Inaugural Editorial:New Era,New Journal

Clinical Cancer Bulletin(CCB),a new journal in the field of cancer,sponsored by Zhongshan Hospital,Fudan University,China,is officially launched.Our mission is to publish original,innovative,high-quality,and timely content in clinical oncology,delivering the most credible and authoritative cancer research resources to oncologists around the world to build a cancer community with a shared aim.Cancer is a serious threat to human health and is the first or second leading cause of death before the age of 70 in 112 of 183 countries according to 2019 World Health Organization data.Furthermore,in GLOBOCAN estimates compiled by the International Agency for Research on Cancer,an estimated 19.3 million new cancer cases and 10 million cancer deaths occurred in 2020 worldwide.Cancer was an unknown entity for a long time.However,in the last 200 years,our knowledge of cancer has rapidly advanced thanks to tremendous government investment,great developments in science and technology,and the hard work and dedication of scientists and medical practitioners.Four major transformations have occurred in the major therapeutic modalities for cancer over the past two centuries.

A Case Report:Severe Bullous Skin Reaction Induced by Anti-PD-1 Antibody(Toripalimab)Therapy in a Patient with Thymic Carcinoma

The development of immune checkpoint inhibitors,such as those targeting programmed cell death protein 1(PD-1),represents a major breakthrough in cancer therapy.Although immune checkpoint blockade therapy has a favorable risk/benefit ratio,it causes significant immune-related adverse events(irAEs),such as cutaneous reactions,in particular,severe bullous skin reactions and toxic epidermal necrolysis.Here,we report a case of a 51-year-old woman with malignant thymoma who developed a severe bullous skin reaction(characterized by a systemic rash,bullae,epidermal desquamation,and Stevens-Johnson syndrome)as a result of treatment with the PD-1 inhibitor toripalimab.The patient was treated with high doses of glucocorticoid,intravenous immunoglobulin,and intensive care,and eventually recovered from the severe irAEs.The intravenous injection of anti-PD-1 antibodies induces cutaneous reactions,which are associated with higher mortality rates.High doses of glucocorticoid combined with intravenous immunoglobulin are effective in alleviating such irAEs.Thus,improving the level of care and preventing skin infections can effectively reduce the risk of death.

Expert Guidance on the Overall Management of Liver Cancer During the COVID-19 Pandemic

The COVID-19 pandemic remains complex,with concentrated and sporadic cases in multiple locations.During COVID-19 outbreaks,the routine diagnosis and treatment of liver cancer patients can be affected to a significant degree.For liver oncologists,it is important to identify strategies and protocols to reduce the risk of COVID-19 infection among patients and medical staff,use limited medical resources to maximally ensure access to anti-tumor treatment and related emergency treatment,and provide support for patients during the disruption caused by the pandemic.Given this requirement,eleven experts in liver cancer treatment-related disciplines from Zhongshan Hospital,Fudan University have written the Expert Guidance on the Overall Management of Liver Cancer During the COVID-19 Pandemic,which aims to provide a reference to assist liver oncologists in conducting clinical work safely and effectively while implementing COVID-19 prevention and control strategies and offer guidance on supporting liver cancer patients during the pandemic.

Brain Metastasis of Non-small-cell Lung Cancer

Non-small-cell lung cancer(NSCLC)is the major histological type of lung cancers and is characterized by a high incidence of brain metastasis(BrM),which remains an intractable disease.BrM is a multi-step and complex biological process.The formation and outgrowth of BrM involve co-evolution and cross-talk among metastatic cells,immune cells,astrocytes,and the brain microenvironment.To date,patients with NSCLC BrM are treated with multimodal treatments including neurosurgery,radiotherapy,chemotherapy,anti-angiogenic treatment,molecular targeted therapy,and immune checkpoint inhibitors.Nevertheless,the overall prognosis remains dismal,with a median overall survival of<1 year.Understanding the detailed processes and mechanisms of NSCLC BrM including the phenotypic and genotypic heterogeneity of primary lung cancer and matched BrM and the specific immune microenvironment features of BrM would be helpful for developing effective therapeutic strategies.Transforming these novel findings into new treatments and integrating them with paradigms in traditional therapies could improve the overall prognosis of patients with NSCLC BrM.Here,we summarize the epidemiology,known mechanisms,and current systemic treatments for NSCLC BrM.On the basis of recent clinical and translational advances,we discuss the future research directions for NSCLC BrM.

