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Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma.

Kožni melanom je z vidika zdravljenja kirurška bolezen, saj kirurgija predstavlja zelo pomemben način zdravljenja pri vseh stadijih bolezni. Ločimo kirurško zdravljenje primarne lezije, regionalnih, in-transit in oddaljenih zasevkov. Pri primarni leziji ločimo diagnostično in široko (radikalno) ekscizijo. Varnostni rob je pri prvi do 5 mm, pri drugi pa med 1 do 2 cm, odvisno od debeline melanoma. Pri regionalnih zasevkih melanoma govorimo glede na njihovo velikost o klinično okultnih in klinično prepoznavnih zasevkih. Prve ugotovimo s pomočjo biopsije sentinel bezgavke in jih nato zdravimo tako kot klinično prepoznavne zasevke z radikalno limfadenektomijo regionalne bezgavčne lože. In-transit zasevke lahko zdravimo s preprosto ekscizijo ali pa v primerih, ko jih je več in so locirani na ekstremitetah s pomočjo tehnično zahtevnih izolirane ekstremitetne perfuzije ali infuzije. Pri sistemskem razsoju je kirurško zdravljenje vedno prvi izbor zdravljenja, v kolikor je možno zasevke odstraniti v celoti. From the treatment perspective, skin melanoma is a surgical disease, as surgery is a very important treatment modality for all stages of this disease. We distinguish between surgical treatments of primary lesions and regional, in-transit and distant metastases. Considering the primary lesion, we distinguish between diagnostic and wide (radical) excision, with the safety margin being up to 5 mm and 1-2 mm, respectively. Depending on their size, locoregional melanoma metastases are either clinically occult or clinically apparent. The first are detected with the help of sentinel lymph node biopsy and are afterwards treated in the same manner as clinically apparent metastases, namely with radical lymphadenectomy of the regional lymph node basin. In-transit metastases can be treated with a simple excision or, in cases of multiple metastases located on the extremities, with the help of technically demanding isolated limb perfusion or infusion. In a systematic assessment, surgical treatment is always the first choice if metastases can be removed completely.

Background: Brain metastasis represents a major complication with a significantly shorter overall survival of many oncological diseases, in particular of lung cancer, breast cancer and malignant melanoma patients. However, despite the poor prognosis, sometimes clinical decision-making, between on the one hand not to harm the patient and on the other hand not withholding a potential therapeutic option, is very challenging. Thus the aim of this retrospective study was to compare various scores, including scores for activities of daily living (ADL) before resection of brain metastases and to analyse their impact on survival. Methods: Our single institution retrospective patient cohort (N = 100) with a median age of 63.6 years, which had all undergone resection of one or more brain metastases, was categorized using the original patient files. The cohort includes 52 patients with lung cancer, 27 patients with breast cancer, 8 patients with colorectal carcinoma and 13 patients with kidney cancer. To categorize, we used different score systems which were capable to evaluate the patient in relation to self-sufficiency, activity and self-determination as part of ADL. The retrospective analysis includes the ECOG-Status, Karnofsky-Index, Barthel-Index, ASA-Classification and Katz-Index. Pre-processing and the analysis of the data was implemented using KNIME, where we used the R-plugin nodes to perform the final statistical tests with R. Results: Our analysis reveals that most of the ADL scores we tested are able to give a reliable prediction on overall survival after brain metastasis surgery. The survival rates decrease significantly with a lower score in all tested score systems, with the exception of the ASA-Risk score. In particular, the Katz Index < 6 was identified to have a significant correlation with a lower cancer specific survival (CSS) (HR 3.33, 95%-CI [2.17–5.00]; p-Value = 9.6*10^− 9), which is easy to use and has reproducible measurements. Conclusions: Pre-operative independence assessment by indices of ADL represents a predictor for overall survival after resection of brain metastases. Especially the easily, objectively and rapidly applicable Katz-Score is a very helpful tool to assess the pre-operative status, which could be additionally included in clinical decision making in daily practice., Finanziert über die DEAL-Vereinbarung mit Wiley 2019-2022.

While systemic therapy for non-metastatic, invasive breast cancer is provided to minimize the risk of recurrence, neoadjuvant therapy (NAT) is given prior to surgery to downstage the tumor and to evaluate treatment response. Downstaging the tumor may allow for less invasive surgery on the breast and axilla, thus avoiding the need for breast reconstruction, improving cosmetic outcomes, and reducing postoperative complications. With the rising number of NAT candidates, it is becoming increasingly important to standardize how tumor response is assessed after surgery. In the post-NAT setting, macroscopic assessment of surgical samples, extent of sampling for histology, and microscopic analysis require a different approach than in the primary surgery setting. In the neo-adjuvant setting, the close collaboration of pathologists, oncologists, surgeons, and radiologists within the multidisciplinary team is essential to ensure the best possible management of breast cancer patients. Here, we provide an update on the suggested procedures for an accurate assessment of tumor response to NAT, including the evaluation of all relevant parameters that correlate with long-term prognosis and inform the subsequent adjuvant interventions.

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma. Patients and methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option. Conclusions: Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EU Clinical Trials Registry ( https://www.clinicaltrialsregister.eu ): EudraCT: 2014-005341-44

Bu W, Wang Z, Meng L, et al. Cancer Manag Res. 2019;11:3887–3898 The authors have advised that because of JilinUniversity’s rule that each paper can have only onefirst author and can’t have co-first authors, they wantto make a change in the author list. As a result, in theaffiliations section the asterisks should be removed fromthe author names Wenhuan Bu, Zilin Wang and LinMeng and the sentence “*These authors contributedequally to this work” should also be removed. Read the original article

Background Kidney autotransplantation (KAT) is the ultimate approach for nephron-sparing surgery. It is a rarely used method in renal tumor surgery today as minimal invasive and open techniques for nephron-sparing surgery improve constantly. In this publication, the complication rate and the long-term functional and oncological outcome at a single center are analyzed. Methods A prospectively constructed database of patients with renal tumors who underwent renal surgery was retrospectively analyzed to identify patients with KAT and describe surgical and oncological outcomes and to obtain long-term follow-up. Data collection included detailed surgical technique, complications (Clavian-Dindo), and hospital stay, as well as functional and oncological outcome and long-term follow-up. Results Between 1976 and 2013, 12 patients (median age 50.5 years) underwent KAT for highly complex renal masses: in five cases for complex renal cell carcinoma (RCC), five cases for complex upper urinary tract carcinoma (UTUC), one case for a renal metastasis, and one case for nephroblastoma. The nephrectomy or nephron-ureterectomy was performed open via a flank or transabdominal. The median surgical time was 360 min (range 270–490 min). Intraoperatively, six cases required blood transfusions (50%). Six patients (50%) developed significant postoperative complications (Clavian-Dindo > 2). In two patients, intermittent hemodialysis for delayed graft function (16.6%) was needed, and in six cases (50%), additional blood transfusions postoperatively were necessary. At discharge from hospital, all patients had functioning grafts. The median hospital stay was 29.5 days (range 18–35). At follow-up (median follow-up of 83.5 ± 40.7 months), six patients had died (50%)—all with functioning grafts (free from hemodialysis). In five cases, recurrence of primary tumor or metastatic disease was recorded. In four cases, the recurrent carcinoma could be resected; in detail, UTUC in three cases and one partial nephrectomy of the autotransplanted kidney was performed. One patient suffered from bone and lung metastasis. Two patients died finally tumor-related. Five patients (41.6%) are presently alive, without evidence of tumor relapse. One patient developed terminal renal failure requiring hemodialysis 105 months after autotransplantation. One additional patient was lost to follow-up; after 69 months, this patient had a functioning kidney and no evidence of disease-recurrence at the last follow-up. A cumulative number of 1424 months without hemodialysis was gained for these 12 patients. In the literature to date, most KAT are performed in benign disease, with minor but frequent complication. Here, we report the largest series of KAT for malignant kidney tumors. The complication rates are similar, compared to the recently reported series for benign indications with an improved graft survival rate. Since KAT requires a complex and challenging surgical approach, it should be performed by experienced kidney transplant surgeons. Conclusion In very complex cases involving renal tumors and multi-morbidity, patients should be counseled well before KAT is considered. At the same time, KAT should not be abandoned in these very rare cases, especially when a nephron-sparing approach is otherwise not feasible. KAT can maintain renal function and quality of life and extend expectancy of life.

