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Neoadjuvant chemo-immunotherapy, radiotherapy and concurrent capecitabine achieved promising efficacy in locally advanced ESCC. Further investigation is warranted.
New England Journal of Medicine, Volume 392, Issue 12, Page 1216-1227, March 27, 2025.
In an observational study, statins were associated with lower risk for these outcomes among patients with chronic liver disease.
Ductal carcinoma in situ (DCIS) is defined as “a neoplastic proliferation of cells within the ductal-lobular structures of the breast that has not penetrated the myoepithelial basement membrane interface.” DCIS is considered to be a nonobligate precursor to invasive cancer, such that the purpose of therapy is primarily to avoid the occurrence of invasive cancer. To achieve this end, DCIS has historically been treated in the same way as invasive breast cancer: surgery, often followed by radiation and antiestrogen therapy (if the DCIS is hormone receptor positive). Advances in mammography and the increasing use of magnetic resonance imaging for breast cancer screening have led to the detection of smaller, low-risk lesions. Growing evidence suggests that low-risk DCIS is unlikely to develop into invasive cancer, leading to a question of whether DCIS can be managed with active surveillance alone, thereby avoiding treatment-associated morbidity.
This randomized noninferiority trial assesses the effect of a strategy of active monitoring vs guideline-concordant care on 2-year risk of ipsilateral invasive breast cancer among women with low-risk breast ductal carcinoma in situ.
Objectives
While there is growing evidence that physical activity reduces the risk of hepatocellular carcinoma (HCC), the impact of occupational physical activity and sedentary behaviour remains unclear. This study aimed to investigate the associations between occupational physical activity and sedentary behaviour and HCC risk.
Design
Matched case-control study.
Setting
Nationwide multicentre, hospital-inpatient data set in Japan, from 2005 to 2021.
Participants
The study included 5625 inpatients diagnosed with HCC and 27 792 matched controls without liver disease or neoplasms. Participants were matched based on sex, age, admission date, and hospital.
Primary measures
The association between levels of occupational physical activity (low, medium, high) and sedentary time (short, medium, long) with the risk of HCC.
Secondary measures
Stratification of HCC risk by viral infection status (hepatitis B/C virus), alcohol consumption levels and the presence of metabolic diseases (hypertension, diabetes, dyslipidaemia, obesity).
Results
High occupational physical activity was not associated with HCC caused by hepatitis B/C virus infection in men. In women, high occupational physical activity was associated with a reduced risk of non-viral HCC, with ORs (95% CIs) of 0.65 (0.45–0.93). Among patients with non-viral HCC, medium occupational physical activity combined with medium alcohol intake further decreased the HCC risk in men with an OR of 0.70 (0.50–0.97), while high occupational physical activity combined with lowest alcohol intake decreased the HCC risk in women with an OR of 0.69 (0.48–0.99). Men and women with medium sedentary time had a lower HCC risk compared with those with long sedentary time, with ORs of 0.88 (0.79–0.98) in men and 0.77 (0.62–0.97) in women, respectively. In patients without viral infection or alcohol use, medium sedentary time reduced the HCC risk associated with fatty liver disease without comorbid metabolic diseases in women.
Conclusions
High levels of occupational physical activity and/or medium periods of sedentary time are associated with a reduced risk of HCC, particularly non-alcoholic steatohepatitis.
Objectives
Cough occurring in patients with renal cell carcinoma (RCC) was first described in 1935 and is a frequently discussed symptom on patient forums. We aimed to systematically review the available evidence to explore the prevalence and risk factors for persistent cough in patients diagnosed with RCC to establish whether cough could be a presenting symptom of RCC.
Design
This epidemiological systematic review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement 2020.
Data sources
Medline, Embase, Science Citation Index, The Cochrane Library, ClinicalTrials.gov and the WHO trials register were searched without language restrictions until 1 June 2023.
Eligibility criteria for selecting studies
We included articles of all study designs reporting cough in patients (18 years or older) with RCC attributed to the disease itself or to treatment.
