Hasil untuk "Neoplasms. Tumors. Oncology. Including cancer and carcinogens"

Tímea Rozsvai, Boglárka Pósfai, László Torday et al.

Testicular germ cell tumors (TGCTs), though typically responsive to therapy, may rarely develop somatic-type malignancy (STM), a transformation associated with poor prognosis and chemoresistance. This study presents two cases of postpubertal-type teratoma with intestinal-type adenocarcinoma as STM, offering insights into their clinical, histopathological, immunophenotypic, and molecular profiles. The first patient, a 63-year-old male, presented with pulmonary and retroperitoneal metastases and underwent orchiectomy, revealing an intratesticular intestinal-type adenocarcinoma. Molecular testing confirmed 12p overrepresentation and pathogenic mutations in CTNNB1, STK11, and MDM2. The second patient, initially diagnosed at age 35 with a mixed TGCT, developed STM as a late recurrence 16 years post-orchiectomy, manifesting as a retroperitoneal mass with vertebral invasion. Histology again confirmed intestinal-type adenocarcinoma, and molecular testing revealed amplification of ERBB2, KRAS, along with mutations in TP53 and PIK3CA. Both cases were managed with capecitabine-oxaliplatin plus bevacizumab, followed by maintenance therapy, achieving disease stabilization for at least 9 months. These cases illustrate the diagnostic and therapeutic complexities of STM, particularly with adenocarcinoma morphology that may mimic primary gastrointestinal neoplasms. Accurate diagnosis required exclusion of alternate primary sites and demonstration of chromosome 12 aberrations using FISH and next-generation sequencing. Our findings emphasize the importance of long-term follow-up in TGCT patients, particularly those with teratomatous elements, and highlight the value of cytogenetic and molecular profiling in confirming STM and identifying potential therapeutic targets. Given the rarity of STM, especially in metastatic or recurrent settings, there is an urgent need for standardized diagnostic protocols and evidence-based treatment strategies. These cases support the use of tumor-specific chemotherapy regimens guided by the histological and molecular characteristics of STM.

Yuxi Luo, Yuxi Luo, Weiwei Ouyang et al.

The anaplastic lymphoma kinase (ALK) gene encodes a transmembrane receptor tyrosine kinase. Most mutations in ALK gene result from translocations with other genes, forming fusion oncogenes. To date, 21 different genes have been identified as ALK fusion partners, each activating distinct signaling pathways that influence cancer cell proliferation, invasiveness, and tumorigenicity. ALK tyrosine kinase inhibitors (ALK-TKIs) have demonstrated significant efficacy in ALK-positive non-small cell lung cancer (NSCLC) and are widely utilized as first-line therapy. Lorlatinib, a third-generation ALK inhibitor, is effective in both treatment-naïve and previously treated patients with advanced NSCLC, exhibiting strong systemic and intracranial antitumor activity. This report presented a case of lung adenocarcinoma with 51 genetic variants, including a rare fusion variant: exon 15 of KIF5B fused to exon 20 of ALK, KIF5B-ALK (K15:A20). Following lorlatinib treatment, partial remission was achieved, and disease stability was maintained for an extended period, suggesting a favorable response to therapy. This case highlighted the potential sensitivity of the KIF5B-ALK (K15:A20) fusion to lorlatinib and the need for further investigation into lorlatinib’s efficacy across different KIF5B-ALK fusion variants. Additionally, other fusion types and treatment options for KIF5B-ALK fusions with varying breakpoints were discussed.

