Cancer Medicine最新文献

Objective

Sarcomas are a heterogeneous group of malignancies, low disease-control levels and the limited durability of responses have prompted the exploration of various novel immunotherapeutic approaches. To preliminarily explore the feasibility of cancer vaccines based on cancer testis antigen in the immunotherapy of sarcomas, we investigate the expression of Cancer/Testis Antigens (CTA) MAGE-A4, PRAME, MAGE-A1, KK-LC-1, and NY-ESO-1 in bone and soft tissue sarcomas, with the aim of assessing their potential for use in sarcoma immunotherapy and determining their expression levels in different subtypes.

Methods and Results

We employed immunohistochemistry and multiplex immunostaining microarrays (MI chips) to assess the expression of MAGE-A4, PRAME, MAGE-A1, KK-LC-1, and NY-ESO-1 in 21 cases of undifferentiated pleomorphic sarcoma (UPS), 26 cases of smooth muscle sarcoma, 28 cases of liposarcoma, 40 cases of osteosarcoma (OS), and 13 cases of chondrosarcoma. MAGE-A1 showed the highest expression in osteosarcoma (32.50%), while it was lower in liposarcoma and undifferentiated pleomorphic sarcoma (10.71% and 10.00%) and undetectable in chondrosarcoma. MAGE-A4 expression was elevated in osteosarcoma and undifferentiated pleomorphic sarcoma (40.00% and 33.00%), but lower in liposarcoma and smooth muscle sarcoma (17.00% and 33.00%). NY-ESO-1 expression was relatively low across all sarcoma subtypes. PRAME expression was highest in undifferentiated pleomorphic sarcoma (47.62%) and low in chondrosarcoma (7.69%). None of the sarcomas expressed KK-LC-1. Additionally, while there was no statistically significant correlation between CTA expression and patient age or gender, some differences related to age and gender were observed.

Conclusions

CTA expression in bone and soft tissue sarcomas was correlated with both CTA type and sarcoma subtype, showing relatively high levels of expression in undifferentiated pleomorphic sarcoma (UPS) and osteosarcoma (OS). The poly-expression of MAGE-A4, PRAME, and MAGE-A1 across all subtypes suggests that these antigens may serve as potential targets for sarcoma-specific immunotherapy.

Background

Cancer is characterized by accelerated glycolysis with enhanced glucose uptake and lactate production, a phenomenon termed Warburg effect (WE). We studied the incidence and clinical impact of Warburg-driven lactic acidosis in lymphoma.

Methods

Patients admitted with newly diagnosed or relapsed/refractory lymphoma and documented lactate levels during the first week of admission were included. Patients with lactatemia were classified as secondary (with a recognizable cause for elevated lactate) or none (WE group).

Results

WE and secondary lactatemia were documented in 58 and 44 patients (15% and 12% of evaluable patients, respectively). Both WE and secondary lactatemia were associated with poor short-term survival. WE at presentation correlated with tumor burden, with most patients having aggressive disease, advanced stage, and extranodal involvement. WE was associated with high rates of early death (26% and 43% at 30- and 60-days, respectively). Higher lactate levels correlated with worse survival. Earlier initiation of chemotherapy was associated with a (nonsignificant) trend toward better outcomes, whereas steroid and/or thiamine therapy did not alter patient outcomes. Glucose administration was associated with worse survival.

Conclusion

WE-driven lactatemia is associated with high tumor burden and increased short-term mortality in lymphoma. Prompt initiation of anti-lymphoma therapy may improve outcomes.

Purpose

The informational needs of patients with Breast Cancer-Related Lymphedema (BCRL) have not been sufficiently addressed in the scientific literature. Moreover, the only existing questionnaire in this field contains many items. Therefore, the purpose of this study is to develop a short-form version of this questionnaire.