Data extraction and synthesis
Data from included articles was extracted using a preprepared and piloted form, and quality assessment was conducted independently by two authors. The risk of bias was assessed in studies other than case reports or case series using the critical appraisal instrument for studies reporting prevalence data. Narrative techniques were used for data analysis and, where appropriate, meta-analysis using a fixed-effects model was performed.
Results
Of 509 studies screened, 105 full-text articles were assessed, with 46 papers subsequently excluded, resulting in 59 analysed in depth. There were 105 patients with RCC reported as having a cough due to the disease itself within 30 case reports and 8 case series. When present, most coughs were described as persistent and dry in nature. The cause of cough was attributed to various aetiologies including pulmonary and endobronchial metastasis and paraneoplastic syndromes. Studies reporting patients with RCC developing a cough because of systemic treatment were heterogeneous. Two studies with 238 patients on temsirolimus and 230 on interferon-α (IFN-α) were suitable for meta-analysis using a fixed-effects model. Patients on temsirolimus were more likely to develop a cough than those on IFN-α (OR 1.95 with a 95% CI of 1.05 to 3.63, overall effect Z=2.12 (p=0.03), I2=0%).
Conclusion
Cough can occur in patients with RCC, as part of the disease pathogenesis, as an adverse effect of systemic treatment or due to unrelated causes such as pre-existing conditions (eg, asthma). Further research is required to determine the true prevalence and cause and to assess whether cough could be a presenting symptom for RCC.
PROSPERO registration number
CRD42022302962.
Objective
Atezolizumab plus bevacizumab demonstrates a significant improvement in overall survival and progression-free survival compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). The combined usage of these two medications could result in substantial consumption of resources, primarily due to their exceptionally high costs. The current study aims to evaluate the cost-effectiveness of atezolizumab plus bevacizumab as a first-line treatment for advanced HCC from the perspective of payers in developed and developing countries.
Design
A partitioned survival model was constructed to evaluate the cost-effectiveness of atezolizumab plus bevacizumab versus sorafenib as a first-line treatment for advanced HCC. The efficacy and safety data incorporated within the model were derived from the IMbrave150 trial. Costs and utilities were extracted from published sources.
Interventions
Atezolizumab plus bevacizumab versus sorafenib.
Outcome measures
Estimates were calculated for costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER) for both treatment strategies. One-way sensitivity, probabilistic sensitivity, expected value of perfect information (EVPI), subgroup and scenario analyses were conducted.
Results
The combination therapy of atezolizumab and bevacizumab results in an additional 0.72 life-years/0.57 QALYs in the USA and 0.64 life-years/0.47 QALYs in China compared with standard sorafenib treatment, although with a significant increase in costs, yielding an average ICER of US$253 247.07/QALY in the USA and US$181 552.71/QALY in China. The probability sensitivity analysis indicated that atezolizumab plus bevacizumab demonstrated a 13.60% likelihood of cost-effectiveness in the USA, whereas this likelihood is negligible (0%) in China. The expected value of uncertainty, as quantified by the EVPI, was estimated at approximately US$3658.41/patient in the USA and US$0/patient in China. The ICER was most sensitive to the cost of subsequent treatment in the USA, and most sensitive to the cost of atezolizumab in China. In scenario analyses, the atezolizumab plus bevacizumab treatment becomes favourable when the cost of atezolizumab decreases to 67.85% and 18.45% of its original price in the USA and China, respectively.
Conclusions
The atezolizumab plus bevacizumab is unlikely to be cost-effective compared with sorafenib for patients with unresectable HCC in the context of the USA and China. The implementation of significant reductions in drug prices may render the treatment economically viable.
Background
Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).
Objective
We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC).
Design
Hepatocyte-specific Tm6sf2 knockout (Tm6sf2 hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance.