Background This study was conducted in order to develop a model for predicting response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) using pretreatment quantitative ultrasound (QUS) radiomics. Methods This was a multicenter study involving four sites across North America, and appropriate approval was obtained from the individual ethics committees. Eighty‐two patients with LABC were included for final analysis. Primary tumors were scanned using a clinical ultrasound system before NAC was started. The tumors were contoured, and radiofrequency data were acquired and processed from whole tumor regions of interest. QUS spectral parameters were derived from the normalized power spectrum, and texture analysis was performed based on six QUS features using a gray level co‐occurrence matrix. Patients were divided into responder or nonresponder classes based on their clinical‐pathological response. Classification analysis was performed using machine learning algorithms, which were trained to optimize classification accuracy. Cross‐validation was performed using a leave‐one‐out cross‐validation method. Results Based on the clinical outcomes of NAC treatment, there were 48 responders and 34 nonresponders. A K‐nearest neighbors (K‐NN) approach resulted in the best classifier performance, with a sensitivity of 91%, a specificity of 83%, and an accuracy of 87%. Conclusion QUS‐based radiomics can predict response to NAC based on pretreatment features with acceptable accuracy., This multi‐institutional study investigated the role of radiomics from quantitative ultrasound (QUS) in predicting the final response to neoadjuvant chemotherapy (NAC) for 82 patients with locally advanced breast cancer (LABC). We had shown the QUS‐radiomics model can predict the response to treatment with an accuracy of 87% from spectroscopic features obtained before the start of NAC.

INTRODUCTION: Quantitative ultrasound parameters based on form factor models were investigated as potential biomarkers of cell death in breast tumor (MDA-231) xenografts treated with chemotherapy. METHODS: Ultrasound backscatter radiofrequency data were acquired from MDA-231 breast cancer tumor–bearing mice (n = 20) before and after the administration of chemotherapy drugs at two ultrasound frequencies: 7 MHz and 20 MHz. Radiofrequency spectral analysis involved estimating the backscatter coefficient from regions of interest in the center of the tumor, to which form factor models were fitted, resulting in estimates of average scatterer diameter and average acoustic concentration (AAC). RESULTS: The ∆AAC parameter extracted from the spherical Gaussian model was found to be the most effective cell death biomarker (at the lower frequency range, r2 = 0.40). At both frequencies, AAC in the treated tumors increased significantly (P = .026 and .035 at low and high frequencies, respectively) 24 hours after treatment compared with control tumors. Furthermore, stepwise multiple linear regression analysis of the low-frequency data revealed that a multiparameter quantitative ultrasound model was strongly correlated to cell death determined histologically posttreatment (r2 = 0.74). CONCLUSION: The Gaussian form factor model–based scattering parameters can potentially be used to track the extent of cell death at clinically relevant frequencies (7 MHz). The 20-MHz results agreed with previous findings in which parameters related to the backscatter intensity (i.e., AAC) increased with cell death. The findings suggested that, in addition to the backscatter coefficient parameter ∆AAC, biological features including tumor heterogeneity and initial tumor volume were important factors in the prediction of cell death response.

Successful studies on radiation therapy for gastric lymphoma led to a decrease in planning target volume (PTV) and radiation dose with low toxicities, maintaining excellent survival rates. It remains unclear as to which effects are to be expected concerning dose burden on organs at risk (OAR) by decrease in PTV vs. dose and whether a direct impact on toxicity might be expected. We evaluated 72 radiation plans, generated prospectively for a cohort of 18 patients who were treated for indolent gastric lymphoma in our department. As a prospective work, four radiation plans with different radiation doses and target volumes (40 Gy-involved field, 40 Gy-involved site, 30 Gy-involved field, 30 Gy-involved site) were generated for each patient. Mean dose burden on adjacent organs was compared between the planning groups. Cohort toxicity data served to estimate parameters for the Lyman–Kutcher–Burman (LKB) model for normal tissue complication probability (NTCP). These were used to anticipate adverse events for OAR. Literature parameters were used to estimate high-grade toxicities of OAR. Decrease of dose and/or PTV led to median dose reductions between 0.13 and 5.2 Gy, with a significant dose reduction on neighboring organs. Estimated model parameters for liver, spleen, and bowel toxicity were feasible to predict cohort toxicities. NTCP for the endpoints elevated liver enzymes, low platelet count, and diarrhea ranged between 15.9 and 22.8%, 27.6 and 32.4%, and 21.8 and 26.4% for the respective four plan variations. Field and dose reduction highly impact dose burden and NTCP for OAR during stomach radiation. Our estimated LKB model parameters offer a good approximation for low-grade toxicities in abdominal organs with modern radiation techniques., Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).

Background: Cancer is associated with a state of systemic inflammation with high levels of circulating inflammatory cytokines. Cytokine gene polymorphisms may affect the inflammatory response in cancer patients and their nutritional and performance status with subsequent effects on their prognosis. Aim: This study investigated the relationship between IL-10 -1082 A/G promoter polymorphism and anorexia, body mass index (BMI) and performance status in patients with gastrointestinal (GI) malignancies. Methods 88 newly diagnosed patients with GI malignancies were genotyped for IL-10-1082 A/G promoter polymorphism by real-time PCR allelic discrimination assay. The prevalence of anorexia, BMI and performance status was compared between patients with different genotypes. Results: In the whole group of patients, anorexia was significantly more prevalent (p < strong>< 0.001) among patients carrying the variant genotypes (AG and GG) who were also found to have significantly lower BMI (p=0.002) and poorer performance status (p=0.027) than those with the wild genotype (AA). In patients with earlier cancer (stages I and II), a variant genotype was significantly associated with more anorexia and lower BMI. Conclusion: These results suggest that IL-10-1082 A/G promoter polymorphism may have an effect on the nutritional and performance status of patients with GI malignancies.

Background: Breast cancer is the most common cancer in Egyptian females. Most patients present at a late stage with subsequent poor outcomes. Aim: To study the awareness of breast cancer, its risk factors and screening. To investigate the impact of caring for a family member with breast cancer on the awareness and future attitudes of caregivers. Methods: The study included 704 females divided into two groups. A non-caregivers group including 248 participants representing the general population and a caregivers group including 456 family caregivers of breast cancer patients. We used a questionnaire comprised of 45 questions assessing four domains: individual risk factors, awareness of risk factors, awareness of screening, and the practice of and barriers to screening. Those who answered more than 50% of the questions correctly were considered to have good knowledge. Results: Sixty-nine percent of participants showed poor knowledge of risk factors. In the screening awareness domain, only 44% of participants scored >50% indicating defective knowledge. Caregivers attained significantly higher scores in all domains (p < 0.001). Yet, the overall assessment showed poor knowledge in both groups. Only 3% of non-caregivers and 19% of caregivers performed mammography (p < 0.001); while 11% and 38%, respectively, underwent breast self-examination (p < 0.001). Higher education level was associated with significantly better knowledge (p < 0.001). Conclusions: Breast cancer knowledge among Egyptian females is deficient. The level of education and caring for a breast cancer patient significantly affect the level of knowledge and attitude towards screening. There is a need to implement a comprehensive national awareness and screening programme.

Background: Hyperglycemia is frequent during steroid therapy and thus it is not uncommon during treatment of lymphoid malignancies. Steroid-induced diabetes (SID) can be complicated by an increased risk of infections, lower chemotherapy efficacy, and even increased mortality. Aim: To determine the prevalence of SID in patients with aggressive lymphoid malignancies during induction therapy and to analyze its impact on treatment outcomes. Methods: The study included 52 patients with lymphoid malignancies; 28 with acute lymphoblastic leukemia (ALL) and 24 with aggressive non-Hodgkin’s lymphomas (NHL). We studied the relation between the development of SID during induction therapy and the rates of complete remission (CR), complication and relapse and survival. Results: Steroid-induced diabetes occurred during induction therapy in 18/28 (64%) and 8/24 (33%) of patients with ALL and NHL, respectively. Older age, and elevated bilirubin level were significantly associated with the development of SID during induction therapy in ALL patients (p = 0.02 and 0.005, respectively), while only older age showed a significant association in NHL patients (p = 0.002). Compared with patients who did not develop SID, those with SID had significantly higher prevalence of febrile neutropenia in the ALL group (p = 0.001) and pneumonia in the NHL group (p = 0.009). Both ALL and NHL patients with SID were significantly less likely to achieve CR and had a significantly worse overall survival. Conclusion: The results of this study suggest that SID is frequent during induction therapy in patients with lymphoid malignancies and associated with more complications and worse treatment outcomes.

Background: Identification of high-risk patients with multiple myeloma (MM) is important for improving treatment outcomes. Efforts to identify significant prognostic markers are unremitting. Angiogenesis plays an important mechanism in the progression of MM. One of the mediators of this angiogenic process is interleukin-10 (IL-10). Aim: To assess the role of IL-10 as a prognostic marker in MM. Methods: This was a cross-sectional study that included 39 newly diagnosed patients with MM. Serum IL-10 level was measured using Magnetic Luminex® Assay multiplex. The relationship between IL-10 and tumor stage and other known prognostic markers in MM was studied. Results: The median (interquartile range) value of IL-10 was 3 (2.9 – 3.2) pg/mL. Interleukin-10 level differed significantly according to the revised International Staging System stage of MM, being higher in higher stages. The median (interquartile range) IL-10 level was 2.89 (2.79 – 2.95) pg/mL in stage I, 3 (2.9 – 3.1) in stage II and 3.2 (3.1 – 3.66) in stage III (p = 0.0009). In addition, higher IL-10 correlated significantly with lower hemoglobin (p = 0.002), lower albumin (p = 0.045), higher creatinine (p = 0.009), higher β2-microglobulin (p = 0.002), higher lactate dehydrogenase (p = 0.0007) and higher bone marrow plasma cell percentage (p = 0.015). Conclusion: The results support a prognostic role of IL-10 in MM and its pathogenesis.

