ABSTRACT
BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Subject(s)
Antibodies, Bispecific , ErbB Receptors , Immunoconjugates , Neoplasms , Receptor, ErbB-3 , Humans , Middle Aged , Male , Female , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/therapeutic use , Aged , Adult , Neoplasms/drug therapy , Neoplasms/pathology , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/immunology , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/immunology , Young Adult , Maximum Tolerated Dose , Adolescent , Neoplasm Metastasis , China , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic useABSTRACT
BACKGROUND AND AIMS: The incidence of HCC has recently been consistently reported to decline in the United States. However, decreased overall mortality of HCC has just been suggested and needs further examination. APPROACH AND RESULTS: Using data from the Surveillance, Epidemiology, and End Results databases, we assessed HCC incidence, incidence-based mortality (IBM), and 1-year survival rates from 1992 through 2017 in the United States. These secular trends were analyzed using the National Cancer Institute's Joinpoint Regression Program. Age-period-cohort analyses were performed to address underlying reasons for the observed temporal trends. The incidence and mortality of liver cancer in the United States by different etiologies were acquired from the Global Burden of Disease study (1990-2019) as a likely validation set. Joinpoint and age-period-cohort analyses were performed by etiologies. The incidence rates of HCC increased during 1992-2011 and sharply decreased thereafter by -2.3% annually (95% CI: -3.5% to -1.1%). IBM peaked in 2013 (age-standardized mortality rate: 6.98 per 100,000 person-years) in the US population. IBM started to decrease significantly in 2013 by -3.2%/year (95% CI: -5.4% to -1.1% per year) after a continuous increase of 3.5% annually during 1993-2013. Overall, the 1-year survival of HCC improved from 21.4% to 56.6% over the study period. However, the highest HCC incidence and mortality risk for patients aged 60-69 and born between 1952-1957 were found. CONCLUSIONS: We found significantly decreased overall HCC-specific mortality since 2013 in the US population, along with decreased incidence and continuously improved survival. The changing etiologies, advances in screening and diagnosis, and improved treatment modality and allocation might all contribute to the downward trends of the disease burden of HCC in the United States.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/epidemiology , Cost of Illness , Humans , Incidence , Liver Neoplasms/epidemiology , SEER Program , United States/epidemiologyABSTRACT
Most hepatocellular carcinoma (HCC) patients have dismal prognoses because they are already in the advanced stage at the time of initial diagnosis and are unable to undergo upfront surgery. Recent studies of immune checkpoint inhibitors (ICIs) and antiangiogenic agents (AAAs) have shown encouraging results for unresectable HCC (uHCC). Here, we report a patient with uHCC who was treated with a combination of anlotinib and sintilimab (sintilimab 200 mg, intravenous glucose tolerance test, q21d and anlotinib 12 mg, orally, d1-14, q21d), an analog of the combination of lenvatinib and pembrolizumab with much lower cost. The patient with recurrent uHCC was downstaged to resectable disease by the combination therapy. After eight cycles of treatment with anlotinib and sintilimab, the patient underwent a second operation. The histology of the resected mass revealed a major and almost complete pathological response. However, this patient was diagnosed with type I diabetes mellitus with ketoacidosis after nearly 10 cycles of combination treatment with anlotinib and sintilimab. Active follow-ups revealed no signs of local recurrence or distant failure. In conclusion, this case report demonstrated that the combination of anlotinib and sintilimab, one of the strategies combining ICIs with AAAs, showed promising efficacy in the treatment of uHCC patients.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Diabetic Ketoacidosis/chemically induced , Indoles/adverse effects , Quinolines/adverse effects , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Hepatocellular/drug therapy , Humans , Indoles/therapeutic use , Liver Neoplasms/drug therapy , Male , Quinolines/therapeutic useABSTRACT
BACKGROUND: Increasing evidence indicates that nutritional status could influence the survival of cancer patients. This study aims to develop and validate a nomogram with nutrition-related parameters for predicting the overall survival of cancer patients. PATIENTS AND METHODS: A total of 8749 patients from the multicentre cohort study in China were included as the primary cohort to develop the nomogram, and 696 of these patients were recruited as a validation cohort. Patients' nutritional status were assessed using the PG-SGA. LASSO regression models and Cox regression analysis were used for factor selection and nomogram development. The nomogram was then evaluated for its effectiveness in discrimination, calibration, and clinical usefulness by the C-index, calibration curves, and decision curve analysis. Kaplan-Meier survival curves were used to compare the survival rate. RESULTS: Seven independent prognostic factors were identified and integrated into the nomogram. The C-index was 0.73 (95% CI, 0.72 to 0.74) and 0.77 (95% CI, 0.74 to 0.81) for the primary cohort and validation cohort, which were both higher than 0.59 (95% CI, 0.58 to 0.61) of the TNM staging system. DCA demonstrated that the nomogram was higher than the TNM staging system and the TNM staging system combined with PG-SGA. Significantly median overall survival differences were found by stratifying patients into different risk groups (score < 18.5 and ≥ 18.5) for each TNM category (all Ps < 0.001). CONCLUSION: Our study screened out seven independent prognostic factors and successfully generated an easy-to-use nomogram, and validated and shown a better predictive validity for the overall survival of cancer patients.
