Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants

Targeted therapy is crucial for advanced colorectal cancer(CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2(ERBB2), B-Raf proto-oncogene, serine/threonine kinase(BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase(ALK/ROS1), neurotrophic receptor tyrosine kinases(NTRKs), ret proto-oncogene(RET), fibroblast growth factor receptor 2(FGFR2), and epidermal growth factor receptor(EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations.

Association of systemic inflammation and body mass index with survival in patients with resectable gastric or gastroesophageal junction adenocarcinomas

Objective:The systemic inflammation index and body mass index(BMI)are easily accessible markers that can predict mortality.However,the prognostic value of the combined use of these two markers remains unclear.The goal of this study was therefore to evaluate the association of these markers with outcomes based on a large cohort of patients with gastric cancer.Methods:A total of 2,542 consecutive patients undergoing radical surgery for gastric or gastroesophageal junction adenocarcinoma between 2009 and 2014 were included.Systemic inflammation was quantified by the preoperative neutrophil-to-lymphocyte ratio(NLR).High systemic inflammation was defined as NLR≥3,and underweight was defined as BMI<18.5 kg/m2.Results:Among 2,542 patients,NLR≥3 and underweight were common[627(25%)and 349(14%),respectively].In the entire cohort,NLR≥3 or underweight independently predicted overall survival(OS)[hazard ratio(HR):1.236,95%confidence interval(95%CI):1.069–1.430;and HR:1.600,95%CI:1.350–1.897,respectively]and recurrence-free survival(RFS)(HR:1.230,95%CI:1.054–1.434;and HR:1.658,95%CI:1.389–1.979,respectively).Patients with both NLR≥3 and underweight(vs.neither)had much worse OS(HR:2.445,95%CI:1.853–3.225)and RFS(HR:2.405,95%CI:1.802–3.209).Furthermore,we observed similar results in subgroup analyses according to pathological stage,age,and postoperative chemotherapy.Conclusions:Our results showed that preoperative elevated NLR and decreased BMI had a significant negative effect on survival.Underweight combined with severe inflammation could enhance prognostication.Taking active therapeutic measures to reduce inflammation and increase nutrition may help improve outcomes.

Routine clinical administration of 4-week alverine citrate and simeticone combination relief global IBS symptoms

Introduction: The primary treatment aim for irritable bowel syndrome (IBS) is to relieve overall symptoms which can significantly impair the patient’s quality of life (QOL);however, it generally requires a high pill burden that may be improved by administration of combinatorial formulations. Thus, the effectiveness of alverine citrate and simeticone combination (ACS) for global symptom relief for IBS was investigated in this non-interventional study. Patients and Methods: ROME III IBS patients (n = 640;52.3% male: mean age: 43.6 ± 12.5 years) with abdominal pain and discomfort ≥60 of 0-100 visual analogue scale (VAS) were included in a prospective, multicenter, non-interventional study at 26 Chinese sites from December 2010 to January 2012. Patients received alverine citrate (60 mg) with simeticone (300 mg) (ACS) 3× daily for 4 weeks. Pain/discomfort and bloating/distension were assessed by VAS. Global symptoms and QOL were assessed by 7-point and 5-point Likert scales, respectively. Post-treatment bowel function was assessed by Bristol Stool Form Scale (BSFS) and treatment-related adverse events (AEs) were recorded. Results: Of 640 patients, 540 (84.4%) completed the study, and 100 (15.6%) withdrew. In total, 87.5% reported bloating at baseline. After 4-week ACS treatment, 89.1% reported global symptom improvement. Furthermore, 4-week ACS treatment reduced pain and bloated VAS scores significantly from 78.4 ± 9.9 to 32.1 ± 21.0 and from 63.2 ± 27.2 to 22.6 ± 20.9, respectively (both p < 0.001), decreased diarrhea or constipation occurrence from 67.2% to 10.2% (p < 0.001), and reduced IBS impact on QOL with only 2 treatment-related AEs. Conclusion: Routine clinical administration of ACS for IBS over a 4-week period provides effective relief of IBS symptoms and improves QOL in IBS patients.

2023 Chinese national clinical practice guideline on diagnosis and management of Crohn’s disease

Inflammatory bowel disease(IBD)is a complex condition,for which standardized diagnostics and treatment are paramount to enhance medical efficacy.Chinese consensus/guidelines for IBD management were formulated in 1978,1993,2001,2007,2012,and 2018,and markedly standardized and improved the clinical management of IBD in China.Recently,given the rising incidence of IBD in China,[1]related clinical and basic research has received much attention.The depth of evidence is increasing,which has laid a solid foundation for updating the consensus guideline.

2023 Chinese national clinical practice guideline on diagnosis and management of ulcerative colitis

The role of Chinese expert consensus in standardization and improvement of the clinical diagnosis and treatment of inflammatory bowel disease(IBD)is self-evident.As clinical and basic research in China becomes standardized under a better understanding of IBD,more data on Chinese patients have become available to develop a consensus and guideline.This guideline,collaboratively developed by the IBD Group,Chinese Society of Gastroenterology,incorporates the latest international consensus statements,[1-7]domestic research findings,and practical considerations,as an update based on the 2018 Chinese consensus on IBD management.[8]The IBD guideline consists of two parts:ulcerative colitis(UC)and Crohn’s disease,and this manuscript presented the UC part.The evidence used in this guideline was collected and analyzed by the standard of guideline,and the contents were organized as problem statements,for clarity.The formulation of this guideline aimed to reflect the latest progress in IBD,providing comprehensive and valuable guidance for the clinical management of IBD.