Methods

The questionnaire items were extracted from the Lymphoedema Needs Questionnaire-Breast Cancer (LNQ-BC). Demographic variables and clinical characteristics were considered separately. Out of 62 items, 24 were selected, and 2 additional questions were included based on feedback from 10 experts. 100 participants with BCRL completed the short-form questionnaire. Exploratory Factor Analysis (EFA) was performed using principal components extraction and varimax rotation, and Cronbach's alpha was calculated for each dimension.

Results

After evaluating the content validity, the instrument's construct validity with 26 items was conducted using EFA. The KMO (Kaiser-Meyer-Olkin) value was equal to 0.879 and Bartlett's sphericity test was significant (p-value < 0.001), indicating the data's adequacy and appropriateness to perform EFA. Five extracted dimensions were named: “Lymphedema information needs” (5 items), “Informational support, peers” (5 items), “Access to a lymphedema care specialist” (5 items), “Physical and daily activities” (7 items) and “Financial issues and compression garments” (4 items). The level of needs in this study in all dimensions was high (more than 77%).

Conclusions

The high factor loadings and the total explained variance of 78.152% support the construct validity of the short questionnaire. Although some items exhibited cross-loadings, the majority loaded strongly on a single factor, indicating good discriminant validity. Providing services according to the needs of patients can be prioritized. Healthcare providers, insurers, and individuals should be better informed about lymphedema, its associated costs, and the importance of implementing appropriate management programs.

Background

Invasive fungal infections (IFIs), particularly Candida infections, are a significant cause of morbidity and mortality in patients with acute leukemia. While fluconazole is widely used for prophylaxis, the optimal dosing regimen remains uncertain. This study aimed to evaluate the efficacy of low-dose fluconazole for primary prophylaxis against invasive Candida infections in patients with acute leukemia receiving intensive chemotherapy.

Methods

A double-blind, randomized clinical trial was conducted with patients diagnosed with acute leukemia. Patients were assigned to receive either low-dose (150 mg/day) or standard high-dose (400 mg/day) fluconazole for primary prophylaxis against invasive Candida infections during intensive chemotherapy. The primary outcomes were the efficacy of antifungal prophylaxis and the safety profile.

Results

A total of 120 patients (60 per group) were enrolled. The overall incidence of Candida infections was similar between the groups (p = 0.615). Candida colonization was higher in the low-dose fluconazole group during the first week, particularly with non-albicans Candida at oral and subaxillary sites (p < 0.001). However, by the third week, both groups showed a significant decline in colonization, with the reduction in the oral cavity being statistically significant (p = 0.03). Aspergillosis occurred in 38.3% of patients, with no significant difference between groups (p > 0.99). Adverse events were similar in both groups (p > 0.05).

Conclusion

Low-dose fluconazole is an effective alternative to high-dose regimens for preventing Candida infections in acute leukemia patients, with similar efficacy and safety. The rising threat of aspergillosis highlights the need for targeted prophylaxis. Further research is needed to refine strategies for high-risk patients.

Trial Registration

Iranian Registry of Clinical Trials (IRCT) number: IRCT20140818018842N37

Background

Applying dose–volume constraints is extremely important in ensuring the safe use of radiotherapy. However, constraints for carbon ion radiotherapy (CIRT) have not been established yet. This review aims to summarize dose–volume constraints for thoracic, abdominal, and pelvic CIRT that have been identified through previous research based on the Japanese models for relative biological effectiveness (RBE).

Results

Constraints are reported for the lungs, liver, stomach, gastrointestinal tract, rectum, sigmoid, bladder, nerves, rib, femoral head, sacrum, and skin. The constraints are classified into hard and soft to aid in determining whether priority should be given to the target coverage or organ-at-risk (OAR) sparing during treatment planning.

Conclusions

Further research is necessary to verify the applicability of the reported constraints and to identify constraints for the OARs that have not been investigated yet.