Özlem Terzi, S. Hatipoğlu

Dear Editor, Exposure to chemotherapy (CT) and radiotherapy (RT) during pregnancy is a complex clinical scenario with limited literature, particularly concerning infants exposed in utero. Potential fetal risks associated with CT include intrauterine growth restriction, congenital malformations, spontaneous abortion, and intrauterine fetal demise. Prenatal radiation exposure has been linked to growth retardation, microcephaly, intellectual disabilities, neocortical ectopia, agenesis of the corpus callosum, and an increased risk of brain tumors. This letter highlights a rare and challenging case of an infant exposed to both chemotherapy and radiotherapy in utero due to the mother’s diagnosis of glioblastoma multiforme (GBM) during pregnancy, raising critical questions about fetal risks and long-term outcomes. Background The incidence of cancer during pregnancy is approximately 1 in 1,000 pregnancies. Chemotherapeutic agents used in cancer treatment typically have molecular weights less than 400 kDa, allowing them to cross the placenta and potentially affect the fetus. Exposure to CT during the first trimester, a critical period of organogenesis, can result in malformations, spontaneous abortions, and intrauterine fetal death. In the second and third trimesters, CT exposure is associated with intrauterine growth restriction, low birth weight, preterm delivery, or stillbirth. Recent studies have reported that infants exposed to prenatal CT may have lower birth weights and lengths. Additionally, intrauterine CT exposure may directly impact the maturation and differentiation of neurons and oligodendrocytes, with oxidative stress and neuroinflammation contributing to neurotoxic effects. Prenatal radiation exposure, particularly between 8 and 15 weeks of gestation, has been associated with growth retardation, microcephaly, intellectual disabilities, neocortical ectopia, agenesis of the corpus callosum, and an increased risk of brain tumors. The exact mechanisms underlying these effects remain unclear. GBM is one of the most common and aggressive primary brain tumors in adults. Standard treatment involves radical surgery followed by concurrent temozolomide-based CT and RT. Managing GBM during pregnancy presents unique challenges due to potential fetal risks. Treatment planning must balance maternal benefits with fetal risks, and there is limited evidence guiding the timing of surgery and the use of RT and CT during pregnancy. Additional considerations include the teratogenic effects of anticonvulsant medications and the management of peritumoral edema during pregnancy. A 2.5-month-old male infant presented to our pediatric hematology and oncology outpatient clinic. He was born spontaneously at 36 weeks' gestation, weighing 1,560 grams. The mother was diagnosed with stage IV GBM and discovered her pregnancy four days before delivery. She did not undergo surgery but received RT during the second month of pregnancy and temozolomide-based CT from the second month until delivery. At presentation, the infant's weight was 2,540 grams (<0.02 percentile), length 42 cm (<0.02 percentile), and head circumference 30 cm (<0.02 percentile); both anterior and posterior fontanelles were closed. Physical examination revealed macrocornea, low-set ears, high-arched palate, skeletal dysplasia, short limbs, hand and foot deformities (clinodactyly, pes equinovarus), bilateral cryptorchidism, and micropenis. Neurological assessment showed hypotonia with normal deep tendon reflexes. Laboratory evaluations, including complete blood count and metabolic screening, were unremarkable. Ophthalmologic examination was normal, but hearing loss was detected. Cardiac evaluation, including echocardiography, was unremarkable. Imaging studies revealed a 24x15 mm hemangioma in the right hepatic lobe on abdominal ultrasonography and a neurenteric cyst on cranial magnetic resonance imaging. Endocrine evaluations were within normal limits. The infant was hospitalized for sepsis the day after the initial outpatient visit and discharged after 30 days. At 4.5 months, follow-up revealed a disproportionately small head circumference relative to body size, consistent with premature fontanelle closure. Outpatient follow-up is ongoing. GBM accounts for approximately 1% of all new cancer cases worldwide. The occurrence of GBM during pregnancy is rare, with tumors detected in approximately 0.1% of all pregnancies. Literature on GBM management during pregnancy is limited to case reports and small case series. Treatment decisions must balance maternal survival benefits against potential fetal risks, with considerations derived from animal studies, epidemiological data, and observational studies. Studies suggest that CT with agents such as anthracyclines, taxanes, or platinum derivatives may be feasible during the second and third trimesters. The fetus is most sensitive to radiation effects between 8 and 15 weeks of gestation. Fetal sensitivity to radiation is related to gestational age and is highly dependent on the dose received. Exposure to radiation doses less than 1.0 Gray during early gestation has been associated with carcinogenic effects in animal studies. During RT, it is recommended that fetal exposure does not exceed 100 mGy to minimize the risk of fetal cancer development. Management of pregnant patients with GBM requires a multidisciplinary approach involving neurosurgeons, neurologists, oncologists, obstetricians, gynecologists, anesthesiologists, pediatric oncologists, and neonatologists. Calculating the potential fetal dose during CT and considering early delivery if the fetus has reached viability are important considerations. Counseling patients about treatment risks is challenging due to limited data, but it is essential for informed decision-making. Data on short- and long-term neurodevelopmental outcomes in children exposed to prenatal CT are limited. Administering CT after 14 weeks' gestation is recommended to avoid affecting organogenesis. Reporting outcomes of pregnant patients exposed to CT and RT is crucial to guide future clinical practice. CONCLUSION This case highlights the significant challenges associated with managing glioblastoma multiforme (GBM) during pregnancy and underscores the potential adverse effects of in utero exposure to chemotherapy (CT) and radiotherapy (RT). While maternal cancer treatment remains a clinical priority, its impact on fetal development must be carefully considered. The observed congenital anomalies and neurodevelopmental concerns in the infant suggest a need for ongoing evaluation of long-term outcomes in children exposed to CT and RT during gestation. Due to the rarity of such cases, data on the safety and long-term effects of prenatal CT and RT exposure are limited. This underscores the necessity for multidisciplinary collaboration between oncologists, obstetricians, neonatologists, and pediatric specialists to optimize both maternal and fetal health outcomes. Further research, including prospective studies and long-term follow-up of affected infants, is essential to develop evidence-based guidelines for managing cancer during pregnancy. Reporting similar cases and aggregating clinical data will provide valuable insights into risk assessment, treatment strategies, and neonatal outcomes. As advancements in cancer therapeutics continue, refining approaches to maternal treatment while mitigating fetal risks will remain a critical area of investigation in oncologic and perinatal care.

