Diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography in gallbladder cancer: A meta-analysis

AIM: To meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose(18F-FDG) positron emission tomography(PET) and PET/computed tomography(PET/CT) in the evaluation of primary tumor in patients with gallbladder cancer(GBCa).METHODS: A comprehensive literature search of studies published through 30 th June 2014 regarding the role of 18F-FDG PET and PET/CT in the evaluation of primary gallbladder cancer(GBCa) was performed. All retrieved studies were reviewed. Pooled sensitivity and specificity of 18F-FDG PET or PET/CT in the evaluation of primary GBCa were calculated. The area under the summary receiving operator characteristics curve(AUC) was calculated to measure the accuracy of these methods. Sub-analyses considering the device used(PET vs PET/CT) were carried out.RESULTS: Twenty-one studies comprising 495 patients who underwent 18F-FDG PET or PET/CT for suspicious GBCa were selected for the systematic review. The meta-analysis of 13 selected studies provided the following results: sensitivity 87%(95%CI: 82%-92%),specificity 78%(95%CI: 68%-86%). The AUC was 0.88. Improvement of sensitivity and specificity was observed when PET/CT was used.CONCLUSION: 18F-FDG-PET and PET/CT demonstrated to be useful diagnostic imaging methods in the assessment of primary tumor in GBCa patients,nevertheless possible sources of false-negative and false-positive results should be kept in mind. PET/CT seems to have a better diagnostic accuracy than PET alone in this setting.

Cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography in tumours other than lung cancer: A systematic review

AIM: To systematically review published data on the cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography(FDG-PET) or PET/computed tomography(PET/CT) in tumours other than lung cancer. METHODS: A comprehensive literature search of studies published in PubMed/MEDLINE, Scopus and Embase databases through the 10th of October in 2013 was carried out. A search algorithm based on a combination of the terms:(1) "PET" or " PET/computed tomography(PET/CT)" or "positron emission tomography"; and(2) "cost-effectiveness" or "cost-utility" or "cost-efficacy" or "technology assessment" or "health technology assessment" was used. Only cost-effectiveness or cost-utility analyses in English language were included. Exclusion criteria were:(1) articles not within the field of interest of this review;(2) review articles, editorials or letters, conference proceedings; and(3) outcome evaluation studies, cost studies or health technology assessment reports. For each included study, information was col-lected concerning basic study, type of tumours evaluated, perspective/type of study, results, unit and comparison alternatives. RESULTS: Sixteen studies were included. Head and neck tumours were evaluated in 4 articles, lymphoma in 4, colon-rectum tumours in 3 and breast tumours in 2. Only one article was retrieved for melanoma, oesophagus and ovary tumours. Cost-effectiveness results of FDG-PET or PET/CT ranged from dominated to dominant. CONCLUSION: Literature evidence about the costeffectiveness of FDG-PET or PET/CT in tumours other than lung cancer is still limited. Nevertheless, FDGPET or PET/CT seems to be cost-effective in selective indications in oncology(staging and restaging of head and neck tumours, staging and treatment evaluation in lymphoma).

Phase I/II Study of Gefitinib and Concomitant Preoperative Radiotherapy in Patients with Locally Advanced Rectal Cancer

Objective: To determine the recommended dose (RD) of gefitinib when combined with concomitant radiotherapy (RT) in a preoperative setting in patients with locally advanced rectal cancer. Secondary objectives were to evaluate acute toxicities, pathological response rate, progression-free and overall survival (OS). Materials and Methods: 20 patients with cT3-4 or cN+ cM0 tumors were enrolled. The planned RT consisted in 50 Gy given in 2 daily fractions of 1.25 Gy in 4 weeks. During RT, gefitinib was planned to be given orally once daily with 2 successive dose levels: 250 mg and 500 mg. Rectal surgery was scheduled 5 - 6 weeks after completion of RT. The median follow-up for all patients was 57 months. Results: Among the first cohort of 6 patients, 1 patient presented a dose limiting toxicity (DLT) (Grade 3 diarrhea/dehydration). In the second cohort, 2/6 patients presented with the same DLT so that 250 mg was considered as the RD. Main acute toxicities consisted in diarrhea (grade 2 - 3, 63%), and skin reaction (in RT fields grade 2 - 3 in 42%). The 5-year actuarial OS and loco-regional control rates were of 80% and 84% respectively. Conclusion: The concomitant daily administration of 250 mg of gefitinib with 50 Gy preoperative RT is feasible with manageable toxicity. The major pathologic response rate is encouraging, though it needs further confirmation. Distant metastasis still represents a concern and new strategies to overcome this issue are warranted.

Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer

Background:Bladder cancer,characterized by a high potential of tumor recurrence,has high lifelong monitoring and treatment costs.To date,tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types.Nonetheless,the existence of soft tumor cells in bladder tumors remains elusive.Thus,our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods:The stiffness of bladder cancer cells was determined by atomic force microscopy(AFM).The modified microfluidic chip was utilized to separate soft cells,and the 3D Matrigel culture system was to maintain the softness of tumor cells.Expression patterns of integrinβ8(ITGB8),protein kinase B(AKT),and mammalian target of rapamycin(mTOR)were determined by Western blotting.Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59(TRIM59).The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models.Results:Using our newly designed microfluidic approach,we identified a small fraction of soft tumor cells in bladder cancer cells.More importantly,the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens,in which the number of soft tumor cells was associated with tumor relapse.Furthermore,we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells.Simultaneously,we detected a remarkable up-regulation in ITGB8,TRIM59,and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions:The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness.Meanwhile,the soft tumor cells become more sensitive to chemotherapy after stiffening,that offers new insights for hampering tumor progression and recurrence.