Subject(s)
Neoplasms , Nutritional Status , Cohort Studies , Humans , Neoplasm Staging , Nomograms , PrognosisABSTRACT
OBJECTIVES: To characterize the chest computed tomography (CT) findings of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to clinical severity. We compared the CT features of common cases and severe cases, symptomatic patients and asymptomatic patients, and febrile and afebrile patients. METHODS: This was a retrospective analysis of the clinical and thoracic CT features of 120 consecutive patients with confirmed SARS-CoV-2 pneumonia admitted to a tertiary university hospital between January 10 and February 10, 2020, in Wuhan city, China. RESULTS: On admission, the patients generally complained of fever, cough, shortness of breath, and myalgia or fatigue, with diarrhea often present in severe cases. Severe patients were 20 years older on average and had comorbidities and an elevated lactate dehydrogenase (LDH) level. There were no differences in the CT findings between asymptomatic and symptomatic common type patients or between afebrile and febrile patients, defined according to Chinese National Health Commission guidelines. CONCLUSIONS: The clinical and CT features at admission may enable clinicians to promptly evaluate the prognosis of patients with SARS-CoV-2 pneumonia. Clinicians should be aware that clinically silent cases may present with CT features similar to those of symptomatic common patients. KEY POINTS: ⢠The clinical features and predominant patterns of abnormalities on CT for asymptomatic, typic common, and severe cases were summarized. These findings may help clinicians to identify severe patients quickly at admission. ⢠Clinicians should be cautious that CT findings of afebrile/asymptomatic patients are not better than the findings of other types of patients. These patients should also be quarantined. ⢠The use of chest CT as the main screening method in epidemic areas is recommended.
Subject(s)
Betacoronavirus , Coronavirus Infections/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Adult , Aged , COVID-19 , China/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Cough/virology , Diarrhea/virology , Female , Fever/virology , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Prognosis , Retrospective Studies , SARS-CoV-2 , Tertiary Care Centers , Tomography, X-Ray ComputedABSTRACT
The survival advantage of surgery to the primary tumor for patients with distant metastatic esophageal cancer has not been adequately evaluated. This study aims to investigate the role of surgery to the primary tumor in distant metastatic esophageal cancer and to evaluate possible different effects of surgery on survival of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). This study included a cohort of 4,367 metastatic esophageal cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database, registered from January 2004 to December 2014. Kaplan-Meier and Cox proportional hazardous models were used to evaluate the overall survival (OS) and corresponding 95% confidence interval (CI). Propensity score matching (PSM) was used to adjust for potential baseline confounding. Both EAC (median OS for surgery group vs. no-surgery group-14.0 vs. 9.0 months, P < 0.001) and ESCC (median OS for surgery vs. no-surgery group-11.0 vs. 7.0 months, P = 0.002) experienced survival benefits from surgery. We found that surgery to the primary tumor, when combined with chemotherapy, was associated with improved survival for patients with M1b disease, both EAC and ESCC, with a greater benefit observed in younger patients, and those with EAC. While the present data indicate a potential survival benefit from surgery for some patients with metastatic esophageal cancer, it is possible that performance status and metastatic disease burden impacted patient selection, influencing these results. Further studies are needed to determine the role of surgery for patients with metastatic esophageal cancer.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Esophagectomy , Neoplasm Metastasis , Adenocarcinoma/pathology , Adenocarcinoma/surgery , China/epidemiology , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/surgery , Esophagectomy/methods , Esophagectomy/statistics & numerical data , Female , Humans , Male , Middle Aged , Neoplasm Metastasis/pathology , Neoplasm Metastasis/therapy , Neoplasm Staging , Outcome and Process Assessment, Health Care , SEER Program/statistics & numerical data , Survival AnalysisABSTRACT