Frank Willig, Frederick J Torpy, Scott H. Harrison et al.

Simple Summary Neoplasia is a complex disease that affects many species across the animal kingdom, including lizards. Currently, cancer in lizard species is an understudied part of veterinary medicine. In this study, we focused on identifying factors that could aid in improving patient care and quality of life for lizards with neoplasia. We identified multiple factors including species, type of neoplasia, and type of treatment significantly associated with both positive and negative outcomes for lizards affected by different types of neoplasia. Specifically, we tested for statistical associations between eight clinical factors and patient outcomes. We used reported cases of neoplasia in lizards from published papers, as well as a clinical oncology database for exotic animal species. We also identified a subset of neoplasia types that were not associated with death due to their neoplasia. Our results highlight the importance of determining variables that aid veterinarians in deciding the most appropriate care for their patients. We expect that future research in this area will improve our understanding of neoplasia in lizards and better improve the identification of predictor variables for improving patient outcomes. Abstract Neoplasia has been reported in lizards, but more research is needed to accurately document the prevalence and prognosis of the various known neoplasms that affect lizards. This study reviewed medical records from an online database, the Exotic Species Cancer Research Alliance (ESCRA), and reviewed published literature to determine the prevalence of neoplasia, malignancy, metastasis, treatment strategies, and outcomes by species and sex. Records from 55 individual lizards, 20 different species, and 37 different tumors were identified. In the literature, 219 lizards, 59 species, and 86 unique tumors were identified from 72 published case reports. Potential signalment factors such as age, sex, and species were evaluated to see if they affected case outcome. Additional factors including neoplasia type, presence of metastasis, and types of pursued treatments were also evaluated. Statistical analysis was performed to determine whether a factor was significantly associated with animal death due to the identified neoplasia or with animal survival or death due to other causes (non-neoplastic outcomes). Komodo dragons and savannah monitors were more likely to die from neoplasia compared to other lizard species. Cases where the status of metastasis was unknown were significantly associated with death due to neoplasia. Having an unknown status of male versus female was significantly associated with non-neoplastic outcomes of death. Leukemia and islet cell carcinoma were significantly associated with death due to neoplastic causes. Chondrosarcoma, myxosarcoma, osteosarcoma, and squamous cell carcinoma were significantly associated with non-neoplastic outcomes of death. Surgery alone and radiation therapy alone each were significantly associated with non-neoplastic outcomes of death, while lizards not receiving treatment were significantly associated with death due to neoplasia. Benign neoplasia was significantly associated with non-neoplastic outcomes of death. These results will aid in the improved diagnosis and management of neoplasia in lizard species, as well as expanding our understanding of prognostic indicators of neoplasia in lizards.

