Cancer Medicine最新文献

Background

Germline genomic sequencing (GS) is increasingly offered to children with cancer. To optimize integration into routine care, assessment of implementation barriers and a better understanding of healthcare professionals' perspectives and experiences are needed.

Methods

Healthcare professionals delivered trio germline GS to newly diagnosed pediatric and adolescent patients with cancer via the PREDICT completed questionnaires with qualitative and quantitative items. Each study site recorded reasons for eligible families' nonenrolment in PREDICT to identify barriers to recruitment. Quantitative data were analyzed via descriptive statistics, whereas qualitative data underwent inductive content analysis, with results integrated for interpretation.

Results

Thirty-three healthcare professionals participated, including 23 oncology professionals and 10 genetic professionals. Healthcare professionals perceived PREDICT as beneficial to participating and future families, and that perceptions of personal benefit and altruism were drivers of family uptake. Concerns included workforce capacity and potential family distress given the trio design and high-stress diagnosis setting. Barriers to recruitment related to clinical decision-making, family factors, and logistics. Although most rated their genetics/genomics knowledge as “good,” regarding germline results, few were “very confident” interpreting (29%), explaining (32%), making treatment recommendations (9.7%), and providing psychosocial support to families (29%). They acknowledged a need for further training in these areas for trainees; yet, fewer were interested in training for themselves.

Conclusion

Successful implementation of routine germline GS will require targeted strategies to address logistical issues and alleviate potential negative psychosocial impacts for families. Recognizing the escalating demand on genetics experts, upskilling of the current workforce and involvement of a broader spectrum of healthcare professionals are warranted.

Background

Financial toxicity is common among families of pediatric patients with cancer. However, the availability of survey and/or screening instruments specific to pediatric family financial toxicity is limited.

Methods

A two-round cross-sectional survey was conducted in Shandong Province, China. We combined classical test theory (CTT) and item response theory (IRT) to validate items of the caregiver-reported scale for pediatric cancer financial toxicity (CRS-PCFT) after Delphi. The scale structure, reliability, and validity were determined and validated by exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The threshold was discussed based on the correlations between CRS-PCFT and socio-factors.

Findings

A 16-item initial scale was determined after Delphi. The data from 206 pilot survey samples was used to select and validate items, and a 10-item CRS-PCFT was developed. The scale showed satisfactory reliability and validity based on data from 398 formal survey samples. When the CRS-PCFT scores were into high and low toxicity groups by the median, they were significantly correlated with education (r = −0.284, p < 0.0001), household income (r = −0.253, p < 0.0001), work status (r = −0.173, p = 0.001), and cancer stages (r = 0.147, p = 0.003).

Interpretation

CRS-PCFT demonstrates robust reliability and validity and makes it more accurate to obtain the pediatric cancer financial toxicity conditions. Additional research should be done to validate CRS-PCFT.

Background

Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.

Methods

NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies. Arm M utilized twice weekly oral SEL and intravenous nivolumab (NIVO). Arm N utilized weekly oral SEL with NIVO plus ipilimumab (IPI). The primary objective of this study was to evaluate the safety of SEL + NIVO and SEL + NIVO+IPI. Secondary objectives included determining the objective response rate (ORR) and progression-free survival (PFS).

Results

Twenty-nine patients were enrolled in the study, of which 26 (90%) had clear cell RCC (ccRCC). Most patients (72%, n = 21) had prior systemic therapies. All patients (100%) developed at least one treatment-emergent adverse event, and 93% had a treatment-related adverse event (TRAE). Grade ≥ 3 TRAE occurred in 31% of patients, including 10% with hyponatremia, 7% with neutropenia, and 7% with thromboembolic events. At a median follow-up of 12.4 months, the ORR in 27 patients evaluable for response was 19% (n = 5). An additional 17 patients (63%) had stable disease (SD) as the best response. The median PFS for the overall cohort was 14.5 months (95% CI 5.2–17.4 months; SEL + NIVO+IPI: 12.2 months, SEL + NIVO: 14.5 months). The median overall survival was 27.8 months (95% CI 15.3–32.5; SEL + NIVO+IPI: unreached, SEL + NIVO: 21.3 months).

Conclusions

SEL in combination with NIVO or NIVO+IPI had a potentially favorable safety profile and showed modest clinical activity in patients with advanced renal cell carcinoma.

Trial Registration: This clinical trial was registered on clinicaltrials.gov (NCT02419495)

Background

The recurrence patterns of different types of pathologic regression of the primary tumor and lymph nodes in patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiotherapy (NCRT) are little known, especially in ypT0N+ patients.