Background

Breast cancer is the most commonly diagnosed cancer in Australia and is the second highest cause of cancer mortality in Australian women. Screening in the form of mammography can significantly reduce mortality; however, research suggests that women from culturally and linguistically diverse (CALD) backgrounds are less likely to participate in mammography screening. While there is an established body of literature describing the lower engagement of CALD populations in screening and the associated challenges they face, less is known about evidence-based interventions to improve engagement.

Methods

A systematic scoping review was conducted to gain insights into best practice interventions to improve engagement of CALD populations in breast cancer screening. The search strategy followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. PUBMED, EMBASE and CINHAL databases were searched for studies published between January 2012 and October 2023.

Results

The search yielded 3249 studies; after removing duplicates, 2011 titles and abstracts were screened, and 121 papers underwent full text review. Forty-one were included in the review. Key intervention types were identified, with combination or multi-component studies being most effective at increasing mammography in CALD populations. Cultural appropriateness and tailoring are the most important considerations to be integrated into screening programs.

Conclusion

CALD populations have lower engagement and experience many challenges in accessing screening services. This review found that the integration of cultural appropriateness and tailoring is critical in the successful delivery of breast screening services to CALD populations. Individual strategies are insufficient to engage this population in screening; multicomponent strategies are the most effective.

Background

Immunosuppressive factors such as regulatory T cells and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial (UC), renal (RCC) and prostate (PCA) carcinoma.

Methods

The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and 1 week OFF) and a fixed dose of pembrolizumab (200 mg IV every 21 days). Patients (pts) were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve UC and RCC), Cohort B (previously treated, anti-PD1/PD-L1 resistant UC and RCC pts), and Cohort C (PCA pts).

Results

Dose levels 1 and 2 were completed without DLTs. We have enrolled 44 pts. (36 evaluable) in the dose expansion cohorts, and the most common resolved grade 3/4 toxicities were diarrhea, hypophosphatemia, acute kidney injury, anemia, and hypothyroidism. For Cohort A (13 pts), B (11 pts), and C (12 pts) the objective response rate was 8%, 0%, and 17%, and the median progression-free survival was 2.9, 3.5, and 3.5 months, respectively. Four partial responses were observed, and two PCA pts. had a complete biochemical response with undetectable PSA. Persistent lower levels of peripheral CD11⁺, CD14⁺ HLA-DR⁻ monocytic MDSCs were associated with clinical benefit.

Conclusion

The combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint-resistant UC/RCC pts. and immune checkpoint-naïve PCA pts.

Trial Registration: NCT02619253

Background

Hepatocellular carcinoma (HCC) is a primary liver cancer often associated with chronic liver disease and characterized by multifocal tumor lesions with synchronous and metachronous lesions, which poses treatment challenges due to potential genomic heterogeneity. This study aims to assess the consistency of actionable mutation profiles across synchronous and metachronous lesions in HCC patients.

Methods

This study analyzed 68 patients with multifocal HCC, including 193 tumor lesions (82 synchronous, 111 metachronous). Genomic profiling of 72 HCC-related genes was performed using next-generation sequencing. We collected clinical and pathological data, including tumor size, grade, fibrosis, and etiology. Patients were categorized into two groups based on the consistency of actionable mutations among multifocal HCC. Statistical analyses compared clinicopathological features between these groups.

Results

A total of 252 and 445 somatic mutations were identified in synchronous and metachronous tumors, respectively. Synchronous tumors had an average of 3.1 somatic mutations and 0.7 actionable mutations per lesion. Metachronous tumors had 4.0 somatic mutations and 1.0 actionable mutations per lesion. Actionable variants were found in 12 (36.4%) of 33 patients and 20 (24.4%) of 82 nodules in the synchronous tumors, and 23 (65.7%) of 35 patients and 42 (37.8%) of 111 nodules in the metachronous tumors. Compared to synchronous tumors, metachronous tumors exhibited significantly aberrant signaling pathways including the Wnt/β-catenin (p = 0.009) and KEAP1/NRF2 (p = 0.022) pathways. There was no correlation with significant clinical differences in tumor characteristics between the consistent and divergent actionable mutation groups. Notably, divergent actionable mutations were identified in 45.6% of patients, which may be beneficial for changing potential therapies for individual tumors.

