis at the time of diagnosis. Despite the introduction of targeted therapy and immunotherapy, enhancing the survival rate and overcoming the development of resistance remain a big challenge. Thus, it is crucial to find potential new therapeutics and targets that can mitigate lung metastasis and investigate its effects on biomarkers, such as cellular metabolomics. In the current study, we investigated the role of cyproheptadine (CPH), an FDA-approved anti-histamine drug in lung metastasis in vitro and in vivo.Methods and resultsCPH showed potent cytotoxicity on different lung cancer cell lines in vitro. Moreover, CPH decreased invasion and migration of LLC1 and A549 cells in Matrigel invasion transwell and plate scratch assays. The in vivo LLC1 syngeneic lung cancer model found decreased number of metastatic nodules on the surface of lungs of Setd7 KO mice compared to SETD7 WT. CPH treatment resulted in decreased growth of LLC1 subcutaneous tumors compared to untreated SETD7 WT. Finally, metabolomic study of tumor tissues showed rewiring of metabolomic pathways and downregulation of amino acids, such as arginine, serine, and glycine) in Setd7 KO and WT treated with CPH compared to untreated Setd7 WT mice.ConclusionThese findings identify CPH as a potential therapeutic agent to block metastasis in advanced NSCLC and suggest SETD7 as a potential target for the prevention of lung metastasis.

Machine learning and deep learning models for preoperative detection of lymph node metastasis in colorectal cancer: a systematic review and meta-analysis

Machine learning and deep learning models for preoperative detection of lymph node metastasis in colorectal cancer: a systematic review and meta-analysis

MR tomographic evaluation of the effectiveness of neoadjuvant chemotherapy for breast cancer based on pharmacokinetic numerical analysis of tumor uptake of paramagnetic contrast in intravenous contrast enhancement

Background. In clinical practice, MRI pathophysiological and pharmacokinetic models with calculations of contrast transport indicators are unacceptably little used.Aim of the study. To propose a pharmacokinetic technique for the quantitative assessment of primary tumors and metastases, the effectiveness of breast cancer chemotherapy (BC), from dynamic contrast enhancement MRI. Material and methods. 18 patients were included who underwent neoadjuvant chemotherapy (NACHT) in four cycles for breast cancer T1-3N0-1M0, followed by radical surgical removal of the tumor. According to the results of a three — year follow-up, patients with a relapse — free course (n = 11) formed group 1, and seven patients with detected metastatic lesions (3 in the liver, 2 in the lungs, 2 in the brain) — group 2. For the initial 120–180 s of MRI with contrast after the injection of a paramagnetic, the simplification is valid for concentrations in tumor and blood and for tranfer coefficient: d{СОПУХОЛЬ(t)} / dt = ККр-Оп * СКРОВЬ (t) , from which it is obvious: ККр-Оп = (СОПУХОЛЬ(Т)) / (∫CКРОВЬ(t) dt), which was used in all calculations of the contrast transfer constant. Gadobutrol contrast is 0.1M/10 kg of body weight, TR = 5.5–6 ms, TE = 2.5 ms. Results. If, after the first cycle of NACHT, the ККр-Оп of the primary breast cancer is < 0.22 ml/min/g of tissue, the probability of subsequent relapse-free course = 0.78. Similarly, a decrease in the KCr-Op Ккр-Оп of the sentinel lymph node after the first cycle of NAHT < 0.08 ml/min/g of tissue with a probability of 0.75 predicts a relapse-free course. Conclusion. The proposed method for calculating the ККр-Оп transfer coefficient allows obtaining additional diagnostic and prognostic information in patients with local and locally advanced forms of breast cancer.

Cancer in the Grand Libreville, Gabon (2013–2017)

BackgroundThe burden of cancer is expected to nearly double in sub-Saharan Africa over the next 20 years. In Gabon, the primary population-based cancer registry to be established is located in the Grand Libreville. This study presents cancer incidence rates covering the first 5-year period of registration in this region. Patients and methods1,549 cancer cases were recorded among residents of the Grand Libreville between 2013 and 2017, 955 (61.6 %) women and 594 (38.3 %) males. ResultsThe age standardized incidence rates (ASR) for all sites were 73.3 per 105 in females and 47.7 per 105 in males, rather similar from those observed in neighbouring countries of central Africa. Breast (ASR 19.0 per 105) and cervical cancers (ASR 16.3 per 105) accounted for half of female cancers. Prostate (ASR 12.0 per 105), liver (ASR 5.1 per 105) and colorectal cancers (ASR of 5.0 per 105) accounted for 41.1 % of male cancers. ConclusionBreast and prostate cancers ranked first in females and males, respectively, even if the incidences appear much lower in comparison with other regional cancer registries rates, implying they may be underestimated. Cancers of the digestive organs were markedly more frequent in men than women, especially for liver, colorectal (and anus) and the mouth and pharynx. The incidence rates of these latter cancers are relatively similar to those of other registries of the central African region. These results may be of importance for implementing more adapted strategies in the battle against cancer.