Background As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G). Patients and methods Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians’ discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors. Results Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant. Conclusions FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC., Highlights • This study compared febrile neutropenia (FN) incidences of 3 breast cancer regimens. • FN incidences were >20% in the 3 regimens (FEC, E(A)C; TC); TC showed the highest. • The relative dose intensities in visiting and non-visiting groups were at high level. • Age and pretreatment absolute neutrophil count were found as significant FN factors.

Chronic lymphocytic leukemia (CLL) typically occurs in the elderly and has a highly variable clinical course. Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients. The management of hematological malignancies, including CLL, during the COVID-19 pandemic is challenging. Here we describe two patients with CLL who got infected with SARS-COV-2 as confirmed by positive nasopharyngeal swab PCR. The 1st patient, who was receiving treatment for CLL-associated autoimmune hemolytic anemia, was hospitalized with mild COVID-19 symptoms. The 2nd patient, who was on active treatment for CLL, had asymptomatic COVID-19 infection and was not hospitalized. Both patients recovered from COVID-19 without related complications.

Background T790M mutation causes resistance to tyrosine kinase inhibitors (TKIs) in approximately 49% of patients with epidermal growth receptor‐mutant non‐small cell lung cancer (NSCLC). The cause of resistance in the remaining half of the cases is a minor mutation or unknown. Here, we conducted a retrospective study of epidermal growth receptor‐mutant NSCLC patients with T790M‐negative or an unidentified mutation to appraise the therapeutic response to first‐ or second‐generation tyrosine kinase inhibitors as a second‐line treatment. Methods The study included 39 patients treated in our institution from April 2012 through March 2020 with second‐line tyrosine kinase inhibitors or chemotherapy after completing a first‐line therapy with tyrosine kinase inhibitors. Results The patients were allocated to two groups: chemotherapy (n = 28) and a tyrosine kinase inhibitor (n = 11) groups. The median progression‐free survival (PFS) was 5.4 months in the chemotherapy group and 3.4 months in the tyrosine kinase inhibitor group (p‐value = 0.36), while the median overall survival (OS) was 16.1 months in the chemotherapy group and 12.8 months in the tyrosine kinase inhibitor group (p‐ value = 0.20). This study showed no significant difference in PFS and OS between the chemotherapy and tyrosine kinase inhibitor groups. Conclusions These observations suggest that first‐ and second‐generation tyrosine kinase inhibitors are not recommended for second‐line treatment in epidermal growth factor receptor‐mutated NSCLC patients with T790M‐negative mutation who have received tyrosine kinase inhibitors as first‐line treatment., T790M mutation is the main cause of therapeutic resistance to TKI in EGFR‐mutant NSCLC patients. There is no effective second‐line therapy for unknown or T790M‐negative mutation patients previously treated with first‐ or second‐generation EGFR TKI. This study showed that first‐ and second‐generation TKIs are not recommended for second‐line treatment in EGFR‐mutated NSCLC patients with T790M‐negative or unknown mutation that have received TKIs as first‐line treatment.

Xiang Tan,1,* Huajian Peng,1,* Peixin Gu,2 Mingwu Chen,1 Yongyong Wang1 1Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingwu Chen; Yongyong Wang Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Road 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaEmail chen535@126.com; wangyongyong@stu.gxmu.edu.cnObjective: To evaluate the correlation between the advanced lung cancer inflammation index (ALI) and the L3 skeletal muscle index (L3SMI) and their prognostic value in elderly patients with esophageal cancer (EC).Materials and Methods: The clinical data of 158 elderly patients with EC were collected retrospectively. The L3SMI measures the area of skeletal muscle at the level of the third lumbar (L3) vertebra using computed tomography (CT). A high L3SMI and low L3SMI group were created using sex-based quartiles. The ALI, prognostic nutrition index (PNI), and geriatric nutrition risk index (GNRI) were calculated according to standard laboratory protocols.Results: The CT diagnostic criteria for senile sarcopenia in South China are height ≤ 32.96 cm2/m2 for females and height ≤ 35.4 cm2/m2 for males. The logistic regression analysis showed that a low L3SMI was significantly associated with a low ALI. Survival analysis revealed EC patients with a low L3SMI and a low ALI had poorer overall survival (OS) than patients with a high L3SMI and a high ALI. Univariate and multivariate Cox analyses showed that the L3SMI and ALI were independent predictors of EC prognosis in elderly individuals.Conclusion: There was a significant correlation between the PNI, GNRI, ALI, and L3SMI. Overall, our findings show the L3SMI and ALI are clinical indicators that can potentially be used to independently predict the prognosis of elderly EC patients and display good predictive value.Keywords: esophageal cancer, sarcopenia, L3 skeletal muscle index, survival, advanced lung cancer inflammation index

Hongchun Chen,1,2 Yuchen Huang,1,2 Ningning Yang,1,2 Wentian Yan,1,2 Ruxue Yang,3 Shan Zhang,4 Panpan Yang,5 Nan Li,1,2 Zhenzhong Feng1,2 1Department of Pathology, Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 2Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 3Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of China; 4Department of Pathology, Second People’s Hospital of Hefei, Hefei, Anhui Province, 230000, People’s Republic of China; 5Department of Pathology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of ChinaCorrespondence: Zhenzhong FengDepartment of Pathology, First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Longzihu District, Bengbu, Anhui, 233000, People’s Republic of ChinaTel +86 1 505 528 9508Email fzz18297301626@163.comPurpose: Solid-pseudopapillary neoplasm (SPN) of the pancreas, a rare tumor, has low malignant potential. However, some patients develop metastasis and recurrence after resection, with aggressive biological behaviors. This study aimed to explore the features and risk factors associated with the aggressive biological behaviors of SPNs.Patients and Methods: We retrospectively analyzed the clinicopathological and long-term follow-up data of 63 patients diagnosed with SPN at the First Affiliated Hospital of Bengbu Medical College between January 2007 and February 2019.Results: Sixty-three patients presented atypical clinical symptoms. The median tumor size was 7.0 cm (range, 2.4– 17 cm), and imaging features were solid and cystic or solid tumors with uneven density. Frequent and diffuse nuclear LEF1 protein expression (94.2%) was observed with LEF1 having a higher sensitivity and specificity. Overall survival significantly correlated with tumor size, Ki-67 index, and lymph node metastasis (P < 0.05).Conclusion: SPN is a rare low-grade malignancy with a specific pseudopapillary structure. LEF1 is an effective biomarker of SPNs. Although SPNs generally display indolent biological behavior, a large tumor size, high proliferation index, and lymph node metastasis may be risk factors for the aggressive behavior and poor prognosis of SPN.Keywords: pancreatic tumor, LEF1, retrospective study, overall survival, metastasis

Yingyun Zhang,1,2 Wei Wang,1,2 Xuedong Xu,1,2 Yankang Li,1,3 Hui Zhang,4 Jianbin Li,1,2 Zhenxiang Li1 1Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 2Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 3Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 4Tumor Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, Jishou, People’s Republic of ChinaCorrespondence: Jianbin Li; Zhenxiang LiDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of ChinaTel +86 13869135266; +86 18654536783Email lijianbin@msn.com; lizx0108@163.comIntroduction: The aim of this study was to investigate the role of local radiotherapy in the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) treated with EGFR tyrosine kinase inhibitors (TKIs).Materials and Methods: Patients with stage IV EGFR-mutant NSCLC treated with radiotherapy concomitant to EGFR TKIs from May 2010 to December 2017 were retrospectively identified. Overall survival (OS) was the primary endpoints of the study.Results: A total of 205 patients were enrolled in the study. One hundred eleven patients received one-time single-site radiotherapy (SSR), and 94 patients received multiple-site radiotherapy (MSR). Patients who received MSR had longer OS (median OS, 40.0 months; 95% confidence interval [CI], 29.6 to 50.4) than those who received SSR (median OS, 28.9 months; 95% CI, 24.3 to 33.5; P=0.031). Thoracic radiotherapy was associated with prolonged median OS (41.7 months, 95% CI, 29.0 to 54.4 vs 27.1 months, 95% CI 22.7 to 31.5; log-rank P< 0.001). Multivariate analysis confirmed that thoracic radiotherapy was independently associated with improved OS (adjusted hazard ratio [HR], 0.514; 95% CI 32.3% to 81.8%; P=0.005).Conclusion: MSR improves survival outcomes in patients with advanced-stage, EGFR-mutant, lung adenocarcinoma, with thoracic radiotherapy having the most significant effect on prognosis.Keywords: advanced-stage lung cancer, adenocarcinomas, radiotherapy, EGFR