Advanced gastric cancer:what we know and what we stillhave to learn

Gastric cancer is a common neoplastic disease and, more precisely, is the third leading cause of cancer death in the world, with differences amongst geographic areas. The definition of advanced gastric cancer is still debated. Different stadiating systems lead to slightly different stadiation of the disease, thus leading to variations between the single countries in the treatment and outcomes. In the present review all the possibilities of treatment for advanced gastric cancer have been analyzed. Surgery, the cornerstone of treatment for advanced gastric cancer, is analyzed first, followed by an investigation of the different forms and drugs of chemotherapy and radiotherapy. New frontiers in treatment suggest the growing consideration for intraperitoneal administration of chemotherapeutics and combination of traditional drugs with new ones. Moreover, the necessity to prevent the relapse of the disease leads to the consideration of administering intraperitoneal chemotherapy earlier in the therapeutical algorithm.

欧洲肿瘤内科协会对新发和复发性卵巢上皮癌的诊断、治疗和随访制定的临床实践指南

发病率卵巢癌在女性常见癌症中（皮肤癌除外）位列第九,在癌症所致的女性死亡原因中居第五位。女性在一生中患卵巢浸润癌的风险是1/71,而死于卵巢浸润癌的风险是1/95。在美国,据估计每年有21 550例的新发病例,且有14 600人死于卵巢癌。然而,在世界不同地区卵巢癌的发病率大不相同,2004年欧盟国家估计每年新发病例42 700例,而病死率为12/10万。

Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and "high-grade" tumor budding was defi ned as 15 buds/high-power f ield.RESULTS: Tumor buds and K-RAS mutation both correctly classif ied 68% of patients. All patients with K-RAS mutation (n=7) or high-grade tumor budding (n=11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P=0.008)].CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

Biased Immunoglobulin Genes Rearrangement in Mantle Cell Lymphoma： Hints to Identify the Normal B-cell Counterpart

Mantle cell lymphoma （MCL） is an aggressive nonHodgkin＇s lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data available on immunoglobulin heavy-chain （IgH） genes rearrangement for their importance in suggesting the MCL normal counterpart B-cell. Some new data suggesting an antigen selection process were also presented in this review.

The clinical challenges of homologous recombination proficiency in ovarian cancer: from intrinsic resistance to new treatment opportunities

Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (PARPi). BRCA1/2 mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and PARPi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from PARPi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared PARPi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to PARPi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of PARPi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.

Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells

Background:Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer.However,the critical elements in control of chemotherapy resistance remain obscure.Methods:We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin(DOX)and mitomycin C(MMC)of bladder cancer cells in a 3D culture system.We then detected the expression of multidrug resistant gene ABCB1,dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1(COUPTF1),cell proliferation marker Ki-67,and cellular senescence marker senescence-associatedβ-galactosidase(SA-β-Gal)in these cells.We further tested the effects of integrin blockade or protein kinase B(AKT)inhibitor on the senescent state of bladder cancer.Also,we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrinα2β1 ligand peptide TFA(TFA).Results:Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC.In mechanism,collagen activated the integrinβ1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p21/p53 pathway,thus attenuating chemotherapy-induced apoptosis.In addition,TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice.Meanwhile,TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo.Conclusions:Based on our finding that integrinβ1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel,we suggest that integrinβ1 might be a feasible target for bladder cancer eradication.

Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling

The extracellular matrix(ECM)serves as signals that regulate specific cell states in tumor tissues.Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression.In this study,we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status.Experiments were conducted using 3D collagen,fibrinogen.

Sleep duration and testosterone levels in community older men: results from the West China Health and Aging Trend study

To the Editor:Testosterone is a fundamental male sex hormone produced by the testicular Leydig cells.Testosterone levels are affected by age,peaking in the 20s and 30s and gradually declining thereafter.[1]Low testosterone level may predispose men,especially older men,to a poor prognosis or death in coronavirus disease 2019(COVID-19).[2]Therefore,testosterone levels have a significant impact on the health status of older men.The identification of modifiable non-drug factors affecting testosterone levels in older men is important for improving their health.

Research progress on KRAS mutations in colorectal cancer

The RAS gene family,responsible for signal transduction within the mitogen activated protein kinase(MAPK)and phosphatidylinositol 3 kinase(PI3K)pathways,is frequently involved in carcinogenesis,and alterations in its member genes can be detected,with variable frequency,in a wide variety of solid and hematological cancers.These alterations may behave as prognostic-predictive biomarkers and driver mutations,making them an interesting therapeutic target.Since their discovery,many strategies have been pursued to act on their signaling pathways.Indeed,in clinical practice,KRAS,the most prominent member of the RAS gene family,represents an especially elusive target in most malignancies;pathway inhibition is carried out upstream,on the EGFR receptor,or downstream,most frequently on the BRAF/MEK/ERK cascade.Recently,clinically relevant direct RAS inhibition has been successfully achieved with the development of potent and selective covalent inhibitors of KRAS c.34G>T(p.G12C).These latest-generation drugs represent both a new and interesting tool in the therapeutic armamentarium and a symbolic end to the myth of KRAS undruggability.However,their clinical relevance and appropriate place in treatment strategies remain to be determined.