International Journal of Cancer最新文献

The precise delivery of drugs to tumor sites and the thermoresistance of tumors remain major challenges in photothermal therapy (PTT). Somatostatin receptor 2 (SSTR2) is proposed as an ideal target for the precise treatment of SCLC. We developed a targeting nano-drug delivery system comprising anti-SSTR2 monoclonal antibody (MAb) surface-modified nanoparticles co-encapsulating Cypate and gambogic acid (GA). The formed SGCPNs demonstrated excellent monodispersity, physiological stability, preferable biocompatibility, and resultant efficient photothermal conversion efficacy. SGCPNs were quickly internalized by SSTR2-overexpressing SCLC cells, triggering the release of GA under acidic and near-infrared (NIR) laser irradiation environments, leading to their escape from lysosomes to the cytosol and then diffusion into the nucleus. SGCPNs can not only decrease the cell survival rate but also inhibit the activity of heat shock protein 90 (HSP90). SGCPNs can be precisely delivered to xenograft tumors of SSTR2-positive SCLC in vivo. Upon NIR laser irradiation, therapy of SGCPNs showed significant tumor regression. In conclusion, SGCPNs provide a new chemo-photothermal synergistic treatment strategy for targeting SCLC.

In order to explore the association between meat consumption and gastrointestinal/colorectal cancer (CRC) risk and to estimate the Israeli population attributable fraction (PAF), we conducted a collaborative historical cohort study using the individual participant data of seven nutritional studies from the past 6 decades. We included healthy adult men and women who underwent a nutritional interview. Dietary assessment data, using food-frequency or 24-h recall questionnaires, were harmonized. The study file was linked to the National Cancer and death registries. Among 27,754 participants, 1216 (4.4%) were diagnosed with gastrointestinal cancers and 839 (3.0%) with CRC by the end of 2016. Using meta-analysis methods applied to Cox proportional hazard models (adjusted for daily energy intake, sex, age, ethnic origin, education and smoking),100 g/day increments in beef, red meat and poultry consumption, and 50 g/day increment in processed meat consumption were associated with hazard ratios (HRs) and 95% confidence intervals of 1.46 (1.06-2.02), 1.15 (0.87-1.52), 1.06 (0.89-1.26), and 0.93 (0.76-1.12), respectively, for CRC. Similar results were obtained for gastrointestinal cancer, although red meat consumption reached statistical significance (HR = 1.27; 95%CI: 1.02-1.58). The PAFs associated with a reduction to a maximum of 50 g/day in the consumption of red meat were 2.7% (95%CI: -1.9 to 12.0) and 5.2% (0.3-13.9) for CRC and gastrointestinal cancers, respectively. Reduction of beef consumption to a maximum of 50 g/day will result in a CRC PAF reduction of 7.5% (0.7%-24.3%). While beef consumption was associated with gastrointestinal/CRC excess risk, poultry consumption was not. A substantial part of processed meat consumption in Israel is processed poultry, perhaps explaining the lack of association with CRC.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, N^ε-[carboxy-methyl]lysine (CML), N^ε-[carboxy-ethyl]lysine (CEL) and N^δ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (P_interaction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HR_Q5vs.Q1 = 1.67, 95% CI: 1.21-2.30, P_trend = .02) or any cause (HR_Q5vs.Q1 = 1.38, 95% CI: 1.05-1.83, P_trend = .09). These associations tended to be stronger among cases with diabetes (P_interaction = .03) and pre-diabetes (P_interaction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First-line immunotherapy (IO)-based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real-world data confirming the adequate first-line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO-based combinations within the ARON-1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non-sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first-line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non-sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6-44.2) in sRCC and 35.3 months (95%CI 30.2-40.4) in non-sRCC patients (p = .013). The median progression-free survival (PFS) was longer in non-sRCC patients compared to sRCC (14.5 vs. 12.3 months, p = .064). In patients treated with first-line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p = .729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p = .606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO-based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted.

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

We aimed to investigate human papillomavirus (HPV) prevalence and genotype distribution and prognostic factors in vaginal cancer (VC). VC patients who received treatment between 1989 and 2020 were retrospectively reviewed. L1 general polymerase chain reaction (PCR) followed by HPV Blot (King Car, I-Lan, Taiwan) and E6 type-specific-PCR were performed for genotyping firstly. P16 and p53 immunohistochemistry staining was performed. Univariate and multivariate analyses identified predictors of clinical outcomes.79 VC patients were eligible for analysis. 73 patients (92.4%) were squamous cell carcinoma (SCC) and 6 (7.6%) as non-SCC. The median follow-up time was 134.3 months (range 0.9-273.4). Among nine initially HPV-negative cases, seven were identified as being positive through HPV16/18/45/52/58 whole-genome amplification followed by Sanger sequencing (WGASS). HPV DNA sequences were detected in 98.6% of SCC and 83.3% of non-SCC, respectively, with HPV16 (49.4%), HPV52 (15.2%) and HPV58 (8.9%) being predominant. Patients with paraaortic lymph node (LN) metastasis had a 5-year cancer-specific survival (CSS) rate of 0%. Multivariate analysis revealed that only p16 and stage were significantly correlated with prognosis. Variables with strong correlations (p16- and HPV-positivity, LN metastasis and stage), were included in models 2-5 alternatively. Stage III/IV (hazard ratio [HR] = 3.64-4.56) and LN metastasis (HR = 2.81-3.44) were significant negative predictors of CSS, whereas p16-positivity (HR = 0.29-0.32) and HPV-positivity (HR = 0.14) were related to better prognosis. In conclusion, 97.5% of VCs were HPV-positive with WGASS. Stage III/IV and LN metastasis were significant negative predictors, whereas p16- and HPV-positivity were significantly associated with better prognosis.

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. The clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than the clone-extinct ones. In contrast to the clone-extinct patients, the clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in the clone-extinct patients. The number of T cell receptor-neoantigen interactions was higher in the clone-extinct patients than in the clone-persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone-extinct patients. In conclusion, we identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT.