Trends in the management of anorectal melanoma:A multiinstitutional retrospective study and review of the world literature

BACKGROUND Anorectal melanoma(ARM)is a rare disease with a poor prognosis.Evidence on optimal treatment is limited and surgical management varies widely.We hypothesized that the frequency of abdominoperineal resection used as primary treatment of ARM has decreased over the past several decades.AIM To update our understanding of outcomes for patients with ARM and analyze management trends around the world.METHODS This is a multi-institutional,retrospective study of patients treated for ARM at 7 hospitals.Hospitals included both large,academic,tertiary care centers and smaller,general community hospitals.Using prospectively maintained institutional tumor registries,we identified 24 patients diagnosed with ARM between January 2000 and May 2019.We analyzed factors prognostic for recurrence and survival.We then used Cox regression to measure overall survival(OS)and melanoma-specific survival.We also performed a literature review to assess trends in surgical management and outcomes.RESULTS Of the 24 patients diagnosed with ARM,12(50.0%)had local,8(33.3%)regional,and 4(16.7%)distant disease at diagnosis.Median time to recurrence was 10.4 mo[interquartile range(IQR)7.5-17.2]with only 2 patients(9.3%)not developing recurrence following surgical resection.Median OS was 18.8 mo(IQR 13.5-33.9).One patient is still alive without recurrence at 21.4 mo from diagnosis;no other patient survived 5 years.Primary surgical management with abdominoperineal resection(APR)vs wide excision(WE)did not lead to differences in OS[hazard ratio=1.4(95%CI:0.3-6.8)].Review of the literature revealed geographic differences in surgical management of ARM,with increased use of WE in the United States and Europe over time and more frequent use of APR in Asia and India.There was no significant improvement in survival over time.CONCLUSION There is wide variation in the management of ARM and survival outcomes remain poor regardless of approach.Surgical management should aim to minimize morbidity.

Comparison of open and closed hyperthermic intraperitoneal chemotherapy: Results from the United States hyperthermic intraperitoneal chemotherapy collaborative

BACKGROUND Cytoreductive surgery(CRS)with hyperthermic intraperitoneal chemotherapy(HIPEC)for peritoneal carcinomatosis can be performed in two ways:Open or closed abdominal technique.AIM To evaluate the impact of HIPEC method on post-operative and long-term survival outcomes.METHODS Patients undergoing CRS with HIPEC from 2000-2017 were identified in the United States HIPEC collaborative database.Post-operative,recurrence,and overall survival outcomes were compared between those who received open vs closed HIPEC.RESULTS Of the 1812 patients undergoing curative-intent CRS and HIPEC,372(21%)patients underwent open HIPEC and 1440(79%)underwent closed HIPEC.There was no difference in re-operation or severe complications between the two groups.Closed HIPEC had higher rates of 90-d readmission while open HIPEC had a higher rate of 90-d mortalities.On multi-variable analysis,closed HIPEC technique was not a significant predictor for overall survival(hazards ratio:0.75,95%confidence interval:0.51-1.10,P=0.14)or recurrence-free survival(hazards ratio:1.39,95%confidence interval:1.00-1.93,P=0.05)in the entire cohort.These findings remained consistent in the appendiceal and the colorectal subgroups.CONCLUSION In this multi-institutional analysis,the HIPEC method was not independently associated with relevant post-operative or long-term outcomes.HIPEC technique may be left to the discretion of the operating surgeon.

Oxidized phospholipids modify plasminogen and apolipoprotein(a): Implications for vascular disease

Whereas the close structural homology between human plasminogen and apolipoprotein(a) has been known for a number of years only recent studies have revealed that both proteins carry linked oxidized phospholipids that may modify the function of these proteins. Future studies should provide a better understanding of oxidized phospholipid adducts and the role played by lipoprotein-associated phospholipase A2 for which cleavage specificity has been established when these modified lipids are in a free form.

环境强化增加结肠癌模型的周细胞和IgA依赖型伤口修复能力和寿命长度

环境强化(Environmental enrichment,EE)多次被证实具有身心治疗作用,通过为实验动物提供复杂的居住条件,能够改善它们的活跃度、行为和交互能力。使用Tcf4Het/+ApcMin/+介导的结肠肿瘤发生模型,发现EE显著改善了肿瘤小鼠的存活率,EE对小鼠肿瘤负荷的影响性别差异。Tcf4Het/+ApcMin/+雄性小鼠的循环型炎性细胞因子和诱导型核激素受体(NHR)信号表达显著降低,这两者都是伤口修复过程中的常见因子。有趣的是,EE激活了肿瘤伤口修复能力,该过程是通过血运重建,浆细胞募集和IgA分泌,在伤口修复过程中利用周细胞更换腺体肿瘤结构,使肠道微生物菌群正常化。EE依赖性变化可能是Tcf4Het/+ApcMin/+介导的结肠肿瘤雄性小鼠存活率显著改善的重要基础。本研究凸显了EE在未来设计结肠癌患者治疗策略中的重要作用。

Management of granulomatous lobular mastitis: an international multidisciplinary consensus(2021 edition)

Granulomatous lobular mastitis(GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence.Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions,etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology.The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidencebased consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

New models for defining prostate cancer biology and patient prognosis

Currently,the prognosis of patients with metastatic prostate cancer is most commonly defined by clinical factors including performance status,presence of visceral metastasis,lactate dehydrogenase level,opioid analgesic use,albumin level,presence of anemia,prostate-specific antigen level,and alkaline phosphatase level(i.e.,Halabi model).1 This model is most commonly used in the current prospective clinical trials today.However,it is only an inference of the underlying biology and not a direct measurement of that biology.