PURPOSE: The aim of this study was to evaluate the efficacy of using nedaplatin to replace cisplatin for concurrent chemoradiotherapy (CCRT) in patients with newly diagnosed locally advanced cervical cancer. METHODS: The medical records of 155 patients with cervical cancer who had undergone CCRT with cisplatin (n = 85) or nedaplatin (n = 70) between January 2012 and January 2017 were retrospectively reviewed. Propensity score analysis with 1:1 matching with the nearest neighbor matching method was performed to assess response rates, progression-free survival, overall survival, and toxicity between 2 groups. RESULTS: Propensity score matching identified 63 patients in each group. After matching, compared with patients treated with cisplatin-based concurrent chemoradiotherapy (CisRT), we found that patients treated with nedaplatin-based concurrent chemoradiotherapy (NedaRT) had a significant higher recurrence rate (25.4% vs 42.9%; P = 0.04). In addition, the 3-year progression-free survival rate for NedaRT group was also worse than that for the CisRT group (52.2% vs 63.4%, P = 0.03). There was no difference in the overall response rates between the CisRT and NedaRT groups (87.3% and 90.5%, respectively; P = 0.57). The rates of 3-year overall survival and grades 3 to 4 toxicities were similar between the 2 groups. CONCLUSIONS: The clinical outcome of this cohort of patients with locally advanced cervical cancer treated with CCRT did in no way provide support for the use of nedaplatin in place of cisplatin in chemoradiation and demonstrated no equivalence of the 2 drugs. Cautions should be taken for the replacement among platinum complexes in cancer treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Organoplatinum Compounds/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Adult , China/epidemiology , Female , Humans , Middle Aged , Propensity Score , Retrospective Studies , Treatment Outcome , Uterine Cervical Neoplasms/mortalityABSTRACT
OBJECTIVE: To demonstrate whether radiotherapy has an effect on the survival of patients with stage IVb (M1) cervical cancer, as it has not been adequately clarified. METHODS: We analyzed International Federation of Gynecology and Obstetrics (FIGO) stage M1 cervical cancer diagnosed in patients between 1992 and 2013 using population-based data from the Surveillance, Epidemiology, and End Results registry. Propensity score (PS) analysis with 1:1 matching and the nearest neighbor matching method was performed to ensure well-balanced characteristics of comparison groups. Data were analyzed by Kaplan-Meier and Cox proportional hazards regression models to evaluate the overall survival (OS) and cancer-specific survival (CSS) months with corresponding 95% confidence intervals (95% CIs). RESULTS: In general, receiving radiotherapy significantly improved OS and CSS both before and after PS matching (PSM) (P < 0.001), with significantly improved OS (hazard ratio, 0.69; 95% CI, 0.62-0.76) and CSS (hazard ratio, 0.79; 95% CI, 0.70-0.89) after PSM in patients with stage M1 cervical cancer. Before PSM, radiotherapy was found to be associated with improved survival even for the patients with stage M1 cervical cancer with extensive metastasis (≥2 metastatic sites) (P < 0.001). Although P value was not significant for brain metastasis, the survival month was numerically improved before PSM (OS and CSS, 1 month vs 4 months). Overall, radiotherapy still significantly improved survival for patients with one metastatic site (ie, oligometastases) either before or after PSM (P < 0.05), with the survival month improved more than 6 months. CONCLUSIONS: The large Surveillance, Epidemiology, and End Results results support that radiotherapy might improve the survival of patients with metastatic cervical cancer. It might be prudent to carefully select suitable patients for radiation therapy for metastatic cervical cancer.
Subject(s)
Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/radiotherapy , Case-Control Studies , Databases, Factual , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Propensity Score , Proportional Hazards Models , SEER Program , United States/epidemiology , Uterine Cervical Neoplasms/pathologyABSTRACT
BACKGROUND: Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest. METHODS AND FINDINGS: We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for â¼71% of Asia's total population. An approximately 1.44-fold (95% CIâ=â1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CIâ=â14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of â¼1,575,500 (95% CIâ=â1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y. CONCLUSIONS: Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary.