Zizhen Zhang,1– 3,* Fangyu Ju,1– 3,* Fei Chen,1– 3 Haoyue Wu,4 Jingyu Chen,1– 3 Jing Zhong,1– 3 Liming Shao,1– 3 Sheng Zheng,1– 3 Liangjing Wang,1– 3 Meng Xue1– 3 1Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310020, People’s Republic of China; 2Institution of Gastroenterology, Zhejiang University, Hangzhou, 310000, People’s Republic of China; 3Zhejiang University Cancer Center, Hangzhou, 310000, People’s Republic of China; 4Institute of Genetics and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meng Xue; Liangjing Wang Email xuemeng@zju.edu.cn; wangljzju@zju.edu.cnAim: Chemoresistance to 5-fluorouracil (5-Fu) is common in colorectal cancer (CRC). Programmed necrosis (necroptosis) is an alternative form of programmed cell death regulated by receptor-interacting protein kinase (RIPK) 1 and 3, assumed as a novel target of cancer therapy. In this study, we aimed to explore whether a novel small molecular agent GDC-0326 could facilitate the effect of 5-Fu through necroptosis.Main Methods: Cell Counting Kit-8 (CCK-8) assay and colony formation were performed to confirm the function of GDC-0326 in CRC cells. Western blot and immunofluorescence were conducted to measure the altered expressions of RIPK1/RIPK3 induced by GDC-0326. Subcutaneous tumor models were used to evaluate the chemotherapeutic effects and concomitant side effects of GDC-0326 in vivo.Key Findings: We found that GDC-0326 effectively suppressed the growth of CRC cells in a dose-dependent manner. The induction of necroptosis by GDC-0326 was correlated with the modulation of RIPK1 and RIPK3. Necrostatin-1 and GSK-872, inhibitors of RIPK1 and RIPK3, respectively, could rescue the cell death induced by GDC-0326. In addition, in vitro and in vivo studies showed that 5-Fu plus GDC-0326 evinced a better antitumor efficacy by suppressing tumor growth and increasing tumor necrosis with no increased toxicity.Significance: This study demonstrates that GDC-0326 plus 5-Fu has augmented antitumor efficacy and acceptable safety, which might be a promising therapeutic strategy for CRC patients in the future.Keywords: GDC-0326, 5-fluorouracil, colorectal cancer, combination therapy

Background Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosomal membrane associated protein 2a (LAMP2a) is the lysosomal membrane receptor of CMA and influences CMA activity. Although it has been suggested that higher expression of LAMP2a is associated with more advanced tumor node metastasis (TNM) stages and shorter survival time in patients with esophageal squamous cell carcinoma (ESCC), the underlying mechanism has not been known yet. Methods In this study, we modulated the activity of CMA through LAMP2a or small molecular compounds in human ESCC cells to investigate its role in ESCC. Results We found that down‐regulating the activity of CMA could inhibit the proliferation and colony formation of ESCC cells as well as increase their sensitivity to cisplatin. Conclusions Our results promote better understanding of how CMA affects human ESCC and provide a new therapeutic target against ESCC through down‐regulating LAMP2a., Inhibiting chaperone‐mediated autophagy can decrease cell growth and increase cisplatin resistance in esophageal squamous cell carcinoma.

Background A novel type of noncoding RNA, circRNA has been reported to participate in the occurrence and development of diseases through many mechanisms. The MAPK pathway is a common signal transduction pathway involved in cell proliferation, inflammation and apoptosis and plays a particularly important role in cancers. However, the role of circRNAs related to the MAPK pathway in gastric cancer has not been explored. Methods A bioinformatics analysis was performed to profile and identify the circRNAs involved in the MAPK pathway in gastric cancer. The tumor-suppressive role of circMAPK1 was confirmed both in vitro and in vivo. Mass spectrometry, Western blot and immunofluorescence staining assays were used to validate the existence and expression of MAPK1–109aa. The molecular mechanism of circMAPK1 was investigated by mass spectrometry and immunoprecipitation analyses. Results In this study, we identified that circMAPK1 (hsa_circ_0004872) was downregulated in gastric cancer tissues compared with adjacent normal tissues. Importantly, lower circMAPK1 expression predicted poor survival in GC patients. CircMAPK1 inhibited the proliferation and invasion of gastric cancer cells in vitro and in vivo. Next, we found that circMAPK1 encoded a novel protein with 109 amino acids in length. Through a series of functional experiments, we confirmed that circMAPK1 exerted a tumor-suppressing effect via the encoded protein MAPK1–109aa. Mechanistically, the tumor suppressor MAPK1–109aa inhibited the phosphorylation of MAPK1 by competitively binding to MEK1, thereby suppressing the activation of MAPK1 and its downstream factors in MAPK pathway. Conclusions Our study revealed that circMAPK1 inhibits the malignant biological behavior of gastric cancer cells through its encoded protein MAPK1–109aa. More importantly, circMAPK1 is a favorable predictor for gastric cancer patients and may provide a new therapeutic target in the treatment of gastric cancer.

Wen Yang,1,* Xia Xu,2,* Ming Xu,1 Jun Zhou,1 Zihan Xi,1 Hui Guo,1 Jie Ming,1 Tao Huang1 1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Huang; Jie MingDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No. 1277, Wuhan, Hubei Province, People’s Republic of ChinaTel +8613807112766; +8613905519049Fax +86 27-85726833Email huangtaowh@163.com; mingjiewh@126.comPurpose: Papillary thyroid cancer (PTC) patients could obtain poor prognosis if they have lymph node metastasis, identification of informative and robust biomarkers for predicting cervical lymph node metastasis is critical for improving clinical decision-making and patient prognosis.Materials and Methods: In this study, we analyzed the expression of X box binding protein 1 spliced-form (XBP1s) in 41 PTC tissue samples and extended our findings using public databases, then we investigated how XBP1s’ contributed to PTC progression in vitro.Results: We found that XBP1s’ expression was lower in PTC patients with cervical lymph node metastasis than non-metastasis patients by immunohistochemical analysis. With publicly accessible dataset, we showed that the XBP1 transcription was significantly decreased in thyroid cancer (TC) tissues with lymph node metastasis as compared to that without lymph node metastasis. Moreover, we also found that XBP1 expression was significantly correlated with patients’ gender, T classification, lymph node metastasis and PTC stages, and low XBP1 expression was associated with poor diseases free survival (DFS). In vitro, XBP1s overexpression could inhibit the invasion, migration, and wound healing capacity of PTC cells. Mechanistically, overexpression of XBP1s could enhance the expression of classical epithelial–mesenchymal transition (EMT) markers such as ZO-1 and E-cadherins, and downregulated N-cadherin in BCPAP cells.Conclusion: These findings suggest that XBP1s is a prognostic maker for thyroid carcinoma patients, and sustaining XBP1s expression might be a new strategy to control PTC progression.Keywords: XBP1s, lymph node metastasis, papillary thyroid cancer, EMT

Kewa Ma,* Jiannan Ye,* Lingling Wang, Chao Sun, Xin Zhou Department of Hematology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao Sun; Xin ZhouDepartment of Hematology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, Jiangsu, 214000, People’s Republic of ChinaTel +86-15961806698; +86 51085350201Fax +86 51085350201Email 13057302309sun@163.com; zx89232@126.comPurpose: Recently, the British Myeloma Research Alliance put forward a Myeloma Risk Profile (MRP) for the first time to stratify the prognosis risk of non-transplanted patients with multiple myeloma. However, only limited studies have evaluated the applicability of this model in the Chinese population. This study aimed to estimate the prognostic value of MRP in newly diagnosed multiple myeloma patients without autologous stem cell transplantation in China.Patients and Methods: Patients with multiple myeloma in Wuxi People’s Hospital from January 1, 2007, to June 30, 2018 were evaluated based on the MRP score, and the relationship between the clinical outcome of patients with MM and the score was analyzed retrospectively.Results: First, significant differences were observed in the overall survival (OS) (P< 0.05) and progression-free survival (PFS) (P< 0.05) between the low-, middle-, and high-risk groups. Second, in the bortezomib treatment subgroup and complex chromosome karyotype subgroup, OS and PFS were significantly shorter in the high-risk group than in the low-risk group (P< 0.05). Third, the depth of remission still showed prognostic significance in the high-risk MRP group.Conclusion: MRP is also applicable in Chinese patients with newly diagnosed MM who did not undergo transplantation, as it is simple and cost effective; hence, it is worth popularizing.Keywords: multiple myeloma, myeloma risk profile, bortezomib, complex chromosome karyotype, prognosis