Apalutamide for metastatic castration-sensitive prostate cancer:final analysis of the Asian subpopulation in the TITAN trial

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial showed improvement in overall survival(OS)and other efficacy endpoints with apalutamide plus androgen deprivation therapy(ADT)versus ADT alone in patients with metastatic castration-sensitive prostate cancer(mCSPC).As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer,a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation.Event-driven endpoints were OS,and time from randomization to initiation of castration resistance,prostate-specific antigen(PSA)progression,and second progression-free survival(PFS2)on first subsequent therapy or death.Efficacy endpoints were assessed using the Kaplan–Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity.Participating Asian patients received once-daily apalutamide 240 mg(n=111)or placebo(n=110)plus ADT.After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide,apalutamide reduced the risk of death by 32%(hazard ratio[HR]:0.68;95%confidence interval[CI]:0.42–1.13),risk of castration resistance by 69%(HR:0.31;95%CI:0.21–0.46),PSA progression by 79%(HR:0.21;95%CI:0.13–0.35)and PFS2 by 24%(HR:0.76;95%CI:0.44–1.29)relative to placebo.The outcomes were comparable between subgroups with low-and high-volume disease at baseline.No new safety issues were identified.Apalutamide provides valuable clinical benefits to Asian patients with mCSPC,with an efficacy and safety profile consistent with that in the overall patient population.

PET药物生产规范

美国食品与药品监督管理局(FDA)公布了联邦法规第212部21条(21CFR212)关于《现行的正电子放射性药物生产规范》的最终规定。该条款旨在确保PET药物符合联邦食品、药品和化妆品规定的产品安全和质量保证要求。新出台的监管制度于2011年12月12日生效,FDA还启动监管自由裁量权,允许新药申请(NDA)和仿制药申请(ANDA)备案程序,此权限一直持续至2012年6月12日,在此期间不中断临床使用PET药物生产。文章介绍了临床应用和临床研究PET药物的概况,包括一些特殊要求;此外,介绍了FDA对药物批准前检查和批准后的报告审查要求。

Role of neuroinflammation in neurodegeneration development

Studies in neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease and Amyotrophic lateral sclerosis,Huntington’s disease,and so on,have suggested that inflammation is not only a result of neurodegeneration but also a crucial player in this process.Protein aggregates which are very common pathological phenomenon in neurodegeneration can induce neuroinflammation which further aggravates protein aggregation and neurodegeneration.Actually,inflammation even happens earlier than protein aggregation.Neuroinflammation induced by genetic variations in CNS cells or by peripheral immune cells may induce protein deposition in some susceptible population.Numerous signaling pathways and a range of CNS cells have been suggested to be involved in the pathogenesis of neurodegeneration,although they are still far from being completely understood.Due to the limited success of traditional treatment methods,blocking or enhancing inflammatory signaling pathways involved in neurodegeneration are considered to be promising strategies for the therapy of neurodegenerative diseases,and many of them have got exciting results in animal models or clinical trials.Some of them,although very few,have been approved by FDA for clinical usage.Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Amyotrophic lateral sclerosis.We also summarize the current strategies,both in animal models and in the clinic,for the treatment of neurodegenerative diseases.

Germline predisposition to soft tissue sarcoma

Soft tissue sarcoma(STS)most often occurs sporadically,but can also arise in the setting of a germline cancer predisposition syndrome(CPS).There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies,occur in all age groups,and can occur in any location in the body.This diversity is also reflected in the many known associated germline cancer predisposition associations.Some STS diagnoses,such as anaplastic rhabdomyosarcoma,are associated with high heritability and other STS,such as Ewing sarcoma,are notably absent from known CPS.Recognizing when a STS is more likely to be hereditary can influence clinical management.Individuals diagnosed with STS due to CPS may be at risk for other malignancies and should undergo additional surveillance for early detection.Additionally,family members should undergo genetic testing as they also may be at risk to develop STS and other CPS-associated malignancies.Some underlying cancer predisposition diagnoses may have implications for the treatment of a concurrent malignancy as in the case of PARP inhibitor therapy in the setting of homologous recombination deficiency.This review summarizes current knowledge of selected STS and their associations with CPS.

Impact of initial fluid resuscitation volume on clinical outcomes in patientswith heart failure and septic shock

Background:Fluid resuscitation is a key treatment for sepsis,but limited data exists in patients with existing heartfailure(HF)and septic shock.The objective of this study was to determine the impact of initial fluid resuscitationvolume on outcomes in HF patients with reduced or mildly reduced left ventricular ejection fraction(LVEF)withseptic shock.Methods:This multicenter,retrospective,cohort study included patients with known HF(LVEF≤50%)presentingwith septic shock.Patients were divided into two groups based on the volume of fluid resuscitation in the first 6 h;<30 mL/kg or≥30 mL/kg.The primary outcome was a composite of in-hospital mortality or renal replacementtherapy(RRT)within 7 days.Secondary outcomes included acute kidney injury(AKI),initiation of mechanicalventilation,and length of stay(LOS).All related data were collected and compared between the two groups.A generalized logistic mixed model was used to assess the association between fluid groups and the primaryoutcome while adjusting for baseline LVEF,Acute Physiology and Chronic Health Evaluation(APACHE)II score,inappropriate empiric antibiotics,and receipt of corticosteroids.Results:One hundred and fifty-four patients were included(93 patients in<30 mL/kg group and 61 patientsin≥30 mL/kg group).The median weight-based volume in the first 6 h was 17.7(12.2–23.0)mL/kg in the<30 mL/kg group vs.40.5(34.2–53.1)mL/kg in the≥30 mL/kg group(P<0.01).No statistical difference was detected in the composite of in-hospital mortality or RRT between the<30 mL/kg group compared to the≥30 mL/kggroup(55.9%vs.45.9%,P=0.25),respectively.The<30 mL/kg group had a higher incidence of AKI,mechanicalventilation,and longer hospital LOS.Conclusions:In patients with known reduced or mildly reduced LVEF presenting with septic shock,no differencewas detected for in-hospital mortality or RRT in patients who received≥30 mL/kg of resuscitation fluid comparedto less fluid,although this study was underpowered to detect a difference.Importantly,≥30 mL/kg fluid did notresult in a higher need for mechanical ventilation.

Clinical utilization of olaparib,a PARP inhibitor,in BRCA1-mutant metastatic acral melanoma

Acral melanoma(AM)is a rare subtype of cutaneous melanoma linked to poor prognosis,largely due to a lacking of effective targeted therapeutic strategies.Whole-genome sequencing(WGS)data revealed that AM showed a different mutation landscape from cutaneous melanoma.1 BRCA1 and BRCA2 mutations appear in about 3%–16%of AMs.2,3 Pharmacologic inhibition of the DNA repair enzyme PARP has been approved by the FDA as monotherapy in patients with deleterious germline BRCA1/2 mutated advanced ovarian cancer,and the usage has been expanded to metastatic breast cancer,pancreatic cancer,and prostate cancer with homologous recombination repair(HRR)gene defects.4 However,whether AM with BRCA mutations is also sensitive to PARP inhibition is unknown.We identified a stageⅣAM patient with a germline BRCA1 frameshift mutation(BRAC1 G1384Nfs∗7)who was resistant to anti-PD1 therapy.Both patient-derived xenograft and cells(PDX/PDC)models from the same AM patient were established.PARP inhibitor olaparib significantly decreased cell proliferation and slowed tumor growth by increasing DNA double-strand breakage in AM cancer cells.Administration of olaparib to the patient achieved stable disease for 3 months.This study provides preclinical and clinical evidence that PARP inhibitors can slow tumor growth in BRCA1-mutant advanced acral melanoma.

Emerging mechanisms of immunotherapy resistance in sarcomas

Sarcomas are a heterogeneous group of over 150 mesenchymal neoplasms of bone and soft tissue.Clinical prognosis remains poor in the metastatic and refractory setting,despite treatment with traditional chemotherapies.A subset of sarcoma patients can exhibit remarkable responses to novel immune therapies;however,most patients will not respond.Emerging data from genetic and transcriptomic datasets suggests that patients who are resistant to checkpoint inhibitor monotherapy may have low expression of immune-related genes,suggesting that the sarcoma was not sufficiently immunogenic to trigger or maintain an immune response to generate tumor-specific immune effector cells.In this review,we discuss the emerging data surrounding potential mechanisms of resistance,including various biomarkers explored in clinical trials of immune therapy for sarcomas.We also review future directions in clinical trials that are focused on boosting tumor immunogenicity to improve the activity of checkpoint inhibitors,as well as adoptive cellular therapy approaches to bypass deficiencies in neoantigens or antigen presentation.

CD24Fc ameliorates immune-related adverse events while preserving anti-tumor therapeutic effect

Dear Editor,In combination,anti-CTLA-4 and anti-PD-1 mAb provide the most effective immunotherapy,although severe immune-related adverse events(irAEs)also occur at high frequency.1 It is urgent to develop strategies to reduce irAEs for wide-spread adoption of immune checkpoint inhibitors(ICIs).