Methods

We included 582 patients with ESCC who had esophagectomy after NCRT or neoadjuvant radiotherapy (NRT) from 3 institutions. The patients were divided into 4 groups: ypT0N0, ypT0N+, ypT+N0, and ypT+N+ according to the type of pathological regression of the primary tumor and lymph nodes. Survival, recurrence pattern and timing, and potential prognostic factors were compared.

Results

A total of 179 patients were classified as ypT0N0, 227 patients as ypT + N0, 45 patients as ypT0N+, and 131 patients as ypT + N+. The median follow-up was 31.7 months in all patients. The restricted mean survival time (RMST) of ypT0N0, ypT + N0, ypT0N+, and ypT + N+ patients decreased sequentially (70.64, 63.84, 55.93 and 39.96 months) and the recurrence rates increased sequentially (22.3%, 29.5%, 44.4% and 54.2%). Both the overall survival (OS) and recurrence-free survival (RFS) in the ypT0N+ group were significantly lower than those in the ypT0N0 group (HR: 2.226, p = 0.007; HR: 2.271, p = 0.003). The distant metastasis (DM) pattern in ypT0N+ was similar to that of ypT + N+, and higher than that of ypN0 (25.6% vs 14.3%, HR: 1.970, p = 0.040).

Conclusions

ESCC patients with various pathological regression types after receiving NCRT or NRT had significantly different survival rates. ypT0N+ patients had a lower survival rate and higher DM rate than ypT0N0 patients. For these lymph node-positive patients, adjuvant chemotherapy does not appear to improve their prognosis.

Background

Immunogenic cell death (ICD) can be triggered by various therapies to induce anti-tumor immune responses, significantly enhancing treatment effectiveness, and is widely utilized in tumor immunotherapy.

Methods

LUAD data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) validated ICD-related molecular subtypes via consensus clustering. Clinical features, ICD genes, driver genes, mutations, tumor microenvironment, immune checkpoints, and drug sensitivity were compared. RT-qPCR, Western blot, immunofluorescence, ELISA, flow cytometry, and tube formation assays validated findings.

Results

Differential expression of 33 ICD genes was observed between tumor and normal tissues. These genes were clustered into two groups via consensus clustering and validated with GEO data. Prognostic analysis indicated superior outcomes in cluster 2 across TCGA and GEO cohorts. Significant disparities in clinicopathological characteristics like stage, gender, and age were noted between subtypes. Cluster 2 exhibited heightened expression of ICD-related genes, driver genes, immune checkpoints, and immune cells. Cluster 2 also showed increased sensitivity to chemotherapy drugs. IFNG overexpression in A549 and H1299 cells induced CRT exposure, HMGB1 release, and ATP secretion, thereby promoting dendritic cell maturation and enhancing CD8+ T cell function. Additionally, IFNG boosted tumor angiogenesis via HMGB1 pathways, which could be mitigated by HMGB1 inhibition.

Conclusion

Identification of novel ICD-related molecular subtypes holds promise for guiding personalized therapies, assessing prognosis, and predicting immunotherapy efficacy in LUAD. IFNG emerges as a potential prognostic biomarker and therapeutic target, influencing both the tumor microenvironment and angiogenesis. These findings offer new insights into therapeutic strategies targeting IFNG-mediated pathways in LUAD.

Background

Recent studies about human epidermal growth factor receptor 2 (HER2)-low values have garnered great interest among oncologists. We aimed to investigate whether HER2-low impacts the prognosis of early-stage breast cancer overall and in specific subgroups, explore differences in clinicopathologic markers, and examine the role of age in HER2-low prognostic stratification.

Materials & Methods

We conducted a retrospective analysis of 6920 HER2-negative breast cancer patients from the First Affiliated Hospital of Wenzhou Medical University (2010–2022). The study focused on the impact of HER2-low status (immunohistochemistry +1 or +2, in situ hybridization not amplified) on overall survival (OS), considering the age at diagnosis.

Results

Generally, HER2-low status correlated with less aggressive cancer indicators. No significant prognostic differences were observed between HER2-low and HER2-0 in the entire cohort, HR-positive, and HR-negative groups. However, in TNBC patients aged ≥ 65, HER2-low correlated with significantly better OS (HR = 0.45, 95% CI 0.24–0.83, p = 0.011), a finding consistent after multivariable adjustment (HR = 0.34, 95% CI 0.14–0.80, p = 0.014). In other subgroups, prognosis did not significantly correlate with HER2 status. The combination of HER2-low status and age plays a key role in prognostic stratification in TNBC. Patients aged ≥ 65 with HER2-0 had considerably poorer prognoses compared to other subgroups.