Yunhe Huang,* Lei Jiang,* Guangxia Wei Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangxia WeiDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Donghu District, Nanchang, Jiangxi, People’s Republic of ChinaEmail uzbher@163.comBackground: Circular RNAs (circRNAs) exert important roles in carcinogenesis. Here, we aimed to uncover the working mechanism of circ_0006168 in esophageal squamous cell carcinoma (ESCC) development.Methods: Western blot assay and real-time quantitative polymerase chain reaction (RT-qPCR) were used to determine protein and RNA expression, respectively. Wound healing assay and transwell migration assay were performed to assess cell migration ability, whereas cell invasion ability was evaluated by transwell invasion assay. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay were utilized to analyze cell proliferation ability. Xenograft tumor model was utilized to assess the role of X-box binding protein 1 (XBP1) in xenograft tumor growth in vivo. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were used to verify intermolecular interactions.Results: XBP1 silencing suppressed the migration, invasion and proliferation of ESCC cells in vitro and restrained the xenograft tumor growth in vivo. MicroRNA-516b-5p (miR-516b-5p) interacted with the 3ʹ untranslated region (3ʹUTR) of XBP1 in ESCC cells. MiR-516b-5p overexpression inhibited the proliferation and motility of ESCC cells. MiR-516b-5p was a molecular target of circ_0006168 in ESCC cells. The interference of circ_0006168 restrained the motility and proliferation of ESCC cells. Circ_0006168 acted as miR-516b-5p sponge to up-regulate XBP1 expression in ESCC cells. MiR-516b-5p silencing or the accumulation of XBP1 largely rescued the proliferation ability and motility in circ_0006168-silenced ESCC cells.Conclusion: In conclusion, circ_0006168 contributed to ESCC development through promoting the proliferation and motility of ESCC cells via mediating miR-516b-5p/XBP1 axis.Keywords: esophageal squamous cell carcinoma, circ_0006168, miR-516b-5p, XBP1

Background Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC., Low expression of miR‐125b‐2‐3p in CRC was linked to lower chemotherapeutic sensitivity and poor survival. The lncRNA XIST promoted CRC invasion and migration by functioning as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. Our findings suggest that the lncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC, which may shed light on their targeted applications.

Mengwei Wang,* Tianwei Xu,* Wenyan Feng,* Junxia Liu, Zhaoxia Wang Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaoxia WangCancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Jiangjiayuan Road 121#, Nanjing, People’s Republic of ChinaTel +86-25-58509810Fax +86-25-58509994Email wangzhaoxia@njmu.edu.cnAbstract: Long noncoding RNAs (lncRNAs) are a class of RNA molecules that are longer than 200 nucleotides and cannot encode proteins. Over the past decade, lncRNAs have been defined as regulatory elements of multiple biological processes, and their aberrant expression contributes to the development and progression of various malignancies. Recent studies have shown that lncRNAs are involved in key cancer-related signaling pathways, including the Hippo signaling pathway, which plays a prominent role in controlling organ size and tissue homeostasis by regulating cell proliferation, apoptosis, and differentiation. However, dysregulation of this pathway is associated with pathological conditions, especially cancer. Accumulating evidence has revealed that lncRNAs can modulate the Hippo signaling pathway in cancer. In this review, we elaborate on the role of the Hippo signaling pathway and the advances in the understanding of its lncRNA-mediated regulation in cancer. This review provides additional insight into carcinogenesis and will be of great clinical value for developing novel early detection and treatment strategies for this deadly disease.Keywords: lncRNAs, Hippo pathway, cancer, tumorigenesis, prognosis

Xinjian Xu,1,* Yiwen Ding,1,* Tianfan Pan,1 Feng Gao,1 Xiangzhong Huang,1 Qiulian Sun2 1Department of Interventional Radiology, Jiangyin People’s Hospital, Jiang Yin City, Jiangsu Province, 214400, People’s Republic of China; 2Department of Radiology, Zhejiangtaizhou Hospital, Taizhou City, Zhejiang Province, 317000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangzhong Huang; Qiulian Sun Email hxzdoc@163.com; sql947435865@163.comPurpose: To investigate the efficacy and safety of CT-guided 125I brachytherapy in the treatment of hepatocellular carcinoma (HCC) refractory to conventional transarterial chemoembolization (TACE).Methods: Nineteen patients with TACE-refractory HCC treated with CT-guided 125I brachytherapy between June 2017 and June 2020 at Jiangyin People’s Hospital were enrolled in this study. In addition, we used the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria to evaluate the treatment response after 125I brachytherapy.Results: Twenty-one tumours were treated with CT-guided 125I brachytherapy in nineteen patients. Twelve tumours (57.1%) showed a complete response, and a partial response was observed in seven tumours (33.3%). The six-month objective response rate was 90.5% (19/21). The adverse effects of CT-guided 125I brachytherapy were tolerable.Conclusion: Our preliminary clinical experience demonstrated that CT-guided 125I brachytherapy was effective and well tolerated for the treatment of TACE-refractory HCC, suggesting that CT-guided 125I brachytherapy has the potential to become an effective alternative treatment for TACE-refractory HCC.Keywords: 125I brachytherapy, TACE, refractory, hepatocellular carcinoma

Jiangang Chen,1,2 Lin Hao,1,3 Shaoqi Zhang,1 Yong Zhang,2 Bingzheng Dong,1,3 Qianjin Zhang,1 Conghui Han1,3 1Medical College of Soochow University, Suzhou, Jiangsu Province, 215123, People’s Republic of China; 2Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, People’s Republic of China; 3Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical College Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu Province, 221009, People’s Republic of ChinaCorrespondence: Conghui HanDepartment of Urology, Xuzhou Central Hospital, Xuzhou Clinical College Affiliated to Xuzhou Medical University, 199 Jiefang South Road, Xuzhou, Jiangsu, 221009, People’s Republic of ChinaEmail conghuihandoctor@163.comBackground: We conducted a two-center study to investigate the prognostic value of preoperative fibrinogen–albumin ratio (FAR) in patients undergoing radical cystectomy (RC).Methods: The clinical and survival data of 267 patients with bladder cancer (BCa) treated with RC were collected, of which 140 patients from Xuzhou Central Hospital were divided into training set and 127 patients from The Second Affiliated Hospital of Nantong University were divided into validation set. X-tile software was used to obtain the optimal cut-off values for preoperative platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and FAR. Receiver operating characteristic (ROC) curves were used to compare the predictive ability of PLR, NLR, FAR and modified Glasgow prognostic score (mGPS). Kaplan–Meier curves were used to assess overall survival (OS) and progression-free survival (PFS) of patients in different FAR groups. Univariate and multivariate Cox regression were used to assess patients’ independent risk factors, and R software was used to construct prognostic nomograms.Results: In the training set, the optimal cut-off values for PLR, NLR and FAR were 76.76, 3.97 and 0.08, respectively. Both in the training and validation sets, FAR had better ability to predict OS and PFS than PLR and NLR, and patients in the higher FAR group had worse OS and PFS. In the multivariate Cox regression analysis, FAR was an independent risk factor for OS [hazard ratio (HR) 3.569, 95% confidence interval (CI): 1.015– 12.546, P=0.047] and PFS [HR 5.071, 95% CI: 1.394– 18.451, P=0.014]. In addition, FAR-based prognostic nomograms had high predictive ability than TNM staging.Conclusion: Preoperative FAR is an independent prognostic factor for OS and PFS in BCa patients treated with RC, and a high FAR predicted a poor prognosis. In addition, a prognostic nomogram based on FAR can better predict individual survival.Keywords: fibrinogen–albumin ratio, bladder cancer, radical cystectomy, overall survival, progression-free survival

Qinge Wang,1 Min Gu,2 Yun Zhuang,1 Jianping Chen1 1Department of Digestive Disease, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Pediatrics, Changzhou Children’s Hospital, Changzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Jianping ChenDepartment of Digestive Disease, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Juqian Road, Tianning District, Changzhou, Jiangsu, 213003, People’s Republic of ChinaEmail Chenjianping123abc@126.comBackground: MAGI1-IT1 is a long non-coding RNA (lncRNA) previously reported to regulate several cancer types, but its functional role in gastric cancer (GC) remains to be defined. This study therefore explored the mechanistic role played by MAGI1-IT1 in the regulation of GC cell proliferation.Methods: 120 pairs of GC patient tumor, paracancerous tissues, human GES-1 control cells and human AGS, MKN-74, MKN-45, and MGC-803 GC cell lines were used to detected MAGI1-IT1, miR-302d-3p, and IGF1 expression by a qPCR approach. An shRNA approach was used to knock down MGI1-IT1 in order to examine the effect of such treatment on GC cell proliferation, and rescue experiments were subsequently conducted. In addition, the functional role of MAGI1-IT1 in GC in vivo was evaluated with a xenograft model system. P < 0.05 was the significance threshold.Results: Elevated MAGI1-IT1 expression was detected in GC cell lines and tissues, and was linked to poorer patient overall survival. Knocking down this lncRNA disrupted GC cell proliferation in vitro and in vivo, and miR-302d-3p was identified as a MAGI1-IT1 target. Notably, miR-302d-3p inhibition partially reversed the impact of MAGI1-IT1 knockdown on GC cell proliferation. IGF1 was subsequently identified as a miR-302d-3p target gene that was upregulated by MAGI1-IT1 through miR-302d-3p.Conclusion: Overall, these results indicated that MAGI1-IT1 controlled GC cell proliferation by modulating the miR-302d-3p/IGF1 axis, suggesting that this may be a viable treatment target in those with GC.Keywords: MAGI1-IT1, cell proliferation, gastric cancer, miR-302d-3p, IGF1