Sanjay De Mel, Sanjay De Mel, Sanjay De Mel et al.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Eiji Nomura, Takatoshi Seki, Kentaro Yatabe et al.

Abstract Background Elderly gastric cancer patients (EGCPs) require treatment according to not just the stage of their cancer, but also to their general condition and organ function, and rather than full treatment, the appropriate amount of treatment is necessary. Methods A total of 425 patients who underwent gastrectomy for primary gastric cancer in our institution between April 2013 and March 2020 were classified by age into two groups: elderly patients (EP, age ≥ 80 years, n = 89); and younger patients (YP, age < 80 years, n = 336). The preoperative, intraoperative, and postoperative conditions of the two groups were then compared. Propensity score matching (PSM) was performed, and factors affecting complications and survival outcomes were examined in detail. In addition, the necessary treatment strategy for EGCPs in the preoperative, intraoperative, and postoperative periods was investigated. Results Of the preoperative factors, American Society of Anesthesiologists physical status (ASA-PS) was significantly higher, and respiratory function was significantly lower in the EP group than in the YP group, and the prognostic nutritional index (PNI) also tended to be lower. Of the intraoperative factors, there was no difference in the level of lymph node dissection. However, the EP group had significantly higher rates of postoperative pneumonia and anastomotic leakage. Of the postoperative factors, on simple comparison, postoperative long-term outcomes of the EP group were significantly worse (63.8% vs. 85.4%, p < 0.001), but there was no significant difference in disease-specific survival (DSS), and the DSS survival curves after PSM were almost identical, indicating that the survival rate in the EP group was decreased by death from other disease. Though the survival rate of laparoscopic surgery was significantly better than that of open surgery in the YP group, there was a significantly lower rate of postoperative complications in the EP group after PSM. Conclusions In EGCPs, one needs to be aware of short-term complications such as pneumonia and anastomotic leakage due to respiratory dysfunction and malnutrition that are present before surgery. Furthermore, to suppress deaths from other diseases that reduce postoperative survival rates, prevention of postoperative complications (particularly pneumonia) through minimally invasive surgery can be effective.

Fan Ren MD, Feng Chen MM, Xiaoqian Xu MM et al.

Background: Lung cancer screening is not limited to low dose computed tomography (LDCT). Recently, molecular biomarkers have been shown to have the potential to improve the current state of early lung cancer detection. The current study determined the efficiency of seven autoantibodies against tumor-associated antigens (7-AABs) and tumor markers in patients with lung cancer. Materials and Methods: An enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of 7-AABs and tumor markers in 354 patients with lung cancer and 108 patients with benign pulmonary disease under care at Ethics Committee of Tianjin Medical University General Hospital. Results: The sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic (ROC) curve of 7-AABs were 30.0%, 84.3%, 86.3%, and 0.61, respectively. When combining the 7-AABs and tumor markers, the sensitivity was 68.6%, the specificity was 52.8%, and the area under the ROC curve was 0.72. The 7-AABs positive expression rate in lung cancer patients was significantly higher than patients with benign pulmonary diseases (30.1% vs 15.7%); however, the 7-AABs positive expression rate was affected by clinical features and pathologic stages. When combining 7-AABs and tumor markers, the combined 7-AABs and tumor marker positive expression rate increased to 68.6%. Conclusion: Based on this study and previous literature, the supplemental diagnostic value of 7-AABs has been confirmed; however, due to the low sensitivity, the value of 7-AABs alone in lung cancer screening is limited. The combination of 7-AABs and tumor markers has improved sensitivity and positivity, but decreased specificity, which makes their performance in cancer screening and early detection worthy of further research.

V. M. Merabishvili, Z. Radzhabova, A. B. Vasil’ev et al.

Introduction. In the 10th revision of the International Classification of Diseases (ICD-10), the code for malignant neoplasms of pharynx (mNN) is C11. These tumors are rare. The state statistics only presents information on morbidity. Data on mortality due to mNN are absent, they are included into the group of other causes of death. The real assessment of the effectiveness of antitumor management of mNN can only be obtained from the population Cancer Registry Database (pCR DB) of the Northwestern federal District of the Russian federation (NwfD Rf) developed by us. This database allows to determine the main analytical values of any parameter included in the case report form. The most reliable criterion of evaluation of the effectiveness of antitumor management is calculation of observed and relative 1-year and corrected 5-year survival rates of patients at the population level and in accordance with international standards.Aim. To perform first in Russia assessment of the effectiveness of antitumor management of mNN with calculation of analytical values including survival (separately for men and women) and detailed characteristics of location and histological structure.Materials and methods. The data of the International Agency for Research on Cancer (IARC), as well as reference books of the p.A. Hertsen moscow Oncology Research Institute and the N.N. petrov National medical Research Center for Oncology were used. Data processing was preformed using mS Excel 2013–2016 and STATISTICA 6.1 licensed software. Survival rates were calculated using modified EuROCARE software. The study was based on the databases of the population cancer registry of Saint petersburg and NwfD Rf developed by us. In total, 950 observations were analyzed. Results. Data obtained during investigation of the incidence and survival rates of mNN confirmed the rarity of this pathology and positive morbidity dynamics, standardized values of which decreased in Russia between 2010 and 2022 by 19.35 %, in NwfD Rf by 27.59 %. The coronavirus pandemic had a significant negative effect on the record keeping. Additionally, between 2010 and 2022 1-year survival of patients with mNN in NwfD Rf increased from 58.5 to 80.6 % (by 22.1 %); 5-year survival increased between 2000 and 2018 from 25.4 to 35.4 % (by 10 %).Conclusion. Analysis of the incidence and survival of patients with malignant neoplasm of rare location can be performed only using a database of population cancer registry of a federal district in compliance with all international rules of its maintenance. unfortunately, currently this is possible only for NwfD Rf.

Caroline Procópio de Oliveira, B. M. Frigieri, H. Fukumasu et al.

(1) Background: Mammary neoplasms in female dogs share many similarities with the same tumor class in humans, rendering these animals a valuable preclinical model for studying novel therapies against breast cancer. The intricate role of extracellular vesicles (EVs), particularly exosomes, in breast carcinogenesis, by transferring specific proteins to recipient cells within the tumor microenvironment, underscores their significance. Melatonin, a hormone recognized for its antitumor effects, adds another layer of intrigue. (2) Methods: EVs obtained from the plasma of dogs diagnosed with mammary tumors were co cultivated with the benign epithelial lineage E-20 using DMEM. The experiment comprised four 24 h treatment groups: control, EVs, melatonin, and EVs + melatonin. A series of assays were conducted, including colony formation, proliferation, and cellular migration assessments. Furthermore, we conducted colony formation, proliferation, and cellular migration assays. We performed immunohistochemistry for proteins of the mTOR pathway, including mTOR and AKT. (3) Results: Exosomes alone significantly increased proliferation, migration, and colony formation rates and, upregulated the expression of mTOR and AKT proteins. However, when melatonin was added, a protective effect was observed. (4) Conclusions: These findings contributed to the use of melatonin to modulate EV-mediated signaling in the clinical veterinary oncology of mammary tumors.

Y. Iztleuov, M. Iztleuov, A. Elubaeva et al.

Relevance: According to WHO, malignant neoplasms rank second in population mortality structure due to a constantly increasing influence of technogenic factors that have a direct carcinogenic effect on the body and suppress defense mechanisms. Ionizing radiation plays a special role in the development of cancer. It is used in industry, agriculture, medicine, and scientific research as a diagnostic tool in modern healthcare and radiation therapy for cancer treatment. The consequences of radiation influence are not only the result of a direct effect on the body but also a delayed one through generations of parents and grandparents. According to the radiobiological hypothesis, any level of radiation, no matter how small, ОБЗОРЫ ЛИТЕРАТУРЫ Онкология и Радиология Казахстана, №4 (70) 2023 45 poses a risk of long-term consequences, including cancer, in exposed people and their descendants of the first two generations. That is, cancerous tumors are likely consequences of the influence of radiation. Despite various theories of the biological effect of low doses of ionizing radiation, most authors attach primary importance to DNA damage in the manifestation of genetic effects (the concept of non-threshold mutational action). The study aimed to highlight the role of ionizing radiation in tumorigenesis. Methods: Data from MEDLINE, Embase, Scopus, PubMed, Cochrane Central Register of Controlled Trials was analyzed to select and analyze relevant information over the past 10 years using the keywords: gamma irradiation, spontaneous oncogenesis, prevention of oncogenesis, Results: Radiation exposure may increase the risk of cancer development due to epigenetic changes leading to increased genomic instability (GI) and/or specific suppression of tumor suppressor genes. Changes in the TP53 gene network expression occur; the most significant genes as predictors of carcinogenesis are ST13, IER3, BRCAI, LRDD, and MRAS. Epigenetic changes also influence individual susceptibility to radiation-induced cancer. In addition to the mutagenic effects of ROS and AFN, there is also evidence that oxidative stress plays a fundamental role in epigenetic modifications. Conclusion: As a result of radiation exposure, damage occurs that causes genetic and epigenetic changes, leading to changes in the level of protein expression due to changes in the methylation of cytosine residues in DNA, modification of histones, and regulation of microRNA expression.

Li Li, Tao Xing, Yiran Chen et al.

Abstract Interferon-gamma (IFN-γ) exerts anti-tumor effects by inducing ferroptosis. Based on CRISPR/Cas9 knockout screening targeting genome-wide protein encoding genes in HepG2 and SK-Hep-1 cell lines, we found that cAMP response element-binding protein (CREB) regulated transcription coactivator 3 (CRTC3) protects tumor cells from drug-induced ferroptosis and significantly inhibits the efficacy of IFN-γ treatment in hepatocellular carcinoma (HCC). Mechanistically, CRTC3 knockout altered tumor cell lipid patterns and increased the abundance of polyunsaturated fatty acids (PUFAs), which enables lipid peroxidation and enhances the susceptibility of HCC cells to ferroptosis inducers. To scavenge for accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells up-regulate SLC7A11 and glutathione peroxidase 4 (GPx4) expressions to enhance the activities of glutamate-cystine antiporter (system xc−) and LPO clearance. As IFN-γ inhibiting system xc−, simultaneous treatment with IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. Sensitizing effects of CRTC3 depletion were confirmed using typical ferroptosis inducers, including RSL3 and erastin. Sorafeinib, a commonly used target drug in HCC, was repeatedly reported as a ferroptosis inducer. We then conducted both in vitro and vivo experiments and demonstrated that CRTC3 depletion sensitized HCC cells to sorafenib treatment. In conclusion, CRTC3 is involved in the regulation of PUFAs metabolism and ferroptosis. Targeting CRTC3 signaling in combination with ferroptosis inducers present a viable approach for HCC treatment and overcoming drug resistance.

L. Mansi

V. Marotta, M. Bifulco, M. Vitale

Simple Summary Only about 4% of thyroid nodules are carcinomas and require surgery. Fine-needle aspiration cytology is the most accurate tool to distinguish benign from malignant thyroid nodules, however it yields an indeterminate result in about 30% of the cases, posing diagnostic and prognostic dilemmas. Testing for genetic mutations, including those of RAS, has been proposed for indeterminate cytology to solve these dilemmas and support the clinician decision making process. A passionate debate is ongoing on the biological and clinical significance of RAS mutations, calling into question the utility of RAS as tumor marker. Recently, the description of a new entity of non-invasive follicular thyroid neoplasm and the accurate review of more recent analyses demonstrate that RAS mutations have limited utility in both the diagnostic and prognostic setting of thyroid nodular disease. Abstract Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.

Lars Kurch, Thomas W. Georgi, Astrid Monecke et al.