Targeting Metabolism to Improve CAR-T Cell Immunotherapy

The transfer of genetically-engineered chimeric antigen receptor(CAR)-T cells has recently become one of the most promising approaches in the treatment of cancer.Like normal T cells,CAR-T cells are dependent on an adequate supply of nutrients and energy to be able to proliferate and mediate anti-tumor responses.However,CAR-T cell proliferation and cytotoxicity are limited by the elevated metabolic demands of actively dividing cancer cells,which deplete nutrients from the tumor microenvironment(TME).Thus,a variety of TME-imposed metabolic“barriers”must be overcome by artificially altering the metabolism of CAR-T cells to increase their clinical performance,especially in solid tumors.In this review,we summarize the metabolic interactions between T cells and the TME,discuss the metabolic reprogramming of T cells,present recent progress in the application of metabolic interventions in CAR-T cell therapy,and finally allude to future directions in this field.

Prevalence and Clinical Implication of t(11;14)in Light-Chain Amyloidosis with or without Coexistent Multiple Myeloma in the Era of Proteasome Inhibitors

Background Light-chain amyloidosis(AL)and multiple myeloma(MM)may coexist in some patients and,although they share some cytogenetic abnormalities,they usually present with different clinical phenotypes.Translocation(11;14)is the most common cytogenetic abnormality in AL,but the prevalence and clinical implication of t(11;14)in patients with AL,with or without coexistent MM,remains unclear.Methods A total of 119 consecutive newly diagnosed AL patients with available fluorescence in situ hybridization(FISH)data were retrospectively included and classified as primary AL alone(pAL-alone)or AL with coexistent MM(AL-MM).Clinical characteristics,FISH profiles,and hematologic and survival outcomes were analyzed.Results There were 53 patients in the pAL-alone group and 66 in the AL-MM group.The prevalence of t(11;14)was significantly higher in the pAL-alone group than the AL-MM group(49.1%vs.26.2%,P=0.012).A significantly higher proportion of the pAL-alone group achieved hematologic response compared with the AL-MM group(60.4%vs.39.4%,P=0.023).Patients with AL-MM experienced significantly shorter hematologic event-free survival(hemEFS)than those with pAL-alone(median,4.8 months vs.44.3 months,P<0.001),as well as significantly shorter overall survival(OS;median,15.2 months vs.not reached,P<0.001).When stratified by the presence or absence of coexistent MM and t(11;14),AL-MM patients with t(11;14)had the worst hemEFS(median,3.8 months,P<0.001)and OS(median,5.4 months,P=0.001).Conclusions Patients with pAL-alone had a higher prevalence of t(11;14)than those with AL-MM.The AL-MM group had poorer outcomes,despite the availability of proteasome inhibitor treatment,with AL-MM patients with t(11;14)showing the worst outcomes.Better diagnostic and treatment approaches are warranted for this population.

The Role of Anaplastic Lymphoma Kinase Receptor in Neuroblastoma

Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors,such as the diagnosis time within the first year and the diversity of the histology and genetic features.Despite improved outcomes in NB patients,it remains a difficult clinical problem and requires new therapeutic targets and methods.The somatic acquired activation point mutations in the receptor tyrosine kinase anaplastic lymphoma kinase(ALK)represent potential targets for treating NB.Herein,we review the underlying mechanisms of ALK in NB development,the latest available strategies to block ALK constitutive activity to treat NB,and discuss the current clinical challenges of resistance to these therapies and the strategies to overcome them.