Conclusion

The study shows substantial inter-tumoral heterogeneity in multifocal HCC, indicating the necessity for comprehensive molecular profiling for tailored treatment strategies. Divergent actionable mutations across lesions suggest that a uniform treatment approach may not be effective in some patients with multifocal HCC.

Background

Carboplatin (CBDCA) is a mainstay of chemotherapy for ovarian cancer and its dose is determined in proportion to the estimated creatinine clearance (CCr). Serum creatinine (SCr) values necessary to estimate CCr vary by measurement method: adding 0.2 mg/dL to SCr by enzymatic methods commonly used in Japan equates to SCr calculated using the Jaffe method, which is widely adopted outside Japan. Although adjustment by adding 0.2 mg/dL to SCr by enzymatic methods may avoid the potential overdose of CBDCA, its impact on the dose intensity (DI) of chemotherapy is unclear.

Methods

We retrospectively studied patients with ovarian cancer treated with CBDCA + paclitaxel (PTX) (TC) after primary surgery. Patients were classified into Cohort A (dose-dense [dd-]TC, SCr-adjusted, n = 18), B (dd-TC, non-adjusted, n = 8), C (tri-weekly [tw-]TC, SCr-adjusted, n = 6), and D (tw-TC, non-adjusted, n = 15), and DI and DI-related measures including average relative DI (ARDI, [RDI of CBDCA + RDI of PTX]/2]) known to correlate with patients’ prognoses were compared.

Results

Although the DI of CBDCA did not differ between Cohorts A and B, the DI of PTX and proportion of patients with ARDI ≥ 85% were higher in Cohort A than B (78 vs. 13%, p = 0.002) as a result of less frequent treatment modification. There was no difference in these measures between Cohorts C and D.

Conclusion

Adjustment of SCr when calculating the CBDCA dose did not compromise the DI of total CBDCA and may rather contribute to maintaining DI in patients receiving dd-TC.

Background

Although control of chemotherapy-induced nausea and vomiting (CINV) is substantially improved with guideline-directed antiemetic prophylaxis, breakthrough CINV remains a significant clinical patient problem. In subsequent cycles after breakthrough occurs, antiemetic guidelines recommend adding agents not used in the initial cycle. This study was designed to evaluate the use of NEPA (netupitant/palonosetron) plus dexamethasone with or without olanzapine for the prevention of CINV in the second cycle of chemotherapy for patients receiving highly (HEC) or moderately emetogenic chemotherapy (MEC) who developed breakthrough CINV in their first cycle despite guideline-directed prophylactic antiemetics.

Methods

This was a Phase 2, single center, open-label study. Patients received guideline-recommended prophylactic antiemetics in Cycle 1 based on the chemotherapy emetogenicity. Patients who experienced breakthrough CINV in Cycle 1 received intravenous (IV) NEPA (Day 1) plus dexamethasone (Days 1–4) and olanzapine (Days 1–4) for HEC or IV NEPA (Day 1) plus dexamethasone (Days 1–4) for MEC in Cycle 2.

Results

Of the 227 patients enrolled in Cycle 1, 100 patients (n = 37 HEC, 63 MEC) experienced breakthrough CINV and received the NEPA-based treatments in Cycle 2. The complete response (no emesis/no rescue use) rates [95% confidence intervals] during the overall (0–120 h) phase were 76% [59%, 88%] and 79% [67%, 89%] in the HEC and MEC groups, respectively.

Conclusion

These results show that NEPA with or without olanzapine is an effective approach for CINV prevention for patients receiving HEC or MEC who develop breakthrough CINV after their first course of chemotherapy. The results support the antiemetic guideline recommendations.

Trial Registration

clinicaltrials.gov identifier: NCT06065722