A 28-year-old female patient with active and difficult-to-treat systemic lupus erythematosus (SLE) was diagnosed with liver-dominant diffused large B-cell lymphoma. Repeated response 18F-FDG-PET studies showed persistently high, and, despite intensified immunochemotherapy, further increasing metabolic activity of one of the hepatic lymphoma residuals, whereas all other initial lymphoma manifestations had achieved complete metabolic remission. As biopsy of the 18F-FDG-PET-positive liver residual turned out to be inconclusive, complete resection was performed. Subsequent histopathological examination, however, revealed only necrotic tissue. Thus, no further lymphoma treatment was scheduled. The patient undergoes regular surveillance and is disease-free 13 months after resection. Similarly, treatment of SLE is no longer required due to lack of activity already after the first two cycles of lymphoma treatment. The case shows how closely SLE and diffused large B-cell lymphoma can be connected and stresses the importance of interdisciplinary treatment approaches. In the future, artificial intelligence may help to further classify 18F-FDG-PET-positive lymphoma residuals. This could lead to an increase of the positive predictive value of interim- and end-of-treatment 18F-FDG-PET. The patient’s point of view enables another instructive perspective on the course of treatment, which often remains hidden to treating physicians due to lack of time in clinical routine.

Dongmei Zhang, Yunzhen Zhou, Yanan Ma et al.

Abstract Precision medicine in hepatocellular carcinoma (HCC) relies on validated biomarkers that help subgroup patients for targeted treatment. Here, we identified a novel candidate oncogene, ribosomal protein L22-like1 (RPL22L1), which was markedly elevated in HCC, contributed to HCC malignancy and adverse patient survival. Functional studies indicated RPL22L1 overexpression accelerated cell proliferation, migration, invasion and sorafenib resistance. Mechanism studies revealed that RPL22L1 activated ERK to induce atypical epithelial-to-mesenchymal transition (EMT) progress. Importantly, the ERK inhibitor (ERKi) could potentiate sorafenib efficiency in RPL22L1-high HCC cells. In summary, these data uncover RPL22L1 is a potential marker to guide precision therapy for utilizing ERKi to enhance the sorafenib efficacy in RPL22L1-high HCC patients.

A. Madaminov, A. Khasanov, S. Khatamov et al.

Abstract According to scientific data, cancer is a very ancient disease, and along with the perfection of humanity it becomes more progressive. The development of technologies that detect molecular changes in the pathogenesis and subsequent development of carcinogenesis has led to the beginning of a new era in oncology. The cell cycle is tightly controlled by a group of protein kinases, including cyclin and cyclin-dependent kinases. These events occur in a strictly regulated time sequence supported by consistent restriction points. p53, p21, p16, retinoblastoma (and other proteins), cyclins and cyclin-related kinases repair DNA before the cell cycle enters the phase of synthesis and mitosis. Loss of regulatory activity of p53 and pRB, stable activation of E2F stimulates uncontrolled cell proliferation, leading to neoplastic cell growth. The Ras/Raf/MEK/ERK signalling pathway is also a complex network of sequentially activated proteins that play a major role in the onset and development of cancer. It can regulate not only the biological functions, such as cell proliferation, cycle regulation, cell differentiation, apoptosis and tissue formation, but it is also associated with tumor development. Stable mutations in the genome or defects in the epigenome lead to dysregulation in the normal biological cycle of the cell, underlying DNA chain damage or dysfunction in the control system, determined by various types of carcinogenic factors, both known and unknown.

Jie Cui, Jie Cui, Yamin Zhang et al.

TBX1 belongs to an evolutionarily conserved family of transcription factors involved in organ development. TBX1 has been reported to have a hypermethylated cytosine guanine dinucleotide island around its second exon, which was related to prostate cancer (PCa) progression. However, the role and exact mechanism of TBX1 in PCa remains unknown. Using human prostate samples, online data mining and multiple in vitro and in vivo models, we examined the biological role and underlying mechanisms of TBX1 in PCa. TBX1 was highly expressed in PCa tissues, and high TBX1 expression was positively associated with Gleason score, pathological tumor stage, pathological lymph node stage, extraprostatic extension and disease/progression-free survival. In vitro and in vivo data demonstrated that TBX1 silencing inhibits PCa cell proliferation and colony formation and increases the cell population at the G0/G1 phase. The exogenous expression of TBX1 rescued these phenotypes. Mechanistically, TBX1 silencing suppressed the expression of 45S ribosomal RNA (rRNA), which was rescued by the exogenous expression of TBX1. TBX1 silencing inhibited the monomethylation of histone 3 lysine 4 (H3K4me1) binding with the non-coding intergenic spacer (IGS) regions of ribosomal DNA (rDNA) and the recruitment of upstream binding factor to the promoter and IGS regions of rDNA. The drug-induced enhancement of H3K4me1 counteracted the effect of TBX1 silencing. These findings indicate that TBX1 exerts its tumor activator function in PCa cells via epigenetic control, thereby promoting rRNA gene transcription. Thus, TBX1 may represent a prognostic biomarker and therapeutic target for PCa patients.