Subject(s)
Cardiovascular Diseases/mortality , Neoplasms/mortality , Respiratory Tract Diseases/mortality , Smoking/mortality , Adult , Asia/epidemiology , Cardiovascular Diseases/economics , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Cost of Illness , Female , Humans , Male , Middle Aged , Neoplasms/economics , Neoplasms/epidemiology , Neoplasms/etiology , Prevalence , Respiratory Tract Diseases/economics , Respiratory Tract Diseases/epidemiology , Respiratory Tract Diseases/etiology , Risk , Risk Factors , Smoking/economics , Smoking/epidemiologyABSTRACT
The association of dietary fiber intake with colorectal cancer risk is established. However, the association may differ between cigarette smokers and nonsmokers. We evaluated this hypothesis in a large colonoscopy-based case-control study. Dietary fiber intakes were estimated by self-administered food frequency questionnaire. Unconditional logistic regression analysis was used to estimate ORs and 95% CIs with adjustment for potential confounders. Analysis also was stratified by cigarette smoking and sex. High dietary fiber intake was associated with reduced risk of colorectal polyps (P-trend = 0.003). This association was found to be stronger among cigarette smokers (P-trend = 0.006) than nonsmokers (P-trend = 0.21), although the test for multiplicative interaction was not statistically significant (P = 0.11). This pattern of association was more evident for high-risk adenomatous polyps (ADs), defined as advanced or multiple ADs (P-interaction smoking and dietary fiber intake = 0.09). Among cigarette smokers who smoked ≥23 y, a 38% reduced risk of high-risk ADs was found to be associated with high intake of dietary fiber compared with those in the lowest quartile fiber intake group (P-trend = 0.004). No inverse association with dietary fiber intake was observed for low-risk ADs, defined as single nonadvanced ADs. Cigarette smoking may modify the association of dietary fiber intake with the risk of colorectal polyps, especially high-risk ADs, a well-established precursor of colorectal cancer.
Subject(s)
Colonic Polyps/epidemiology , Colonoscopy , Colorectal Neoplasms/epidemiology , Dietary Fiber/administration & dosage , Smoking/epidemiology , Adenomatous Polyps/epidemiology , Adenomatous Polyps/pathology , Adult , Aged , Case-Control Studies , Colonic Polyps/pathology , Colorectal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Precancerous Conditions/epidemiology , Precancerous Conditions/pathology , Risk Factors , Risk Reduction Behavior , Tennessee/epidemiologyABSTRACT
BACKGROUND: Cutaneous malignant melanoma (CMM) causes most skin cancer deaths in the United States (US). The mortality has been decreasing in the US population. We hypothesize that this population-level reduction is mainly attributable to the treatment advances, rather than the successful primary and secondary prevention. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) databases, we collected the incidence, incidence-based mortality (IBM), and 5-year survival (5-YS) rates of CMM from 1994 to 2019. Trends by stage and sex were examined by joinpoint regression analyses and age-period-cohort analyses. RESULTS: The overall incidence of CMM rose by 1.6% yearly from 1994 to 2006 (95% confidence interval [CI]: 0.9% to 2.2%) and then increased with a numerical trend. And we projected the incidence will continue to increase until 2029. In contrast, the IBM for all CMM has decreased yearly by 2.8% (95% CI: -3.9% to -1.8%) since 2010 after continuously increasing by 3.8% annually (95% CI: 3.2% to 4.4%) from 1996 to 2010. For early-stage (localized and regional) CMM, we found the incidence since 2005 plateaued without further increase, while the incidence for CMM at distant stage continuously increased by 1.4% per year (95% CI: 0.9% to 2.0%). Improvements in 5-YS were observed over the study period for all CMM and were most obvious in distant stage. And significant period effects were noted around the year 2010. CONCLUSION: This study demonstrated improved survival and reduced mortality of CMM at the US population level since 2010, which were consistent with the introduction of novel therapies. Encouraging effects of primary prevention among adolescents in the most recent cohorts were found. However, the plateaued overall incidence and early diagnosis rates indicated that advances in primary and secondary prevention are very much needed to further control the burden of CMM.
Subject(s)
Melanoma , Skin Neoplasms , Adolescent , Humans , United States/epidemiology , Melanoma/epidemiology , Melanoma/therapy , Melanoma/diagnosis , Skin Neoplasms/epidemiology , Skin Neoplasms/therapy , Skin Neoplasms/diagnosis , Incidence , Forecasting , Regression AnalysisABSTRACT
The causal role of cigarette smoking in the risk of colorectal neoplasm has been suggested but not established. In a case-control study including 2060 colorectal polyp patients and 3336 polyp-free controls, we evaluated 21 functional genetic variants to construct a tobacco-carcinogen-metabolizing genetic risk score. Data regarding cigarette smoking were obtained through telephone interviews. Cigarette smoking was associated with an elevated risk of both adenomas and hyperplastic polyps. The association with smoking was stronger in participants with a high carcinogen-metabolizing risk score than those with a low risk score. Smoking 30 or more cigarettes per day was associated with a 1.7-fold elevated risk of any polyps (95% confidence interval = 1.3-2.2) among those with a low genetic risk score and 2.9-fold elevated risk (95% confidence interval = 1.8-4.8) among those with a high genetic risk score (P interaction = 0.025). A similar pattern of interaction was observed in analyses conducted separately for those with adenomas only (P interaction = 0.039) and hyperplastic polyps only (P interaction = 0.024). Interaction between carcinogen-metabolizing genetic risk and cigarette smoking was found in relation to high-risk adenomas (P interaction = 0.010) but not low-risk adenomas (P interaction = 0.791). No apparent interaction was found for duration of smoking. This study shows that the association between cigarette smoking and colorectal polyp risk is modified by tobacco-carcinogen-metabolizing polymorphisms, providing support for a causal role of cigarette smoking in the etiology of colorectal tumors.
Subject(s)
Carcinogens/metabolism , Colonic Polyps/genetics , Colorectal Neoplasms/etiology , Colorectal Neoplasms/genetics , Nicotiana/chemistry , Polymorphism, Genetic , Smoking/adverse effects , Adenoma/etiology , Adenoma/genetics , Adult , Aged , Case-Control Studies , Colonic Polyps/etiology , Disease Susceptibility , Enzymes/genetics , Female , Genotype , Humans , Hyperplasia/complications , Interviews as Topic , Male , Middle Aged , Risk , Risk Factors , Tobacco Smoke PollutionABSTRACT
EGFR exon 20 insertion (20ins)-positive non-small-cell lung cancer (NSCLC) is an uncommon disease with limited therapeutic options and dismal prognosis. Here we report the activity, tolerability, potential mechanisms of response and resistance for dual targeting EGFR 20ins with JMT101 (anti-EGFR monoclonal antibody) plus osimertinib from preclinical models and an open label, multi-center phase 1b trial (NCT04448379). Primary endpoint of the trial is tolerability. Secondary endpoints include objective response rate, duration of response, disease control rate, progression free survival, overall survival, the pharmacokinetic profile of JMT101, occurrence of anti-drug antibodies and correlation between biomarkers and clinical outcomes. A total of 121 patients are enrolled to receive JMT101 plus osimertinib 160 mg. The most common adverse events are rash (76.9%) and diarrhea (63.6%). The confirmed objective response rate is 36.4%. Median progression-free survival is 8.2 months. Median duration of response is unreached. Subgroup analyses were performed by clinicopathological features and prior treatments. In patients with platinum-refractory diseases (n = 53), confirmed objective response rate is 34.0%, median progression-free survival is 9.2 months and median duration of response is 13.3 months. Responses are observed in distinct 20ins variants and intracranial lesions. Intracranial disease control rate is 87.5%. Confirmed intracranial objective response rate is 25%.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Antibodies, Monoclonal , ExonsABSTRACT
BACKGROUND & AIMS: The present study aimed to compare the ability of the GLIM criteria, PG-SGA and mPG-SGA to diagnose malnutrition and predict survival among Chinese lung cancer (LC) patients. METHODS: This was a secondary analysis of a multicenter, prospective, nationwide cohort study, 6697 LC inpatients were enrolled between July 2013 and June 2020. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and quadratic weighted Kappa coefficients were calculated to compare the ability to diagnose malnutrition. There were 754 patients who underwent follow-up for a median duration of 4.5 years. The associations between the nutritional status and survival were analyzed by the Kaplan-Meier method and multivariable Cox proportional hazard regression models. RESULTS: The median age of LC patients was 60 (53, 66), and 4456 (66.5%) were male. There were 617 (9.2%), 752 (11.2%), 1866 (27.9%), and 3462 (51.7%) patients with clinical stage â , â ¡, â ¢, and â £ LC, respectively. Malnutrition was present in 36.1%-54.2% (as evaluated using different tools). Compared with the PG-SGA (used as the diagnostic reference), the sensitivity of the mPG-SGA and GLIM was 93.7% and 48.3%; the specificity was 99.8% and 78.4%; and the AUC was 0.989 and 0.633 (P < 0.001). The weighted Kappa coefficients were 0.41 for the PG-SGA vs. GLIM, 0.44 for the mPG-SGA vs. GLIM, and 0.94 for the mPG-SGA vs PG-SGA in patients with stage â -â ¡ LC. These values were respectively 0.38, 0.39, and 0.93 in patients with stage â ¢-â £ of LC. In a multivariable Cox analysis, the mPG-SGA (HR = 1.661, 95%CI = 1.348-2.046, P < 0.001), PG-SGA (HR = 1.701, 95%CI = 1.379-2.097, P < 0.001) and GLIM (HR = 1.657, 95%CI = 1.347-2.038, P < 0.001) showed similar death hazard ratios. CONCLUSIONS: The mPG-SGA provides nearly equivalent power to predict the survival of LC patients as the PG-SGA and the GLIM, indicating that all three tools are applicable for LC patients. The mPG-SGA has the potential to be an alternative replacement for quick nutritional assessment among LC patients.