Malignant Esophageal Glomus Tumor With CARMN::NOTCH2 Fusion: An Additional Tumor Underscoring the Frequent Tendency of Esophageal Glomus Tumors for Aggressive Behavior

Malignant glomus tumors are rare tumors of pericytic origin with a propensity to develop in the upper gastrointestinal tract. Hereby we demonstrate a tumor of a 20-year-old man, who presented with dysphagia and an exophytic esophageal mass. Histologic examination of the resected mass revealed a multinodular tumor in the esophageal wall composed of epithelioid cells showing nesting and monomorphic atypia, staghorn vessels and scanty stroma. Immunohistochemically, the neoplastic cells were positive for SMA, and H-caldesmon, while desmin was negative. Collagen IV and laminin decorated a dense intercellular basal membrane meshwork. RNA-sequencing using TruSight RNA Pan-Cancer Panel revealed a CARMN::NOTCH2 fusion, that is a recurrent, frequently described and so far specific genetic alteration in glomus tumors. In spite of the adjuvant chemotherapy regimens, the patient died of disseminated metastatic disease 2 years after the diagnosis. Our patient presentation and the previous reports in the literature highlight the frequently aggressive behavior of glomus tumors arising in the esophagus.

Biomimetic Nano‐delivery of Small‐Molecule Piceatannol Modulates Tumor Stemness and Suppresses Colorectal Cancer Metastasis via Hippo/YAP1/SOX9 Signaling

AbstractSuppressing tumor metastasis is a crucial strategy for improving survival rates in patients with colorectal cancer (CRC), with cancer stem cells (CSCs) being the primary drivers of metastasis. Current therapeutic approaches targeting CSCs are limited, and their molecular mechanisms remain unclear. To address this challenge, a biomimetic nanoparticle delivery system, CMD‐BHQ3‐PTL/DOX@RBCM is developed, to deliver the stem cell regulator, piceatannol (PTL). This system used carboxymethyl dextran (CMD) and Black Hole Quencher 3 (BHQ3) to encapsulate PTL and the cytotoxic drug doxorubicin (DOX) within a red blood cell membrane (RBCm), enhancing stability and biocompatibility while allowing gradual drug release under hypoxic conditions. The effects of PTL are investigated on CSCs using molecular biology experiments, plasmid construction, and high‐throughput sequencing and elucidated the molecular mechanisms underlying this biomimetic nanoparticle delivery system. The therapeutic efficacy of PTL is validated at the tissue level using subcutaneous and metastatic tumor models in human and murine systems. The results demonstrated that CMD‐BHQ3‐PTL/DOX@RBCM effectively addressed the challenges of specificity and biocompatibility in vivo, significantly inhibiting CSC‐related tumor metastasis. This inhibitory effect is closely associated with the Hippo/YAP1/SOX9 pathway. This study highlights the effectiveness of the pH‐responsive biomimetic nanoparticle system CMD‐BHQ3‐PTL/DOX@RBCm in delivering PTL to tumor sites, with SOX9 and its upstream Hippo/YAP1 pathway playing a critical role in the underlying mechanism.

DNA methylation classifier to diagnose pancreatic ductal adenocarcinoma metastases from different anatomical sites

BackgroundWe have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites.MethodsFor this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain.ResultsThe updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition.ConclusionsThe updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.

RNF4 mediated degradation of PDHA1 promotes colorectal cancer metabolism and metastasis

This study investigates the role of RNF4-mediated ubiquitination and degradation of PDHA1 in colorectal cancer (CRC) metabolism and metastasis. Integrating (The Cancer Genome Atlas) TCGA and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, proteomic, clinical, and metabolomic analyses were performed, revealing PDHA1 as a prognostic marker in CRC. Immunohistochemical staining confirmed lower PDHA1 expression in metastatic CRC tissues. In vitro experiments demonstrated that PDHA1 overexpression inhibited CRC cell proliferation, migration, and invasion. RNF4 was identified as a key mediator in the ubiquitination degradation of PDHA1, influencing glycolytic pathways in CRC cells. Metabolomic analysis of serum samples from metastatic CRC patients further supported these findings. In vivo experiments, including xenograft and metastasis models, validated that RNF4 knockdown stabilized PDHA1, inhibiting tumor formation and metastasis. This study highlights the critical role of RNF4-mediated PDHA1 ubiquitination in promoting glycolytic metabolism, proliferation, and metastasis in CRC.