Background Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. Methods Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC (stage III-IVa) deemed fit for CRIO by consensus of the Multidisciplinary meeting will be eligible. In the first stage of a two-stage minimax design, we aim to recruit a total of 15 patients. If fewer than 7 patients achieved a complete response in the first stage, we will conclude the treatment is not more effective than standard treatment. The co-primary endpoints of CRIO are the safety of treatment (acute and late toxicities) and the rate of complete response. Secondary endpoints would include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers (CD73, CD39, PD-1, PD-L1) will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET/CT scan will be explored. Discussion CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent and adjuvant durvalumab for patients with unresectable stage III-IVa cSCC. Trial registration: Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246)

Yunning Huang,1,* Yuanyuan Yang,2,* Yuanyi Xu,2,* Qian Ma,3,4,* Fengying Guo,2 Yuan Zhao,2 Yuejia Tao,2 Mengqi Li,2 Jiaxin Guo2 1Department of Gastrointestinal Surgery, The Affiliated People’s Hospital of Ningxia Medical University, Yinchuan City, Ningxia Province, 750001, People’s Republic of China; 2Department of Pathology, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People’s Republic of China; 3College of Life Sciences, Ningxia University, Yinchuan City, Ningxia Province, 750021, People’s Republic of China; 4College of Basic Medicine, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunning Huang; Yuanyi Xu Email nxhyncc@126.com; nxxyy@hotmail.comPurpose: Gastric cancer (GC) is one of the most fatal digestive tumors worldwide. Abnormal activation or accumulation of the nuclear factor-erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) axis is a malignant event in numerous solid tumors. However, its involvement in angiogenesis of GC remains unknown. This study investigated the role of the Nrf2/HO-1 axis in angiogenesis of GC.Methods: The expression of Nrf2, HO-1, and vascular endothelial growth factor (VEGF) in BGC-823 cells under hypoxia was analyzed using immunocytochemistry, immunofluorescence, Western blotting, and quantitative polymerase chain reaction. The effects of brusatol (Nrf2 inhibitor) and tert-butylhydroquinone (Nrf2 inducer) on these factors and angiogenesis were examined using immunofluorescence, Western blotting, quantitative polymerase chain reaction, and tube formation assay. Moreover, immunohistochemistry and Western blotting were used to determine these factors and microvessel density in tumor and normal tissues of tumor-bearing and tumor-free mice, respectively. Immunohistochemistry and Western blotting were employed to examine these factors and microvessel density in human paracancerous tissues, well-differentiated GC, and poorly differentiated GC. The correlations between Nrf2, HO-1, and VEGF gene expression in 375 patients with GC from The Cancer Genome Atlas cohort were analyzed.Results: The expression of Nrf2, HO-1, and VEGF was increased in hypoxic BGC-823 cells (P< 0.05). Although brusatol decreased their expression and angiogenesis (P< 0.05), tert-butylhydroquinone had the opposite effect (P< 0.05). Moreover, the expression of Nrf2, HO-1, and VEGF, and microvessel density in tumor tissues was higher than that recorded in normal tissues of nude mice (P< 0.05). Similarly, these parameters were low in paracancerous tissues, but high in GC tissues (P< 0.05). Also, they were weak in well-differentiated GC, but strong in poorly differentiated GC (P< 0.05). In addition, there was a significant correlation between Nrf2, HO-1, and VEGF (P< 0.05).Conclusion: The Nrf2/HO-1 axis may regulate the angiogenesis of GC via targeting VEGF. These findings provide a promising biomarker and potential treatment target for GC.Keywords: gastric cancer, angiogenesis, Nrf2, HO-1, VEGF

Background Diagnostic mammography projections (DxMM) have been traditionally used in the assessment of women recalled after a suspicious screening mammogram. Digital breast tomosynthesis (DBT) reduces the tissue overlap effect, thus improving image assessment. Some studies have suggested DBT might replace DxMM with at least equivalent performance. Objective To evaluate the replacement of DxMM with DBT in women recalled at screening. Methods We searched PubMed, EMBASE, and the Cochrane Library databases to identify diagnostic paired cohort studies or RCTs comparing DBT vs DxMM, published in English that: reported accuracy outcomes, recruited women recalled for assessment at mammography screening, and included a reference standard. Subgroup analysis was performed over lesion characteristics. We provided pooled accuracy estimates and differences between tests using a quadrivariate model. We assessed the certainty of the evidence using the GRADE approach. Results We included ten studies that reported specificity and sensitivity. One study included 7060 women while the remaining included between 52 and 738 women. DBT compared with DxMM showed a pooled difference for the sensitivity of 2% (95% CI 1%–3%) and a pooled difference for the specificity of 6% (95%CI 2%–11%). Restricting the analysis to the six studies that included women with microcalcification lesions gave similar results. In the context of a prevalence of 21% of breast cancer (BC) in recalled women, DBT probably detects 4 (95% CI 2–6) more BC cases and has 47 (95%CI 16–87) fewer false‐positive results per 1000 assessments. The certainty of the evidence was moderate due to risk of bias. Conclusion The evidence in the assessment of screen‐recalled findings with DBT is sparse and of moderate certainty. DBT probably has higher sensitivity and specificity than DxMM. Women, health care providers and policymakers might value as relevant the reduction of false‐positive results and related fewer invasive diagnostic procedures with DBT, without missing BC cases., This systematic review found that in women of average risk of breast cancer with suspicious lesions at mammography screening, DBT probably has higher specificity difference (6%) than diagnostic views of 2D mammography in women recalled for assessment (moderate certainty evidence). The sensitivity is also probably higher with DBT; however, the difference was not so large (2%). The clinical impact of these results in a screening program is a probable reduction of 47 false positive results, including related invasive procedures, and most likely a small increase of 4 additional true BC lesions per 1000 women recalled for assessment. Our results were consistent in women with calcified lesions, but with a larger imprecision in the sensitivity differences. These results were taken into account by the GDG, together with other considerations (ie, feasibility) to issue a conditional recommendation in favor of DBT which is available on the ECIBC website (https://healthcare‐quality.jrc.ec.europa.eu/european‐breast‐cancer‐guidelines/diagnosis/DBT).

Background NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. Methods NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. Results NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. Conclusions We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.

Jian Yang,1 Feng Bi,2 Hongfeng Gou1 1West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China; 2Department of Medical Oncology, Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaCorrespondence: Feng BiDepartment of Medical Oncology, Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 37# Wai Nan Guoxue Road, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaTel +86-28-85423609(O)Fax +86-28- 85423609Email bifeng@scu.edu.cnHongfeng GouWest China Hospital, Sichuan University, 37# Wai Nan Guoxue Road, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaEmail joan_gou1977@163.comAbstract: Due to specific genetic characteristics, therapeutic options for colorectal cancer (CRC) with DNA mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) are limited. Although programmed death 1 (PD-1) blockade has been shown to be highly effective therapy for dMMR/MSI-H CRC, there is a need to develop new therapeutic paradigms to further improve survival rates of patients with dMMR/MSI-H CRC. So far, there is no case report on the use of immunotherapy combined with radiotherapy (RT) for the treatment of dMMR/MSI-H metastatic CRC (mCRC). Here, we report a 64-year-old patient diagnosed with mCRC who experienced a complete pathological response (pCR) after successfully conversion treatment with pembrolizumab and RT, and remains to be tumor-free during a follow-up of 11 months while off therapy. Immunohistochemical staining for MLH1, MSH2, MSH6, and PMS2 on the intestinal biopsy samples revealed loss of MLH1 and PMS2 protein expression. The present case report adds to the limited data on the safety and effectiveness of local RT combined with immunotherapy for patients with dMMR/MSI-H mCRC. This combination therapy appears to be a potential treatment for dMMR/MSI-H mCRC and deserves further exploration.Keywords: immunotherapy, radiotherapy, pembrolizumab, pathological complete response, colorectal cancer