Subject(s)
Lung Neoplasms , Malnutrition , Humans , Male , Female , Cohort Studies , Prospective Studies , Malnutrition/diagnosis , Inpatients , Lung Neoplasms/complications , Lung Neoplasms/diagnosis , Nutritional Status , Nutrition AssessmentABSTRACT
Malnutrition is a common comorbidity among patients with cancer. However, no nutrition-screening tool has been recognized in this population. A quick and easy screening tool for nutrition with high sensitivity and easy-to-use is needed. Based on the previous 25 nutrition-screening tools, the Delphi method was made by the members of the Chinese Society of Nutritional Oncology to choose the most useful item from each category. According to these results, we built a nutrition-screening tool named age, intake, weight, and walking (AIWW). Malnutrition was defined based on the scored patient-generated subjective global assessment (PG-SGA). Concurrent validity was evaluated using the Kendall tau coefficient and kappa consistency between the malnutrition risks of AIWW, nutritional risk screening 2002 (NRS-2002), and malnutrition screening tool (MST). Clinical benefit was calculated by the decision curve analysis (DCA), integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI). A total of 11,360 patients (male, n=6,024 (53.0%) were included in the final study cohort, and 6,363 patients had malnutrition based on PG-SGA. Based on AIWW, NRS-2002, and MST, 7,545, 3,469, and 1,840 patients were at risk of malnutrition, respectively. The sensitivities of AIWW, NRS-2002, and MST risks were 0.910, 0.531, and 0.285, and the specificities were 0.768, 0.946, and 0.975. The Kendall tau coefficients of AIWW, NRS-2002, and MST risks were 0.588, 0.501, and 0.326, respectively. The area under the curve of AIWW, NRS-2002, and MST risks were 0.785, 0.739, and 0.630, respectively. The IDI, cNRI, and DCA showed that AIWW is non-inferior to NRS-2002 (IDI: 0.002 (-0.009, 0.013), cNRI: -0.015 (-0.049, 0.020)). AIWW scores can also predict the survival of patients with cancer. The missed diagnosis rates of AIWW, NRS-2002, and MST were 0.09%, 49.0%, and 73.2%, respectively. AIWW showed a better nutrition-screening effect than NRS-2002 and MST for patients with cancer and could be recommended as an alternative nutrition-screening tool for this population.
Subject(s)
Malnutrition , Neoplasms , Humans , Male , Nutrition Assessment , Nutritional Status , Malnutrition/diagnosis , Mass Screening/methods , Neoplasms/diagnosisABSTRACT
Understanding patterns of shared and type-specific etiologies for colorectal polyps may provide insights into colorectal carcinogenesis. The authors present the first systematic comparison of risk factors by colorectal polyp type in a large colonoscopy-based case-control study of 3,764 polyp-free controls and 2,543 polyp patients, including 1,444 cases with adenomas only, 662 cases with hyperplastic polyps (HPPs) only, and 437 cases with synchronous HPPs and adenomas. Surveys were completed to obtain information on usual dietary intake and other lifestyle factors. Six lifestyle factors, including cigarette smoking, obesity, no regular use of nonsteroidal anti-inflammatory drugs, high intake of red meat, low intake of fiber, and low intake of calcium, were found to be independently associated with the risk of polyps. The risk of polyps increased progressively with an increasing number of adverse lifestyle factors. Compared with participants with no or only 1 risk factor, odds ratios for those with 5 to 6 risk factors were 2.72 (95% confidence interval: 1.94, 3.79) for adenoma only, 4.12 (95% confidence interval: 2.78, 6.09) for HPPs only, and 9.03 (95% confidence interval: 5.69, 14.34) for synchronous HPPs and adenomas. This study provides strong evidence that lifestyle modification is important for the prevention of colorectal polyps, especially advanced and multiple adenomas, which are established precursors of colorectal cancer.