Results
TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific Tm6sf2 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of Tm6sf2 knockout was verified in orthotopic MASLD-HCC mice, while mice bearing Tm6sf2-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-)+CD8+ T cells in the tumours of Tm6sf2 hep mice and orthotopic Tm6sf2 knockout mice, while the tumour-suppressive effect of Tm6sf2 was abolished after depleting CD8+ T cells. The correlation between TM6SF2 and CD8+ T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-B signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8+ T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of Tm6sf2 knockout in mice. Moreover, introducing Tm6sf2 by adenovirus improved immunotherapy response against MASLD-HCC in mice.
Conclusion
Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8+ T cells via NF-B-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.
Recently, we were intrigued by a recent study by Montironi et al,1 in which they discovered that an inflamed subclass in hepatocellular carcinoma (HCC) patients is associated with a response to immunotherapy. The authors used a 20-gene signature to distinguish these patients and further found different immune infiltration between inflamed and non-inflamed class at the bulk level. We commend the authors for undertaking this study, which holds significant clinical implications. We also observed that Li et al2 have validated the predictive value of inflamed class in two additional RNA-seq datasets from patients who received anti-PD1 therapy. However, the use of combination immunotherapy, which includes dual immune checkpoint inhibitors or is combined with anti-VEGF agents, has become a growing trend in HCC.3–6 Here, we first performed unsupervised clustering on the RNA-seq data from 289 patients enrolled in the…
Background
Genomic screening uncovered interferon-gamma (IFN) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood.
Objective
We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC).
Design
We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial (NCT03419481) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems.
Results
HCC patients showing higher HDAC1/2/3 expressions exhibited deficient IFN signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFN-responsive genes. Intratumoural recruitment of IFN+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFN responses.
Conclusion
Our immunoepigenetic strategy harnesses IFN-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance (NCT05873244).
This phase 1 nonrandomized clinical trial evaluated the safety and efficacy signaling of combined pembrolizumab and mRNA-2752 to treat patients with high-risk ductal carcinoma in situ.
This secondary analysis of a randomized clinical trial compares the efficacy of superficial curettage followed by imiquimod cream, 5%, with that of surgical excision among patients with nodal basal cell carcinoma at 5-year follow-up.
This secondary analysis of the COMET randomized clinical trial examines patient-reported outcomes at baseline and over time in patients with low-risk ductal carcinoma in situ randomized to receive either active monitoring or guideline-concordant care.
Objectives
Our study investigated the impact of oesophageal cancer and its treatments on work productivity, leisure time, household chores and informal care in Switzerland. We assessed indirect costs for patients treated at different stages of adenocarcinoma or squamous cell carcinoma of the oesophagus.
Design and setting
A retrospective, non-interventional survey was conducted among patients diagnosed with early or advanced oesophageal cancer in Switzerland. Between January 2023 and October 2023, 126 patients participated from seven clinical centres across German, French and Italian language regions.
Outcome measure
Self-reported lost time over a 4-week period, which was monetised to estimate indirect costs using respondents’ approximate earnings derived from national statistics.
Results
Of the 126 patients, 24 (19.0%) were disease-free at the time of the study, while 15.1% of patients were in stage I, 13.5% in stage II, 27.0% in stage III and 25.4% in stage IV. Most patients, across age groups and disease stages, reported no impact on their leisure time (62.2%), household chores (70.3%) or informal care needs (78.4%) in the last 4 weeks. For those affected, the mean loss of time was 9.5 hours per week for leisure (n=28) and 13.3 hours for household chores (n=21). Additionally, patients received an average of 11.8 hours of informal care per week (n=16). Among the patients who were employed at the beginning of the 4-week recall period (n=25), 57.1% reduced the degree of employment and/or missed work due to the disease and its treatments during that time, while 46.7% experienced presentism (decreased productivity at work). The estimated mean indirect costs over a 4-week period was (Swiss Francs) CHF2005 (1874) per patient, with loss of work productivity being the largest contributor.
Conclusion
Oesophageal cancer in Switzerland affects patients’ professional and personal lives, resulting in lost time and informal caregiving, leading to societal costs.
This JAMA Patient Page describes renal cell carcinoma and its risk factors, signs and symptoms, treatment, and prognosis.
