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Background: The combination of programmed cell death protein 1 (PD-1) inhibitors and chemotherapy has shown promising results in the treatment of various malignancies. This meta-analysis aims to evaluate the effectiveness and safety of combing PD-1 inhibitor with chemotherapy in patients with advanced NPC.

Methods: A thorough search of the literature was carried out using comprehensive methods. The assessed outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).

Results: This meta-analysis included seven studies with a total of 1204 patients. The use of a combination therapy involving PD-1 inhibitor and chemotherapy demonstrated significant improvements in OS (HR=0.60, 95%CI: 0.45, 0.80; P<0.001), PFS (HR=0.51, 95%CI: 0.42, 0.61; P<0.001), ORR (RR=1.23, 95%CI: 1.07, 1.40; P=0.003) and DCR (RR=1.13, 95%CI: 1.03, 1.23; P=0.003) compared to other treatments in patients with advanced NPC. Subgroup analyses based on PD-1 inhibitor type, chemotherapy regimen and study design indicated that these factors influenced OS but not PFS. Prognostic factor analysis consistently demonstrated a PFS benefit associated with the combination treatment across various patient subgroups. The incidences of AEs, grade 3 or higher AEs were comparable between the two groups. However, the combination group was significantly more likely to discontinue treatment because of AEs.

Conclusion: This meta-analysis provides evidence supporting the effectiveness and safety of PD-1 inhibitor plus chemotherapy in advanced NPC. The combination therapy showed superior outcomes in terms of OS, PFS, ORR, and DCR.

Objective: To evaluate short-term (2008-2017) cancer incidence trends in Italy for individuals aged 20-49 years by sex and cancer type.

Methods: Observational study from population-based data collected by 20 Italian Cancer Registries, covering 33% of the Italian population. The age-standardized incidence rates (ASRs), overall and stratified by area, sex, cancer site or type, and major age groups (i.e., 20-39, 40-49), were computed.

Results: In 2008-2017, cancer incidence rates were almost two times higher in Italian women aged 20-49 than in age-corresponding men (202.2 vs 112.4 per 100,000) on account of elevated rates of breast and thyroid cancers. Contrasting trends emerged according to cancer sites/types. ASRs for female breast cancer increased steadily from 2008 (82.4) to 2014 (86.2) and remained unchanged thereafter (i.e., 86.5 in 2017). During the study period, there was an increase for testicular cancer, skin melanoma in both sexes, and thyroid cancer until 2013 (followed by a slight decrease from 2014 to 2017). Conversely, ASRs consistently declined for colorectal cancer and were substantially stable or slightly decreasing for cervix uteri (from 8.1 to 7.7), ovary (from 7.5 to 6.9) and non-Hodgkin lymphoma (from 8.3 to 7.6 in men and from 5.9 to 5.5 in women).

Conclusions: Study findings do not support a unique temporal pattern for the incidence of early-onset cancer in Italy until 2017, as reported in other countries. Increases in incidence documented in both sexes for some tumor sites was counterbalanced by a decrease in other sites. The importance of supporting prevention strategies from the youngest of ages must be emphasized, and the role of anticipated screening should be carefully addressed.

Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRAS^G12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRAS^G12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRAS^G12D and KRAS^G12V are more common than KRAS^G12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRAS^G12C inhibitors.

Lynch syndrome is the most common hereditary cancer predisposition, accounting for 1-5% of colorectal cancer cases, and is driven by germline mutations in DNA mismatch repair genes. Despite established diagnostic criteria, such as the Amsterdam guidelines, Lynch syndrome remains largely underdiagnosed. To address this gap, universal tumour screening has been introduced for all newly diagnosed cases of colorectal cancer and endometrial cancer, significantly improving early detection. The surgical management of colorectal cancer in patients with Lynch syndrome remains controversial. While extended colectomy reduces the risk of metachronous colorectal cancer, surgical strategies must be carefully individualised based on patient-specific factors. Chemoprevention with aspirin has shown promise in reducing the risk of colorectal cancer, with ongoing trials investigating optimal dosing. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionised the treatment of Microsatellite Instability-High/deficient Mismatch Repair colorectal cancer, offering durable responses and significant survival benefits. In addition, the neoadjuvant use of immune checkpoint inhibitors is paving the way for non-surgical interventions, potentially transforming the management of colorectal cancer in patients with Lynch syndrome. A multidisciplinary approach and continued research are essential to optimise cancer prevention, treatment and quality of life for people with Lynch syndrome.