Subject(s)
Adenomatous Polyps/epidemiology , Colonic Polyps/epidemiology , Hyperplasia/epidemiology , Life Style , Aged , Alcohol Drinking , Anti-Inflammatory Agents, Non-Steroidal , Body Mass Index , Case-Control Studies , Colon/pathology , Colonoscopy , Diet , Educational Status , Exercise , Female , Health Behavior , Humans , Male , Middle Aged , Rectum/pathology , Risk Factors , SmokingABSTRACT
This study aimed to tentatively evaluate the effects of dietary vitamin E (VE) on goose reproductive physiology through the investigation of reproductive performance, egg characteristics, antioxidant capacity, and immune status in breeding geese. A total of 480 female and 96 male Jiangnan White breeding geese were randomly assigned to four treatments with four replicates, and each replicate had 30 females and six males. Four levels of VE were successively added to four treatment diets from 48 to 54 weeks of age, representing the effects of VE deficiency (0 IU/kg), basic-dose VE (40 IU/kg), middle-dose VE (200 IU/kg), and high-dose VE (2000 IU/kg). Neither the egg-laying rate nor the healthy-gosling rate were affected by any of the VE supplementations (p > 0.05). The qualified egg rate, hatchability of fertilized eggs, and spleen index were increased by each VE supplementation (p < 0.05). Egg fertility, the concentration of plasma reproductive hormones (i.e., the follicle-stimulating hormone, estradiol, and progesterone), follicular development, and antioxidant enzyme activitiesi.e., the concentration of malondialdehyde (MDA), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)in the liver and ovary were improved by 200 IU/kg of dietary VE (p < 0.05). Plasma VE concentration, immunoglobulin A, and immunoglobulin G content were increased, whereas plasma vitamin D3 concentration was reduced by increasing dietary VE levels to 2000 IU/kg (p < 0.05). The VE deposition of yolk, the yolk color depth, and the albumen rate were increased by each VE supplementation (p < 0.05). Antioxidant enzyme activities (i.e., MDA concentration, T-AOC, SOD, and GSH) in yolk were improved by 200 IU/kg and 2000 IU/kg of dietary VE (p < 0.05), compared with 0 IU/kg. The VE deposition was significantly correlated with GSH activity and the MDA concentration in egg yolk (p < 0.05). However, the high intake of dietary VE (2000 IU/kg vs. 200 IU/kg) decreased egg fertility (p < 0.05) and reduced the antioxidant capacity in the liver and ovary (p < 0.05). The qualified egg rate was positively correlated to immunoglobulin production (p < 0.05). Egg fertility and hatchability were correlatively improved by increased antioxidant enzyme activity; decreased MDA in the liver and ovary; hatchability; and enhanced immune status (p < 0.05). To sum up, both VE deficiency and high-dose VE (2000 IU/kg) reduced reproductive performance, whereas a dose of 200 IU/kg VE achieved optimal fertility, possibly through enhancing antioxidant capacity and immune status.
ABSTRACT
BACKGROUND: We evaluated the relative attribution and interactions of treatment and patient-related risk factors for second primary malignancies (SPMs) in cervical and endometrial cancer survivors. METHODS: Stage I-III cervical and endometrial cancer survivors' data from the Surveillance, Epidemiology, and End Results (SEER) registry between January 1988 and December 2015 were analyzed. The standardized incidence ratio (SIR), excess absolute risk (EAR), and corresponding 95% confidence interval (95% CI) values were calculated. Analyses were classified based on proxies of human papillomavirus (HPV), smoking, hormone, and radiotherapy (RT) status. Additive and multiplicative interactions were assessed. RESULTS: Cervical cancer survivors had a higher risk for developing potentially HPV and smoking-related SPMs, especially in the RT group (SIRHPV = 3.7, 95% CI: 2.9-4.6; SIRsmoking = 3.2, 95% CI: 2.8-3.6). Second vaginal cancer patients had the highest SIR (23.8, 95% CI: 14.9-36.0). There were strong synergistic interactions between RT and the proxy of smoking (Pinteraction < 0.001), accounting for 36% of potentially smoking-related SPMs in cervical cancer survivors. CONCLUSIONS: RT, HPV, and smoking promote SPMs in cervical cancer to different extents. The SPM burden in cervical cancer survivors could be mostly attributed to smoking and RT and their interactions.