Danfeng Li,1,* Yongming Zeng,1,* Peilin Shen,2,* Xiaosheng Lin,1 Tian Yang,1 Binlie Chen,1,3 Zhiyan Ma,1,3 Huaiming Wang1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 3Medical College, Shantou University, Shantou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaiming WangDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College Email 13750417745@163.comPurpose: This study aimed to explore the function and clinical significance of AVL9 in colorectal cancer (CRC).Materials and Methods: The GEO, TCGA, and GEPIA databases were searched to evaluate the expression level of AVL9, while the SurvExpress online tool was used to explore its related clinical survival prognosis. The cBioPortal and LinkedOmics databases were used to identify AVL9 expression-related genes. Protein–protein interaction (PPI) networks were analyzed using Cytoscape 3.7.1 and DAVID6.8, which was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) signal pathway enrichment. The immunohistochemistry of AVL9 in CRC was detected using an online tool protein atlas. RNA isolation and reverse transcription–quantitative polymerase chain reaction (RT-qPCR) assays were used to detect AVL9 expression in tissue and plasma samples.Results: Our study confirmed that AVL9 was highly expressed in CRC lesions versus the adjacent normal tissues (P < 0.001). High AVL9 expression was negatively associated with survival outcomes (P < 0.05). GO analysis showed that AVL9 expression-related genes were enriched in single organismal cell–cell adhesion, post-transcriptional regulation of gene expression, and negative regulation of the vascular endothelial growth factor receptor signaling pathway (P < 0.05). On a KEGG pathway analysis, these genes were mainly involved in progesterone-mediated oocyte maturation, axon guidance, the insulin signaling pathway, and the ubiquitin-mediated proteolysis signaling pathways (P < 0.05). In the PPI analysis, the KBTBD2, KIAA1147, EPDR1, and RNF216 genes interacted with AVL9, and GEPIA predicted that their expression levels were all positively correlated with AVL9. Furthermore, a clinicopathological parameter analysis found that high AVL9 expression was positively correlated with differentiation and TNM stage. RT-qPCR analysis further showed that plasma AVL9 expression was upregulated in CRC patients versus healthy controls.Conclusion: AVL9 could serve as a potential biomarker and therapeutic target for CRC.Keywords: AVL9, biomarker, colorectal cancer, prognosis

Background En bloc resection (ERBT) is a valid alternative to piecemeal resection for non–muscle-invasive bladder cancer (NMIBC), guaranteeing pathological outcomes. However, very few studies investigated long-term oncological outcomes of ERBT. Objective To report long-term oncological outcome of ERBT. Design, setting, and participants This is a retrospective analysis of prospectively collected data. We included patients who underwent ERBT from June 2010 to February 2014, and were diagnosed with NMIBC at pathology evaluation. Outcome measurements and statistical analysis The primary study endpoint was recurrence-free survival at 5 yr. Secondary outcomes were presence of detrusor muscle, recurrence rate at the first follow-up cystoscopy, progression to muscle-invasive bladder cancer (MIBC) at 5 yr, and factors associated with long-term oncological outcomes. Kaplan-Meier curves were used to describe recurrence-free survival time. A univariate analysis was used to investigate factors associated with recurrence. Results and limitations Overall, 74 patients were included in this study. The median age was 71 (66–76) yr. Most of the patients presented with only one bladder tumor, and the median tumor diameter was 2 (interquartile range [IQR] 1–2.5) cm. After histopathological examination, eight, 35, and 31 patients were diagnosed with low-, intermediate-, and high-risk disease, respectively. All the en bloc resected tumors showed the presence of detrusor muscle. The median follow-up was 72 (IQR 66–90) mo. The recurrence rate at the first follow-up cystoscopy was 5.4% (four out of 74 patients). Overall, 57 (77%) patients were free of recurrence at 5 yr. No progression to MIBC was observed: progression-free survival was 100%. Limitations include retrospective design and small size. Conclusions Our findings showed that ERBT for NMIBC presents an optimal long-term oncological outcome. Further studies with larger cohorts are necessary for confirming our preliminary results and for a direct comparison with the traditional piecemeal resection. Patient summary In case of superficial bladder tumors, transurethral resection of the entire tumor and its base in one piece seems to provide good long-term results in terms of recurrence and progression rates., Take Home Message Our findings show that patients undergoing en bloc transurethral resection for non–muscle-invasive bladder cancer have very promising 5-yr recurrence- and progression-free survival rates.

Background To improve and compare outcomes in healthcare, it is necessary to standardise outcome measurements. There are no widely accepted standardised outcome measures reflecting quality of care for bladder cancer (BCa) patients. Objective The aim of this study was to create a standardised set of outcomes for patients with muscle-invasive or metastatic BCa, using the value-based healthcare principles. Design, setting, and participants A multidisciplinary working group of 25 healthcare professionals and patient representatives was assembled, to develop the set. Outcome measurements and statistical analysis We used an online RAND-modified Delphi process to prioritise, discuss, and reach consensus regarding the outcomes, case-mix variables, and treatment factors. Results and limitations Recognising the heterogeneity of patients with BCa, the working group defined the scope as patients with muscle-invasive and metastatic BCa. A total of 24 outcomes, including ten patient-reported outcomes, were included in the standard set of outcomes, covering survival, complication rates, recurrence of disease, readmissions after treatment, and quality of life (QoL). Fourteen case-mix variables were included. The EQ-5D and European Organisation for Research and Treatment of Cancer quality of life (EORTC-QLQ) questionnaires were recommended to measure QoL. Conclusions We developed the first standardised set of patient-centred outcomes for muscle-invasive and metastatic BCa. The sue of this set enables institutions to monitor, compare, and improve the quality of BCa care, on an international level. Patient summary Our group of healthcare professionals and patient representatives recommended a standardised set of patient-centred outcomes to be followed during the treatment of patients with muscle-invasive or metastatic bladder cancer, in order to monitor, compare, and improve the quality of care., Take Home Message We developed the first standardised set of patient-centred outcomes for muscle-invasive and metastatic bladder cancer. The use of this set enables institutions to monitor, compare, and improve the quality of bladder cancer care on an international level.

Jin Li,1,* Yang Zhou,1,2,* Xinxin Wang,2 Yanyan Yu,2 Xueyan Zhou,3 Kuan Luan1 1College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, 150001, Heilongjiang Province, People’s Republic of China; 2Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang Province, People’s Republic of China; 3School of Technology, Harbin University, Harbin, 150001, Heilongjiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuan LuanCollege of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, 150001, Heilongjiang Province, People’s Republic of ChinaEmail luankuan@hrbeu.edu.cnPurpose: This study investigated the predictive value of apparent diffusion coefficient (ADC) histogram parameters of the primary tumor for regional lymph node metastasis (LNM) in pathological T3 stage rectal cancer.Patients and Methods: We retrospectively studied 175 patients with T3 stage rectal cancer who underwent preoperative MRI, including diffusion-weighted imaging, between January 2015 and October 2017. Based on pathological analysis of surgical specimens, 113 patients were classified into the LN− group and 62 in the LN+ group. We analyzed clinical data, radiological characteristics and histogram parameters derived from ADC maps. Then, receiver operating characteristic curve (ROC) analyses were generated to determine the best diagnostic performance.Results: The mean (p=0.002, cutoff=1.08× 10– 3 s/mm2), coefficient of variation (CV) (p=0.040, cutoff=0.249) of the ADC map, carbohydrate antigen 199, and N stage with magnetic resonance (mrN stage) were independent factors for LNM. Combining these factors yielded the best diagnostic performance, with the area under the ROC curve of 0.838, 72.9% sensitivity, 79.1% specificity, 65.2% positive predictive value, and 84.5% negative predictive value.Conclusion: With the mean > 1.08× 10– 3 s/mm2 and CV < 0.249, the ADC improved the diagnostic performance of LNM in T3 stage rectal cancer, which could assist surgeons with neoadjuvant chemoradiotherapy.Keywords: diffusion-weighted magnetic resonance imaging, rectal cancer, lymph node metastasis, histogram analysis

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana‐Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor‐genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population., Mucosal melanoma is a rare form of melanoma that arises from mucosal membranes within the nose, intestines or vaginal cavity. It can be treated with new immunotherapies that target immune checkpoints with some success but not all patients respond to these therapies. This study examines the genetic changes within mucosal melanoma to look for patterns that may help predict who will respond well to immunotherapy and who will not respond. Some interesting trends were observed but more work is needed to determine genetic mutations in mucosal melanoma that are associated with treatment.

Background Intensive acute lymphoblastic leukemia (ALL) regimens in children improve the 5-year event-free survival (EFS) to reach ~ 90%. Adolescents and young adults (AYA) have EFS (30% to 45%). Young AYA ALL patients treated with pediatric chemotherapy protocols such as Dana Farber Consortium Protocol (DFCP) experience a better prognosis. This study aimed to assess the efficacy [EFS and overall survival (OS)] and the toxicity of DFCP in the treatment of Egyptian AYA with newly diagnosed ALL. A retrospective study was performed on 41 patients with newly diagnosed ALL (15 and 39 years) who were treated with DFCP. EFS and OS were estimated using the Kaplan-Meier method. Results Thirty-eight patients (92.68%) achieved complete remission (CR). Eleven patients (26.83%) relapsed. Ten (24.39%) patients died. One, two, and three years of EFS were 75.61%, 72.91%, and 67.51% respectively. One, two, and three years OS were 85.3%, 77.26%, and 74.39% respectively. Neutropenia was the most common adverse event observed in 100% of patients. Conclusion DFCP can be considered as an effective ALL protocol for the AYA group of patients with good CR, EFS, and OS rates. DFCP seemed to be feasible in AYA despite the toxicities experienced.