Microbiota transplantation： concept, methodology and strategy for its modernization

Fecal microbiota transplantation （FMT） has become a research focus of biomedicine and clinical medicine in recent years. The clinical response from FMT for different diseases provided evidence for microbiota-host interactions associated with various disorders, including Clostridium difficile infection, inflammatory bowel disease, diabetes mellitus, cancer, liver cirrhosis, gut- brain disease and others. To discuss the experiences of using microbes to treat human diseases from ancient China to current era should be important in moving standardized FMT forward and achieving a better future. Here, we review the changing concept of microbiota transplantation from FMT to selective microbiota transplantation, methodology development of FMT and step- up FMT strategy based on literature and state experts＇ perspectives.

USP33, a new player in lung cancer, mediates Slit-Robo signaling

Ubiquitin specific protease 33 （USP33） is a multifunctional protein regulating diverse cellular processes. The expression and role of USP33 in lung cancer remain unexplored. In this study, we show that USP33 is down-regulated in multi- ple cohorts of lung cancer patients and that low expression of USP33 is associated with poor prognosis. USP33 medi- ates Slit-Robo signaling in lung cancer cell migration. Downregulation of USP33 reduces the protein stability of Robol in lung cancer cells, providing a previously unknown mechanism for USP33 function in mediating Slit activity in lung cancer ceils. Taken together, USP33 is a new player in lung cancer that regulates Slit-Robo signaling. Our data suggest that USP33 may be a candidate tumor suppressor for lung cancer with potential as a prognostic marker.

Combining methylated SEPTIN9 and RNF180 plasma markers for diagnosis and early detection of gastric cancer

Dear Editor,Early diagnosis is critical for successful treatment of gastric adenocarcinoma(GA).However,the sensitivities of tumor markers carcinoembryonic antigen(CEA),cancer antigen 19-9(CA19-9)and CA72-4 for GA detection are approximately 20%[1],and the sensitivities of all markers combined for early gastric cancer detection is still very low[2].DNA methylation plays a major role in tumorigenesis and therefore has obvious potential as a non-invasive biomarker for cancer detection[3].Through genome-wide methylation analysis and histological verification,we previously identified ring finger protein 180(RNF180)as a novel preferentially methylated gene in GA[4,5].

Time-adjusted average Mayo endoscopic score predicts the risk of disease extent progression in distal ulcerative colitis patients

Background:Ulcerative colitis(UC)is a chronic lifelong disease.The disease extent of UC can progress over time.This study aimed to assess whether cumulative inflammatory burden(CIB)is associated with disease extension in distal UC(proctitis[E1]and left-sided colitis[E2])patients,and to develop a quantified indicator of CIB.Methods:In this retrospective study based on a prospective registry,distal UC patients receiving colonoscopies in Xijing Hospital(Xi’an,China)fromJanuary 2000 to May 2019 were studied.We developed a new score,namely the time-adjusted average Mayo endoscopic score(TA-MES),calculated as dividing the sum of the cumulative averageMES over a period of surveillance time by the length of the endoscopic examination interval,to quantify the CIB.Cox regression was used to identify other potential risk factors.Results:A total of 295 UC patients were followed for 1,487.02 patient-years.Among them,140 patients(47.5%)experienced disease extension.Multivariate analysis showed that the TA-MES was significantly associated with disease extension in E1(hazard ratio[HR],2.90;95%confidence interval[CI],1.58–5.33,P=0.001)and E2(HR,1.89;95%CI,1.16–3.09,P=0.011)patients.Other risk factors included hemoglobin of<90 g/L and appendiceal skip inflammation;the protective factors included age,E2 at diagnosis,former smoking,and 5-aminosalicylic acid dose.Otherwise,MES at diagnosis,maximal MES,and mean MES failed to estimate the risk of disease extension.Conclusion:TA-MES is a good quantified indicator of CIB and is independently associated with increased disease extension in distal UC patients.Whether the dynamic multiple scoring system could be used as a risk factor in other chronic relapsing–remitting diseases is a direction for future research.

Observation on therapeutic efficacy of ursodeoxycholic acid in Chinese patients with primary biliary cirrhosis:a 2-year follow-up study

The efficacy of ursodeoxycholic acid(UDCA)on long-term outcome of primary biliary cirrhosis(PBC)has been less documented in Chinese cohort.We aimed to assess the therapeutic effect of UDCA on Chinese patients with PBC.In the present study,67 patients with PBC were treated with UDCA(13–15 mg∙kg^(-1)∙day^(-1))and followed up for 2 years to evaluate the changes of symptoms,laboratory values and histological features.As the results indicated,fatigue and pruritus were obviously improved by UDCA,particularly in patients with mild or moderate symptoms.The alkaline phosphatase andγ-glutamyl transpetidase levels significantly declined at year 2 comparing to baseline values,with the most profound effects achieved in patients at stage 2.The levels of alanine aminotransferase and aspartate aminotransferase significantly decreased whereas serum bilirubin and immunoglobulin M levels exhibited no significant change.Histological feature was stable in patients at stages 1–2 but still progressed in patients at stages 3–4.The biochemical response of patients at stage 2 was much better than that of patients at stages 3–4.These data suggest that,when treated in earlier stage,patients in long-term administration of UDCA can gain favorable results not only on symptoms and biochemical responses but also on histology.It is also indicated that later histological stage,bad biochemical response and severe symptom may be indicators of poor prognosis for UDCA therapy.

Research highlights of clinical oncology early 2022

Advance in clinical oncology is highly relied on development of cancer research and clinical trials.There has been ample evidence regarding the new therapeutic drugs,agents or techniques for the treatment of cancer.We did a broad literature search to catch the latest progress in the cancer therapy.Here is a brief review of the newly released results of clinical trials including surgical modalities,immune checkpoint blockade,chimeric antigen receptor T-cell(CAR T)therapy,antibody-drug conjugates and tumor vaccines,etc.Biomarkers or patient assessment of cancer therapy were also discussed.