Conclusion

This extensive retrospective study demonstrates that HER2-low status cannot serve as an independent prognostic factor in the entire cohort, nor in the HR-positive and HR-negative groups individually. However, the combined factors of HER2-low status and age may indicate a potential contribution to the prognostic stratification of TNBC.

Background

Venadaparib, a novel poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated high PARP-1/2 selectivity over other PARP family members and exhibited strong PARP-trapping activity, effectively inhibiting tumor growth in homologous recombination deficient (HRD) cancer in vitro and in vivo.

Methods

This phase 1, dose-finding study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib as monotherapy in patients with advanced solid tumors that progressed after standard-of-care therapy. The study employed a conventional 3+3 design, with doses ranging from 2 mg/d to 240 mg/d.

Results

Among the 32 enrolled patients, the most common tumor types were breast (16 patients) and ovarian (12 patients) cancers. No dose-limiting toxicities (DLTs) were observed up to 240 mg/d. The most frequent grade 3 or 4 adverse events were anemia (50%), neutropenia (22%) and thrombocytopenia (6%). Tumor shrinkage by Response Evaluation Criteria in Solid Tumours (RECIST) was observed at doses ≥ 40 mg/d, regardless of BRCA mutation status.Two partial responses out of four ovarian cancer patients receiving venadaparib ≥ 40 mg/d were reported. Clinical benefit, defined as stable disease or partial response, was observed at the lowest tested dose. Venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg/d based on tumor samples. The recommended phase 2 dose (RP2D) was defined as 160 mg once daily.

Conclusions

Further studies are warranted to explore efficacy and safety of venadaparib in other tumor types and in combination with various agents, as well as to explore relevant biomarkers. (ClinicalTrials.gov ID: NCT03317743).

Purpose

To characterize trends and patterns in treatment characteristics and perioperative outcomes of patients with urothelial muscle-invasive bladder cancer (MIBC).

Materials and Methods

We utilized the National Cancer Database to assess trends and patterns in treatment modalities (radical cystectomy [RC] with or without neoadjuvant/adjuvant treatments, trimodal bladder-sparing treatment [trimodal treatment], and others) among MIBC patients diagnosed between 2004 and 2017. We also assessed trends and patterns of short-term post-surgery outcomes, including 30-day and 90-day mortality, and readmissions.

Results

Among 83,259 MIBC patients, those who received RC, trimodal treatment, and transurethral resection of bladder tumor (TURBT) plus chemotherapy were 34,715 (41.7%), 7,372 (8.9%), and 6,171 (7.4%), respectively. A substantial proportion (29,314; 35.2%) of MIBC patients received other treatments, including TURBT-only. From 2004 through 2017, the proportion of MIBC patients who utilized guideline-recommended treatments, whether RC (from 36.4% to 42.8%) or trimodal treatment (from 7.9% to 10.2%), increased. Among those who received RC, there was a substantial increase in neoadjuvant chemotherapy (NAC) utilization, from 7.8% to 29.4%. Conversely, utilization of RC without perioperative treatments decreased from 62.3% to 32.7%. There was a significant decrease in 30-day (2.8%–1.8%) and 90-day (7.1%–5.3%) mortality rates among RC recipients.

Conclusion

There was a shift in treatment modalities for MIBC, with increased utilization of RC with NAC. A decrease in post-surgery mortality rates may indicate improved outcomes, although the unmet need for NAC utilization requires further investigation.

Background and Objectives

Immune checkpoint inhibition (ICI) has revolutionized treatment for metastasized melanoma, but many patients remain unresponsive. Concerning potential adverse events, reliable biomarkers to predict ICI response are needed. In this context, neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR) have emerged. Liver metastases also limit ICI efficacy, correlating with diminished overall survival (OS) and progression-free survival (PFS) and may siphon activated T cells from the systemic circulation, creating an ‘immune desert state’. We evaluated the predictive role of NLR and dNLR for ICI response and the impact of liver metastases on systemic immunity and treatment efficacy.

Patients and Methods

In this single-center retrospective study, we included 141 stage IV melanoma patients undergoing ICI. NLR and dNLR were calculated from absolute neutrophil count, absolute lymphocyte count, and white blood cell count.

Results

Elevated NLR and dNLR were associated with poor response to ICI and inferior PFS. Patients with liver metastases exhibited higher NLR and dNLR levels and showed diminished response to ICI.

Conclusions

Elevated baseline NLR and dNLR predict poor response to ICI and PFS in stage IV melanoma. Liver metastases are negative predictors for ICI response, with associated higher NLR and dNLR levels potentially contributing to therapy resistance.