Subject(s)
Cancer Survivors , Endometrial Neoplasms , Neoplasms, Second Primary , Papillomavirus Infections , Uterine Cervical Neoplasms , Endometrial Neoplasms/epidemiology , Female , Humans , Incidence , Neoplasms, Second Primary/epidemiology , Papillomaviridae , Papillomavirus Infections/complications , Papillomavirus Infections/epidemiology , Risk Factors , SEER Program , Survivors , Uterine Cervical Neoplasms/epidemiologyABSTRACT
BACKGROUND: Cancer cachexia is a complex metabolic syndrome characterised by a loss of muscle with or without loss of fat mass, and is associated with high morbidity and mortality. Despite its clinical importance, there is a lack of simple tools to screen patients for cancer cachexia. The aim of this study was to evaluate and validate the patient-generated subjective global assessment (PG-SGA) as a screening tool for cancer cachexia. METHODS: This is a secondary analysis of a multicentre, cross-sectional, observational study. Cancer cachexia was diagnosed when there was weight loss ≥5% during the past 12 months and at least three of the five following conditions were present: decreased muscle strength, fatigue, anorexia, low Fat-Free Mass Index (FFMI) and abnormal laboratory findings. A quadratic discriminant analysis was conducted for the ability of PG-SGA to predict cachexia. RESULTS: A total of 4231 patients with cancer were included in this analysis, and 351 patients (8.3%) were diagnosed as having cachexia. The highest incidence of cachexia was found among patients with pancreatic cancer (32.5%), oesophageal cancer (21.5%) and gastric cancer (17.9%). Compared with patients without cachexia, patients with cachexia had a lower body mass index, FFMI, hand grip strength, total protein, prealbumin, albumin, haemoglobin and Karnofsky performance status (p<0.05), while they had a higher C reactive protein level and PG-SGA Score (4.71±3.71 vs 10.87±4.84, p<0.05). The best cut-off value for PG-SGA was 6.5, with 79.8% of sensitivity and 72.3% specificity for cachexia, and the area under the receiver operating characteristic curve was 0.846 (95% CI 0.826 to 0.866, p<0.001). CONCLUSIONS: PG-SGA is a highly specific tool that can be used to screen patients for cancer cachexia.
Subject(s)
Malnutrition , Neoplasms , Cachexia/complications , Cachexia/etiology , Cross-Sectional Studies , Early Detection of Cancer/adverse effects , Hand Strength , Humans , Malnutrition/etiology , Neoplasms/complications , Nutrition Assessment , Nutritional Status , Weight LossABSTRACT
BACKGROUND: Completing Patient-Generated Subjective Global Assessment (PG-SGA) questionnaires is time consuming. This study aimed to develop and validate an easy-to-use modified PG-SGA (mPG-SGA) for cancer patients. METHODS: Seventy professionals assessed the content validity, comprehensibility, and difficulty of the full PG-SGA. A survey including the PG-SGA and other questionnaires was completed by 34 071 adult hospitalized cancer patients with first cancer diagnosis or recurrent disease with any tumour comorbidities from the INSCOC study. Among them, 1558 patients were followed for 5 years after admission. Reliability and rank correlation were estimated to assess the consistency between PG-SGA items and to select mPG-SGA items. The external and internal validity, test-retest reliability, and predictive validity were tested for the mPG-SGA via comparison with both the PG-SGA and abridged PG-SGA (abPG-SGA). RESULTS: After deleting items that more than 50% of professionals considered difficult to evaluate (Worksheet 4) and items with an item-total correlation <0.1, the mPG-SGA was constructed. Nutritional status was categorized using mPG-SGA scores as well-nourished (0 points) or mildly (1-2 points), moderately (3-6 points), or severely malnourished (≥7 points) based on the area under curve (0.962, 0.989, and 0.985) and maximal sensitivity (0.924, 0.918, and 0.945) and specificity (1.000, 1.000, and 0.938) of the cut-off scores. The external and internal validity and test-retest reliability were good. Significant median overall survival differences were found among nutritional status groups categorized by the mPG-SGA: 24, 18, 14, and 10 months for well-nourished, mildly malnourished, moderately malnourished, and severely malnourished, respectively (all Ps < 0.05). Neither the PG-SGA nor the abridged PG-SGA could discriminate the median overall survival differences between the well-nourished and mildly malnourished groups. CONCLUSIONS: We systematically developed and validated the mPG-SGA as an easier-to-use nutritional assessment tool for cancer patients. The mPG-SGA appears to have better predictive validity for survival than the PG-SGA and abridged PG-SGA.