Lynch syndrome is a genetic condition predisposing to cancer, particularly colorectal cancer and endometrial cancer, due to germline mutations in MisMatch Repair genes. More rarely, Lynch syndrome is the result of a constitutional MLH1 promoter methylation. This review summarizes the current knowledge about the role of this epigenetic mechanism in the Lynch syndrome. Universal Tumor Screening, performed on tumoral specimens to identify features suggestive of Lynch syndrome, shows the same features both in the case of sporadic cancers and Lynch syndrome-cancers due to a constitutional MLH1 methylation: microsatellite instability, deficiency of MisMatch Repair proteins, and methylation of MLH1 gene. Over the last few years, identifying methylation of MLH1 promoter on tumors was used to discern sporadic tumors from Lynch syndrome tumors: the methylation of the MLH1 promoter was usually explained as a somatic event and this could lead to a missed diagnosis of some Lynch syndrome cases. Therefore, establishing criteria to decide when to test patients for constitutional MLH1 methylation is urgent. In the case of microsatellite instability/deficiency of MisMatch Repair tumors with MLH1 methylation, a germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently from family history. The prevalence of germline MLH1 epimutations is not precisely known and possibly underestimated. The associated cancer risk could be similar to that due to a MLH1 sequence variant. MLH1 epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance. On the contrary, primary epimutations are often "de novo" events, and their transmission does not follow Mendelian rules.

Background: Lynch syndrome (LS), an autosomal dominant disorder resulting from germline pathogenic variants in DNA mismatch repair genes, poses an elevated risk of developing different types of cancer, particularly colorectal and endometrial. Early identification of LS individuals is vital for implementing preventive measures. This study aims to assess the adherence rate of LS individuals to colorectal surveillance and identify influencing factors.

Methods: Data from the Hereditary Digestive Tumors Registry at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from 1995 to 2018 were analyzed. The study included 397 LS patients, as categorized based on adherence to surveillance. Statistical analyses, including multivariable logistic regression, were employed to identify factors influencing adherence.

Results: Out of 397 LS patients, 305 (76.8%) completed surveillance, and 92 (23.2%) were lost during surveillance. Fifty-two patients developed colorectal cancer during the surveillance: 34 among patients who completed the surveillance and 18 among those who did not (p<0.036). Factors positively influencing adherence included genetic counseling and higher education, while the distance from the referral center had a negative impact. The survival rate was 83.5% at 240-months.

Conclusions: This study emphasizes the importance of adhering to a regular colorectal surveillance program for LS individuals. Genetic counseling and higher education emerged as a crucial factor positively affecting adherence. The negative impact was observed for geographical distance from the referral center.

Population-based screening programs aim to detect the disease at an early stage, so less treatment will be needed as well as having better oncological outcomes when diagnosed earlier. In the majority of European countries, breast cancer screening programs are designed based on women age.Meta-analysis of randomized clinical trial data demonstrates a reduction in the relative risk of breast cancer mortality due to screening, which has been estimated to be approximately 20%.One of the controversies about the population breast screening programs is that age-based screening ignores women's individual breast cancer risk. Identification of high-risk women may intensify the screening measures and will optimize the population screening programs to align them to individual risks.Family history of breast cancer is one of the risk factors to consider along with the recently developed polygenic risk scores to stratify women into a risk group. Other factors to assess risk include: mammographic breast density; B3 lesions with atypia in breast biopsy specimens; hormonal and lyfestyle and, potentially, epigenetic markers. Still, there are some difficulties in validating these factors and reflecting the interaction between risk factors in the models.Ongoing screening trials (e.g., WISDOM and MyPebs) are currently evaluating the clinical acceptability and utility of risk-stratified screening programs in the general population, and should provide valuable information for the possible implementation of such programs.Communication of complex risk information to the women, as well as assessing ethical concerns need to be addressed before implementation of risk stratified programs.

Introduction: Tumour BRCA1/2 sequencing has progressively increased along with the expanding indications for poly(ADP-ribose) polymerase inhibitors. In our study, we investigated the feasibility and outcomes of a workflow for the identification of germline carriers based on tumour sequencing results.