RAS Signaling Targeted Cancer Therapy

Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,especially the Cys12 mutation in KRAS G12C,have been identified,paving the way for irreversible inhibitor development.A series of clinical trials have proven their efficacies,and the first RAS G12C-targeting drug sotorasib(AMG-510)received approval for non-small cell lung cancer treatment in May,2021.In another approach,the development of indirect RAS inhibitors that target components of the RAS signaling pathway,including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1,MEK,AKT,and SHP2,has also made significant progress.This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs,discusses clinical challenges,and proposes beneficial strategies for RAStargeted therapy.

Radiation-induced Oral Mucositis is a Critical Dilemma for Patients and Physicians During Radiotherapy for Nasopharyngeal Carcinoma

The combination of radiotherapy(RT)and chemotherapy is associated with a high cure rate but an increased risk of radiation-induced oral mucositis(RIOM)in patients with nasopharyngeal carcinoma(NPC).As a dose-limiting complication,RIOM remains a critical dilemma for patients and physicians,potentially leading to radiation interruptions and compromised tumor control.In this review,we discuss and analyze the pathological mechanisms and factors affecting prevention/treatment of RIOM.RT may induce RIOM via a positive feedback loop,consequently amplifying superoxide production,the immunoinflammatory response,dysbacteriosis,infection,and epithelial basal cell death.Routine interventions for RIOM focus on oral care,oral-pain relief,nutritional support,and infection control;however,recent novel and effective methods have been proposed according to the pathological mechanisms and influencing factors.Some patients with low-recurrence-risk NPCs may be treated with reduced-dose RT,reduced-dose chemotherapy,or RT alone(without chemotherapy)to prevent severe RIOM.Furthermore,traditional herbal medicine extracts,such as Kangfuxin and honey,may help to control RIOM.In addition to the routine application of antibiotics to treat oral dysbacteriosis and hormones to suppress immune inflammatory responses,edaravone and GC4419 can also be used to scavenge oxygen free radicals and reduce superoxide ions to protect the oral mucosa and limit the occurrence of RIOM.

Novel agents for multiple myeloma with extramedullary disease

Multiple myeloma(MM)is the second most common hematological malignancy.The introduction of proteasome inhibitors(PIs)and immunomodulatory drugs(IMiDs)greatly improved the outcomes for these patients.Extramedullary disease(EMD),an aggressive manifestation of MM,remains a significant treatment challenge.Recently,active clinical development of remarkable novel agents for MM with new mechanisms of action has begun.These agents show promising anti-MM effects and provide the opportunity to extend the survival of patients.They include next-generation PIs and IMiDs;monoclonal antibodies;chimeric antigen receptor T cells;antibody-drug conjugates;bispecific T cell engager antibodies;and small molecular inhibitors.However,few clinical trials have focused on patients with EMD,and the effectiveness of these agents has not been well evaluated and compared in these patients.In this review,we summarize the efficacy of these novel agents in MM patients with EMD.

^(18)F-FDG PET/MR Imaging for Evaluating of Obstructive Jaundice:Chinese Expert Consensus

The cause of obstructive jaundice is usually complex which renders its differential diagnosis and lesion localization challenging in clinical practice.Integrated Positron Emission tomography/Magnetic Resonance(PET/MR)offers complementary information from PET and MR in the diagnosis of obstructive jaundice and is becoming widely adopted in clinical setting.While preserving its diagnostic accuracy,it is important to standardize and streamline the clinical scan protocol of PET/MR in evaluating obstructive jaundice.Based on literature review and experience of large number of clinical cases from the author group,this article reports an expert consensus on imaging protocol optimization and case interpretation template standardization.

Immune Checkpoint Inhibitor-induced Immune-mediated Hepatitis in A Lung Cancer Patient Undergoing Long-term Immunotherapy:A Case Report

Immune-mediated hepatitis(IMH)induced by immune checkpoint inhibitors(ICIs)is an immune-related adverse event(irAE).IMH usually occurs 8-12 weeks after the first dose of ICI therapy.We report an unusual case of a lung cancer patient who developed IMH 2 years after initial ICI treatment and relapsed during corticosteroid therapy.A 55-year-old male with stageⅣB lung cancer received ICIs(for over 2 years)and chemotherapy as a second-line therapy.Grade 4 IMH occurred 2 years after initial immunotherapy and was diagnosed as hepatitis via laboratory and imaging tests with the simultaneous exclusion of other causes.The patient responded well to the corticosteroids;however,he decided to discontinue treatment prematurely,meaning that the total treatment period was less than 4 weeks.This led to IMH reoccurrence and the need to readminister corticosteroids at a higher dose than before.Ultimately,the patient's IMH was controlled and did not reoccur.This case illustrates that immune-related toxicity needs to be monitored in patients undergoing long-term ICI therapy.Improving patient education is also essential for the management and treatment of irAEs.