Evolution in the diagnosis and treatment of carcinoma of unknown primary: a multicenter Canadian analysis

Abstract Background Guidelines for the management of patients with cancer of unknown primary (CUP), who have metastatic disease without an identified primary tumor site, have evolved. We sought to describe the diagnostic work-up and outcomes of patients with CUP in Canada over the last decade. We also sought to identify factors associated with improved prognosis in CUP, including primary tumor site identification, identification of “favorable subtypes,” and concordance with published guidelines. Methods With ethics board approval, patients with histologically confirmed CUP between 2012 and 2021 in 3 Canadian cancer centers were reviewed and clinicopathological variables retrospectively collected. The primary endpoint was to describe significant trends in CUP diagnosis and management over the decade using linear regression models. Univariable (UVA) and multivariable (MVA) logistic regression analyses identified variables correlated with primary site identification and overall survival (OS). Kaplan–Meier curves with the log-rank test were used to compare OS outcomes. Results In total, 907 patients were included, with a median follow-up of 5.1 months. There was an increase in both 5-year survival and identification of primary tumors over the decade. Diagnostic tests including next-generation sequencing were independently associated with primary site identification on UVA. However, primary site identification was not found to be predictive of survival; instead, patients with “favorable subtypes” of CUP had significantly longer OS. Conclusions Survival in patients with CUP in Canada has been increasing over the last decade. Identifying the primary site does not influence survival, and efforts should be focused on discovering novel “favorable subtypes” which have superior outcomes.

Non‐functional metastatic thyroid carcinoma with oesophageal invasion and ulceration in a cat

AbstractAn adult, male, neutered, domestic shorthair cat was presented with a 2‐month history of dysphagia and a movable cervical mass. Cytology of the cervical mass was consistent with carcinoma. Thoracic radiographs revealed pleural effusion, cardiomegaly, diffuse patchy interstitial pattern and pulmonary nodules. Fluid analysis of the pleural effusion was consistent with marked septic neutrophilic inflammation, and Pasteurella multocida was isolated. Contrast‐enhanced cervical and thoracic computed tomography scan revealed a cervical mass in the region of the right thyroid lobe, with circumferential invasion of the oesophageal wall and well‐defined pulmonary nodules consistent with distant metastases. Oesophago‐gastroscopy was performed and revealed a proximal, oesophageal, mural mass causing severe intraluminal obstruction. Humane euthanasia was elected. Postmortem examination with histology and immunohistochemistry confirmed a thyroid carcinoma with oesophageal invasion and pulmonary metastases. The oesophageal mucosa was extensively disrupted and ulcerated by the thyroid carcinoma. Additionally, echocardiogram and postmortem examination confirmed cardiomyopathy and congestive heart failure.

Construction and Validation of a Novel T/NK-Cell Prognostic Signature for Pancreatic Cancer Based on Single-Cell RNA Sequencing

Background Evidence with regards to the distinction between primary and metastatic tumors in pancreatic cancer and driving factors for metastases remains limited. Methods Single-cell RNA sequencing (scRNA-seq) was conducted on metastatic pancreatic cancer. Bioinformatics analysis on relevant sequencing data was used to construct a risk model to predict patient prognosis. Furthermore, immune infiltration and metabolic differences were assessed. The biological function of key differential genes was evaluated. Results Paired primary and metastatic tumor tissues from 3 pancreatic cancer patients were collected and conducted scRNA-seq. Subsequently, the T/NK cell subgroup was the most different cell type between primary tumors and liver metastases and was selected for further analysis. Eventually, 6 specifically expressed genes of T/NK cells (B2M, ZFP36L2, ANXA1, ARL4C, TSPYL2, FYN) were used constructing the prognostic model. The stability of this model was validated by an external cohort. Meanwhile, different immune infiltration abundances occurred between high and low risk groups stratified by the model. The high-risk group had a stronger metabolic capability. Conclusions A novel prognostic T/NK-cell signature for pancreatic cancer was constructed based on scRNA-seq data and externally validated. The involved key genes may play a role in multiple metabolic pathways of metastasis and affect the tumor immune microenvironment.

Retraction Note: LncRNA LINC00261 overexpression suppresses the growth and metastasis of lung cancer via regulating miR-1269a/FOXO1 axis

Retraction Note: LncRNA LINC00261 overexpression suppresses the growth and metastasis of lung cancer via regulating miR-1269a/FOXO1 axis

Case report: Benign lateral neck ectopic thyroid tissue mimicking cervical lymph node metastasis

AbstractWe herein report a rare case of benign lateral neck ectopic thyroid tissue that presentation micmicked cerivcal lymph node metastasis of follicular thyroid cancer and discuss its management pearl.

Advances in the Management of Lung Cancer Brain Metastases

Lung cancer, both non-small cell and small cell, harbors a high propensity for spreading to the central nervous system. Radiation therapy remains the backbone of the management of brain metastases. Recent advances in stereotactic radiosurgery have expanded its indications and ongoing studies seek to elucidate optimal fractionation and coordination with systemic therapies, especially targeted inhibitors with intracranial efficacy. Efforts in whole-brain radiotherapy aim to preserve neurocognition and to investigate the need for prophylactic cranial irradiation. As novel combinatorial strategies are tested and prognostic/predictive biomarkers are identified and tested, the management of brain metastases in lung cancer will become increasingly personalized to optimally balance intracranial efficacy with preserving neurocognitive function and patient values.

Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in Establishing Resistance to Cisplatin in Human Cancer Cells

Abstract: The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7–4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.