Methods: Between April 2020 and December 2022, BRCA1/2 tumour testing results from 2020 patients were reviewed. Analysed tumours included: 323 ovarian, 104 breast, 314 pancreas-biliary, 87 prostate, 374 gastrointestinal, 309 lung, and 509 less common histologies. Testing was performed through small (only BRCA1/2, 16%) or comprehensive (>50 genes) next-generation sequencing panels (84%). Patients with pathogenic/likely pathogenic variants were referred for genetic counselling and germline testing.

Results: Tumour BRCA1/2 pathogenic variants were identified in 145 patients (7%). The pathogenic variant frequency ranged between 23% (75/323 ovarian) and 3.5% (11/314 pancreas-biliary). The highest frequency was observed in high-grade ovarian carcinomas (27%, 64/235). By 30 June 2023, 79 out of 145 patients (54%) underwent subsequent genetic counselling and germline testing. In these patients, mostly affected with ovarian carcinoma (67%, 53/79), 48 were confirmed germline pathogenic variants (61%).

Conclusions: In our tumour-to-germline testing approach, we observed the BRCA1/2 pathogenic variant frequency reported in other large unselected ovarian cancer cohorts, thus confirming its effectiveness in identifying putative germline carriers irrespective of eligibility for germline testing. As the range of tumours subjected to genetic testing broadens, this approach is expected to also be effective in other tumour settings for enhancing the identification of carriers, reducing the burden on genetic services, and avoiding unnecessary concerns related to germline testing.

Background and aims: Recent studies have shown that combining polygenic risk score (PRS) and carrier status for germline pathogenic variants in colorectal cancer (CRC) susceptibility genes (e.g. MLH1, MSH2, MSH6, PMS2) may increase the success of predicting CRC. This study aims to examine the prediction performance of CRC in Norwegian data using the status of pathogenic variants in the mismatch repair (MMR) genes with the available PRS models in the literature.

Methods: Our Norwegian cohort included 805 CRC cases, 86 of which carried a pathogenic variant in one of the MMR genes. As a control group, we included 8856 individuals without a cancer diagnosis, of which 179 were carriers for a pathogenic MMR variant. We first conducted a broad experiment to determine the best-performing PRS model for the Norwegian cohort. Afterwards, we established a combined analysis with the PRS model and the status of MMR genes.

Results: Among 10 PRS models tested, the best-performing PRS model for the Norwegian cohort included 204 single nucleotide polymorphisms (SNPs) (AUC=0.604). We also observed that the combined model of PRS and the status of MMR significantly improved the prediction performance.

Conclusion: The findings suggest that a combined model of a PRS and the status of MMR genes improves the prediction performance of CRC in Norwegian data.

Background: The need for predictive factors regarding the response to immune checkpoint inhibitors (ICIs) is increasing. Recent research indicates that an enhanced response to ICIs is associated with a higher body mass index (BMI). This study aims to evaluate the relationship between response to ICIs and BMI in solid tumors.

Methods: We retrospectively analyzed patients with advanced cancer treated with ICIs at one academic center. We compared the treatment responses of patients classified as underweight/normal weight (BMI <25) and overweight/obese (BMI ⩾ 25) according to their BMI at the initiation of ICI treatment. After excluding underweight patients, we also compared the progression-free survival (PFS) and overall survival (OS) of normal-weight, overweight, and obese patients.

Results: Overall, 113 patients were evaluated. Forty-seven (41.6%) patients had BMI <25 and 66 (58.4%) patients had a BMI ⩾ 25. In underweight/normal patients, median PFS was 7.7 months (95% CI: 4.7-10.6) while it was 8.0 months (95% CI: 4.1-11.9) in overweight/obese patients (HR 1.16, 95% CI: (0.76-1.75), p=0.477). In underweight/normal patients, the median OS was 21.7 months (95% CI: 11.6-31.7) compared to 18.7 months (95% CI: 12.7-24.6) in overweight/obese patients (HR 1.06, 95% CI: (0.69-1.64), p=0.774). The objective response rate (ORR) was 38.3% in underweight/normal patients and 34.8% in overweight/obese patients (p = 0.707). After excluding underweight patients, there were also no significant differences in PFS (p = 0.914), OS (p = 0.642), and ORR (p = 0.909) between patients of normal weight, overweight, and obesity.

Conclusion: Our research found no correlation between BMI and response to ICIs. Additional prospective studies are necessary to assess the effect of BMI on the response to ICIs.