Comparison of Capillary and Venous Glucose Concentrations:A Real-world Study in Patients Undergoing Fluorodeoxyglucose-positron Emission Tomography

Objective Fasting capillary blood glucose(CBG)must be measured before fluorodeoxyglucose-positron emission tomography(FDG-PET)imaging.In this study,we aimed to investigate whether a recently measured fasting venous blood glucose(VBG)concentration could be substituted for CBG.Methods This retrospective study included 520 of 1,378 patients who had undergone FDG-PET at our institution in June 2022.None of the study patients had a history of diabetes mellitus.Each study patient’s CBG was measured immediately before FDG administration,whereas the VBG(VBG<7.8 mmol/L)was measured within one week before and after PET imaging.We used Bland−Altman plots to compare the two blood glucose concentrations.Results The 520 participants(315 male,205 female;ages 13-87 years)accounted for 37.7%(520/1378)of all patients.The median CBG and VBG were 5.7 mmol/L(interquartile range,5.2-6.2 mmol/L)and 5.1 mmol/L(interquartile range,4.8-5.8 mmol/L),respectively.There was a moderate positive correlation between CBG and VBG(r=0.4370,95%CI:0.3625-0.5059,P<0.0001).Bland-Altman plots revealed that only 5.8%(30/520)of the dots exceeded the 95%limits of agreement and these were all within acceptable limits,indicating that the bias was not clinically significant.Conclusion When performing FDG-PET on patients without diabetes,a VBG of<7.8 mmol/L within the previous week may be an acceptable alternative to CBG.

Nomogram to Predict Prognosis of Patients with Gastric Cancer after Radical Gastrectomy

Objective To establish an effective prognostic nomogram for patients with gastric cancer after radical gastrectomy.Methods In the present study,we retrospectively analyzed the records of 1635 patients with gastric cancer treated at Changhai Hospital from January 2014 to December 2019.Final independent prognostic factors of overall survival to build a nomogram were screened using univariate and multivariate analyses.The predictive accuracy and discriminating ability of the nomogram were determined using the concordance index(C-index)and calibration curves.The results were validated using bootstrap resampling of 701 patients.The survival curves for low-,middle-,and high-risk patients were used to evaluate the accuracy of the nomogram.Results Multivariate analysis of the primary cohort revealed independent factors for survival as follows:age,sex,body mass index(BMI),depth of tumor invasion(T),lymph node metastasis(N),perineural invasion(PNI),tumor deposits,Alpha fetoprotein(AFP),and lactate dehydrogenase(LDH).Combining these predictors in the nomogram achieved powerful prognostic ability in the training and test sets.The C-index of the training set was 0.772(95%CI,0.748 to 0.796)compared with the C-index values of the AJCC 8^(th)(0.718),T(0.683),N(0.726)and that of the testing set(0.726[95%CI,0.684 to 0.767]),which were significant higher than the C-index values of the TNM system.The calibration curve for probability of survival showed good consistency between predictions made using nomogram compared with actual observations.The survival curves showed significant differences between-high,middle-,and low-risk groups.Conclusion We constructed a more accurate and comprehensive nomogram to predict the prognosis of gastric cancer after surgery,which may serve as a potential tool to guide personalized treatment.

Immune Checkpoint Inhibitor-associated Myocarditis with Myasthenia Gravis:A Case Report

Immune checkpoint inhibitors(ICIs)have revolutionized the management of various cancers.However,myocarditis is a rare but severe complication associated with ICI use.We describe the case of a 62-year-old woman who presented with ICI-associated myocarditis alongside myasthenia gravis.Consequently,the patient was treated with initial high doses of corticosteroids combined with immunosuppressive therapy,and improved outcomes and clinical remission were observed.The overlap of myocarditis with myasthenia gravis is associated with high morbidity and mortality.The early administration of high dose of corticosteroids combined with immunosuppressive therapy was associated with improved outcomes in our patient.

Artificial Intelligence in Neuro-oncology:Friend or Foe of Neurosurgeons?

As one of the tumors with substantial treatment difficulties,brain tumors have a high mortality rate and high treatment costs.Furthermore,surgical rection of deep-seated tumors or tumors involving eloquent areas is still a challenge for neurosurgeons.Therefore,accurate and early tumor diagnosis,selection of treatment options,and prediction of prognosis are important to improve patients’outcomes.Recently,with the rapid development of computational technology,the frequency of its application in clinical work has increased enormously and the acquisition of medical data has become more convenient and efficient.Furthermore,with the advancement of artificial intelligence(AI)—particularly,machine and deep learning—the applications of AI in medicine and especially neuro-oncology have enhanced diagnosis,treatment,and prognosis prediction of brain tumors topreviously unachievable levels.This article presents an overview of the applications of AI in neuro-oncology for diagnosis,prognosis,surgical treatment,and education.Furthermore,the advantages,perspectives,and challenges of AI for clinical applications in neuro-oncology are discussed.

Clinical Diagnosis and Treatment Recommendations for Immune Checkpoint Inhibitor-Associated Myocarditis

Immune checkpoint inhibitors(ICIs)are often beneficial in the treatment of multiple types of malignant tumors.However,ICI-associated myocarditis has introduced new clinical challenges.This report highlights the key clinical issues of ICI-associated myocarditis,such as risk factors,diagnosis and differential diagnosis,clinical classification and treatment,monitoring of outcomes,and restart of treatment.Additionally,practical guidance and suggestions for the diagnosis and treatment of ICI-associated myocarditis are proposed with reference to the relevant consensuses or guidelines and newly published evidence-based studies in China and other countries in combination with clinical experience of physicians from Shanghai,China.

Comprehensive Prevention of COVID-19 Infection in Immunocompromised Individuals with Cancer or Solid Organ Transplant

The COVID-19 pandemic has impacted the world for 3 years.As of February 28,2023,more than 750 million confirmed cases and 6.8 million deaths have been reported globally by the World Health Organization.In China,approximately 9.9 million confirmed cases have been reported,including 120,000 deaths.Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to evolve,and the current circulating variant is Omicron.Infections with Omicron are usually mild with a low rate of severe disease,but it has high transmissibility,and the mean basic regeneration number(R0)of the variant is 9.5.During the Omicron era,more COVID-19 breakthrough infections have occurred than in previous variant eras.

Research progress of circular RNAs in drug resistance of liver cancer

Liver cancer is one of the common malignant tumors in the world.Although the current treatment methods for liver cancer are increasing,there are still many problems and challenges that need to be solved,such as drug tolerance.Circular RNA is a kind of non-coding RNA that exists stably in the body.In recent years,studies have confirmed that it plays an important role in the occurrence,development,recurrence and drug resistance of liver cancer.This article reviews the impact of circular RNA on the drug resistance of liver cancer and its regulatory mechanism,aiming to provide a reference intervention target for drug resistance in liver cancer,and at the same time provide a stable reference marker for predicting drug resistance.

DESTINY-Breast04:Calm Thinking on the HER2-low

The DESTINY-Breast04(DB-04)trial is a phaseⅢclinical trial that examined the efficacy of trastuzumab deruxtecan(T-DXd),an anti-HER2-antibody drug,in patients with low HER2 expression(HER2-low)advanced breast cancer.The study enrolled patients with HER2-low,unresectable,and/or recurrent metastatic breast cancer(mBC)who were resistant to previous endocrine therapy and had received one or two previous lines of chemotherapy.Among the 557 enrolled patients,494(88.7%)patients had hormone receptor-positive(HR+)mBC and 63(11.3%)patients had hormone receptor-negative(HR−)mBC.