Huajian Peng, Xiang Tan Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaCorrespondence: Xiang Tan Email tanxiang588@126.comObjective: To evaluate the correlation between systemic inflammation markers and sarcopenia in elderly patients with esophageal squamous cell carcinoma (ESCC) and their prognostic value.Materials and Methods: The clinical data of 121 elderly patients with ESCC were collected. The skeletal muscle area at the level of the third lumbar vertebrae (L3) was measured by computed tomography (CT), and then the skeletal muscle index (SMI) was calculated. The neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI) and Geriatric Nutritional Risk Index (GNRI) were calculated according to laboratory standards. Univariate and multivariate Cox proportional hazards models were used to determine prognostic factors for overall survival (OS).Results: A total of 121 elderly ESCC patients were enrolled. Among them, 65 patients had sarcopenia. NLR, PNI and GNRI are significantly related to sarcopenia. The OS of ESCC patients with sarcopenia and/or NLR> 2.24 was significantly worse.Conclusion: PNI, GNRI, NLR and sarcopenia were significantly related. Sarcopenia and NLR are independent prognostic factors for elderly ESCC, and when combined have better prognostic value.Keywords: esophageal squamous cell carcinoma, sarcopenia, neutrophil-to-lymphocyte ratio, survival, nutrition

Background Pleural effusion from patients with advanced non‐small cell lung cancer (NSCLC) has been proved valuable for molecular analysis, especially when the tissue sample not available. However, simultaneous detection of multiple driver gene alterations especially the fusions is still challenging. Methods In this study, 77 patients with advanced NSCLC and pleural effusion were enrolled, 49 of whom had matched tumor tissues. Supernatants, cell sediments, and cell blocks were prepared from pleural effusion samples for detection of driver alterations by a PCR‐based 9‐gene mutation detection kit. Results Mutations in EGFR, KRAS, and HER2 were detected in DNA and cfDNA, fusions in ALK was detected in RNA and cfRNA. Compared with matched tumor tissue, the supernatant showed the highest overall sensitivity (81.3%), with 81.5% for SNV/Indels by cfDNA and 80% for fusions by cfRNA, followed by cell blocks (71.0%) and the cell sediments (66.7%). Within the group of treatment‐naïve patients or malignant cells observed in the cell sediments, supernatant showed higher overall sensitivity (89.5% and 92.3%) with both 100% for fusions. Conclusions CfDNA and cfRNA derived from pleural effusion supernatant have been successfully tested with a PCR‐based multigene detection kit. Pleural effusion supernatant seems a preferred material for detection of multigene alterations to guide treatment decision of advanced NSCLC., CfDNA and cfRNA derived from pleural effusion supernatant have been successfully tested with a PCR‐based multi‐gene detection kit. Pleural effusion supernatant seems a preferred material for detection of multi‐gene alterations to guide treatment decision of advanced NSCLC.

Hussain Almasmoum Laboratory Medicine Department, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, 7607, Saudi ArabiaCorrespondence: Hussain AlmasmoumLaboratory Medicine Department, Faculty of Applied Medical Science, Umm Al-Qura University, Al Abdeyah, Makkah, 7607, Saudi ArabiaTel +966 125270000-ext4521Email haamasmoum@uqu.edu.saAbstract: Colorectal cancer (CRC) is one of the most common types of cancers. It is associated with a poor prognosis and high mortality. The role of mucins (MUCs) in colon tumorigenesis is unclear, but it might be significant in the progression of malignancy. Some mucins, such as MUC1 and MUC13, act as oncogenes, whereas others, such as MUC2 and MUC6, are tumor suppressors. However, there are still mucins with unidentified roles in CRC. In this review, we discuss the reported roles of mucins in CRC. Moreover, we review the capability of the mucin family to serve as a sensitive and specific histopathological marker for the early diagnosis of CRC. Lastly, the role of mucin genes clustered on chromosome 7q22 in CRC and other cancers is also discussed.Keywords: colorectal cancer, mucins, MUC3, MUC12, MUC17, chromosome 7q22.1

The m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.

Background Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear. Methods Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation. Results The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients’ prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8+ T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration. Conclusions Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.

Background Pulmonary metastasectomy (PM) is an established treatment for selected patients with metastatic sarcomas. The aim of this study was to examine our institutional experience and evaluate factors predicting outcome. Methods We retrospectively reviewed all patients undergoing PM for bone sarcoma in our center from 2001 to 2019. Survival was calculated from the date of PM. Impact on survival of clinical parameters was assessed. Results Thirty-eight patients (27 males, 71%) were included. Histology was osteosarcoma (n = 20, 53%), Ewing sarcoma (n = 13, 34%) and chondrosarcoma (n = 5, 13%). Twelve patients (31.5%) had synchronous metastases, all received chemotherapy before PM. Median number of metastases was 3 (1 to 29). Twenty (53%) patients had mediastinal lymph node sampling. One patient had positive lymph nodes. Ninety-day mortality was 0%. Three and 5-year PFS were 24.5 and 21%, respectively. Three and 5-year OS were 64.5 and 38.5%, respectively. More than three metastases and progression under chemotherapy were significant independent predictors for OS. Conclusion PM is a safe procedure and encouraging long-term outcome can be achieved. Patients with progression of pulmonary metastases under chemotherapy as well as patients with more than three metastases had significantly worse OS.

Qiuli Xu,1,* Liang Ye,2,* Litang Huang,1,* Li Zhou,3 Xi Chen,4 Mingxiang Ye,3 Guannan Wu,3 Ping Zhan,3 Tangfeng Lv,3 Yong Song1 1Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Southeast University, Sch Med, Nanjing, Jiangsu, People’s Republic of China; 2Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tangfeng LvDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, #305, East Zhongshan Road, Nanjing, People’s Republic of ChinaTel/Fax +86 25-8086-3591Email bairoushui@163.comYong SongDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Southeast University, Sch Med, Nanjing, Jiangsu, People’s Republic of ChinaTel/Fax +86 25-8086-3591Email yong.song@nju.edu.cnPurpose: The survival time of patients with leptomeningeal metastasis (LM) of lung cancer is very short, and the clinical characteristics of LM are varied, making the clinical diagnosis difficult. At present, a positive CSF fluid (CSF) cytology result remains the gold standard for diagnosing LM in lung cancer; however, the process of collecting CSF is traumatic and far less convenient than blood collection. With the development in technology, an increasing number of studies prefer to use liquid biopsy to diagnose or predict the occurrence of the disease. Therefore, we aimed to explore whether serum exosomal miRNA can replace miRNA from CSF to identify or predict the occurrence of LM.Patients and Methods: Herein, four pairs of serum and CSF samples were collected at four different time points from a patient with LM from non-small cell lung cancer (NSCLC). Serum and CSF exosomes were extracted. Western blot (CD63, TSG101) and electron microscope analyses were used to verify exosome extraction, after which exosomal miRNA sequencing was performed. Next, exosomal miRNA from serum and CSF samples from seven patients with LM and 30 patients without LM were collected for validation.Results: Sequencing results of serum exosomal miRNA and CSF exosomal miRNA showed that there were 44 exosomal miRNAs stably co-expressed at four different time points. Then, three common miRNAs related to LM were found (hsa-miR-483-5p, hsa-miR-423-5p, and hsa-miR-342-5p). Subsequently, exosomal miRNA was extracted from serum and CSF samples from seven patients with LM and 30 patients without LM for verification, and the expression of these exosomal miRNA was detected. The results showed that miRNA-483-5p and miRNA-342-5p significantly differed in LM−/+ patients (P = 0.0142 and P = 0.0031, respectively), whereas miRNA-423-5p had no difference (P = 0.0921). Additionally, as the symptoms improved, the expression of these miRNAs decreased or remained stable.Conclusion: Serum exosomal miRNA (hsa-miR-483-5p, and hsa-miR-342-5p) may be involved in LM of lung cancer and may replace CSF to predict LM in NSCLC.Keywords: non-small cell lung cancer, leptomeningeal metastasis, exosome, miRNA, liquid biopsy

Objectives This study aimed to establish a machine learning prediction model that can be used to predict bone metastasis (BM) in patients with newly diagnosed thyroid cancer (TC). Methods Demographic and clinicopathologic variables of TC patients in the Surveillance, Epidemiology, and End Results database from 2010 to 2016 were retrospectively analyzed. On this basis, we developed a random forest (RF) algorithm model based on machine‐learning. The area under receiver operating characteristic curve (AUC), accuracy score, recall rate, and specificity are used to evaluate and compare the prediction performance of the RF model and the other model. Results A total of 17,138 patients were included in the study, with 166 (0.97%) developed bone metastases. Grade, T stage, histology, race, sex, age, and N stage were the important prediction features of BM. The RF model has better predictive performance than the other model (AUC: 0.917, accuracy: 0.904, recall rate: 0.833, and specificity: 0.905). Conclusions The RF model constructed in this study could accurately predict bone metastases in TC patients, which may provide clinicians with more personalized clinical decision‐making recommendations. Machine learning technology has the potential to improve the development of BM prediction models in TC patients., We developed a random forest prediction model for bone metastases in thyroid cancer (TC) patients. This facilitates personalized diagnosis and refined clinical decision making for bone metastases in TC patients.