Yasha Ektefaie, William Yuan, Deborah A. Dillon et al.

Abstract Histopathologic evaluation of biopsy slides is a critical step in diagnosing and subtyping breast cancers. However, the connections between histology and multi-omics status have never been systematically explored or interpreted. We developed weakly supervised deep learning models over hematoxylin-and-eosin-stained slides to examine the relations between visual morphological signal, clinical subtyping, gene expression, and mutation status in breast cancer. We first designed fully automated models for tumor detection and pathology subtype classification, with the results validated in independent cohorts (area under the receiver operating characteristic curve ≥ 0.950). Using only visual information, our models achieved strong predictive performance in estrogen/progesterone/HER2 receptor status, PAM50 status, and TP53 mutation status. We demonstrated that these models learned lymphocyte-specific morphological signals to identify estrogen receptor status. Examination of the PAM50 cohort revealed a subset of PAM50 genes whose expression reflects cancer morphology. This work demonstrates the utility of deep learning-based image models in both clinical and research regimes, through its ability to uncover connections between visual morphology and genetic statuses.

Xiao Wei, Xiao Wei, Hongbo Guo et al.

Cerenkov luminescence tomography (CLT) is a promising non-invasive optical imaging method with three-dimensional semiquantitative in vivo imaging capability. However, CLT itself relies on Cerenkov radiation, a low-intensity radiation, making CLT reconstruction more challenging than other imaging modalities. In order to solve the ill-posed inverse problem of CLT imaging, some numerical optimization or regularization methods need to be applied. However, in commonly used methods for solving inverse problems, parameter selection significantly influences the results. Therefore, this paper proposed a probabilistic energy distribution density region scaling (P-EDDRS) framework. In this framework, multiple reconstruction iterations are performed, and the Cerenkov source distribution of each reconstruction is treated as random variables. According to the spatial energy distribution density, the new region of interest (ROI) is solved. The size of the region required for the next operation was determined dynamically by combining the intensity characteristics. In addition, each reconstruction source distribution is given a probability weight value, and the prior probability in the subsequent reconstruction is refreshed. Last, all the reconstruction source distributions are weighted with the corresponding probability weights to get the final Cerenkov source distribution. To evaluate the performance of the P-EDDRS framework in CLT, this article performed numerical simulation, in vivo pseudotumor model mouse experiment, and breast cancer mouse experiment. Experimental results show that this reconstruction framework has better positioning accuracy and shape recovery ability and can optimize the reconstruction effect of multiple algorithms on CLT.

ZHAO Yang, CHANG Fujiang, GE Lei et al.

Objective To screen and verify hub genes TPM1 and CALD1 that can affect the diagnosis and prognosis of bladder cancer (BLCA). Methods We obtained gene chip expression data of 414 and 188 cases of bladder cancer from TCGA and GEO, respectively. By constructing a weighted gene co-expression network analysis (WGCNA) and identifying differentially-expressed genes between tumor tissues and normal tissues, the pivotal genes that were highly associated with bladder cancer were obtained, and the STRING database was used to construct a protein interaction network to screen out prognostic-related pivotal genes. We took 29 cases of bladder cancer samples from People's Hospital of Zhengzhou as external verification results. Results A total of 915 and 464 differentially-expressed genes were screened from the TCGA database and GSE13507, respectively. Two modules with the strongest correlation were obtained through WGCNA: the blue module (Pearson cor=0.60, P=1E-44) and the cyan module (Pearson cor=0.52, P=7E-19), and 156 intersection genes were obtained. Through protein interaction network analysis, 10 pivotal genes were screened out. TPM1 and CALD1 genes had the greatest correlation with the survival of bladder cancer patients, which was verified by external experimental verification group. Conclusion TPM1 and CALD1 are closely related to the prognosis of bladder cancer patients. They are also pivotal genes to promote tumor progression.