Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the ...most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis.
We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival.
Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy.
The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.
Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study ...was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients.
Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used.
KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0-61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1-25.0, p = 0.0016). Increased MAFA (T1-T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2-3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2-8.4, p = 0.0168).
Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.
Background
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This ...study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.
Methods
Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).
Results
The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months 95% confidence interval (CI), 33.4–51.2 months, and the median DFS was 13.6 months (95% CI, 12.3–14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4–24.6 months). In addition to the known clinical factors, KRAS mutations (
p
= 0.005), BRAF mutations (
p
= 0.01), and MS status (
p
= 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%;
p
= 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index hazard ratio (HR), 1.05 per point, completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.
Conclusion
For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.
Circulating cell‐free DNA (cfDNA) was found in increased amounts in cancer patients and tumor‐associated molecular alteration can be detected in cancer patient's samples. For this reason, the cfDNA ...analysis is actually considered as a new concept of liquid biopsy. We evaluated the presence and integrity of plasma cfDNA by ALU‐based qPCR and the methylation profile of OSMR and SFRP1 genes promoter in a large cohort of colorectal cancer (CRC) patients (n = 114) in comparison to healthy subjects (n = 56) and patients with adenomatous lesions (n = 22). Moreover, we studied the prognosis value focusing on histopathological staging and survival. The cfDNA concentration and the integrity index were increased in CRC patients. The ALU83 and ALU244 fragment dosage showed a moderate discriminant capacity between CRC patients and controls and CRC and adenoma patients. Especially, cfDNA was significantly higher in CRC patients at advanced histopathological stage. In addition, the increased cfDNA level was associated with poor prognosis. A comparison of methylation profile in matched tissue and plasma on 25 CRC patients was performed and only three mismatched cases were observed. A lower methylation quantification was observed in cfDNA than tissue DNA. The cfDNA methylation frequency was statistically different in controls, adenoma and CRC patients and this frequency increased with the histopathological stage of tumor. The adenoma and CRC patients methylated cfDNA showed a higher quantity of ALU83 and ALU244. An integrated approach, combining the detection of ALU fragments and cancer type‐specific epigenetic alteration, can improve diagnostic efficiency and better define the prognostic value for CRC disease.
What's new?
Liquid biopsy of circulating cell‐free DNA (cfDNA) is an emerging approach in cancer screening that can potentially facilitate the early detection of tumor‐derived molecular alterations. In our study, designed to explore the utility of liquid biopsy in colorectal cancer (CRC) detection, cfDNA quantification was found to be sufficiently capable of differentiating CRC patients from healthy controls and from patients with adenomatous polyps. Moreover, among CRC patients, those with higher cfDNA levels experienced worse prognosis, suggesting that cfDNA dosage predicts survival. CRC detection through cfDNA quantification may be improved through the addition of methylation biomarkers.
Despite substantial progress in treatment of T-cell acute lymphoblastic leukemia (T-ALL), mortality remains relatively high, mainly due to primary or acquired resistance to chemotherapy. Further ...improvements in survival demand better understanding of T-ALL biology and development of new therapeutic strategies. The Notch pathway has been involved in the pathogenesis of this disease and various therapeutic strategies are currently under development, including selective targeting of NOTCH receptors by inhibitory antibodies. We previously demonstrated that the NOTCH1-specific neutralizing antibody OMP52M51 prolongs survival in TALL patient-derived xenografts bearing
mutations. However, acquired resistance to OMP52M51 eventually developed and we used patient-derived xenografts models to investigate this phenomenon. Multi-level molecular characterization of T-ALL cells resistant to NOTCH1 blockade and serial transplantation experiments uncovered heterogeneous types of resistance, not previously reported with other Notch inhibitors. In one model, resistance appeared after 156 days of treatment, it was stable and associated with loss of Notch inhibition, reduced mutational load and acquired
mutations potentially affecting the stability of the heterodimerization domain. Conversely, in another model resistance developed after only 43 days of treatment despite persistent down-regulation of Notch signaling and it was accompanied by modulation of lipid metabolism and reduced surface expression of NOTCH1. Our findings shed light on heterogeneous mechanisms adopted by the tumor to evade NOTCH1 blockade and support clinical implementation of antibody-based target therapy for Notch-addicted tumors.
Background
Local excision might represent an alternative to total mesorectal excision for patients with locally advanced rectal cancer who achieve a major or complete clinical response after ...neoadjuvant chemoradiotherapy.
Methods
Between August 2005 and July 2011, 63 patients with mid-low rectal adenocarcinoma who had a major/complete clinical response after neoadjuvant chemoradiotherapy were enrolled in a multicenter prospective phase 2 trial and underwent transanal full thickness local excision. The main endpoint of this study was to evaluate the 5- and 10-year overall, relapse-free, local, and distant relapse-free survival, which were calculated by applying the Kaplan–Meier method. The rate of patients with rectum preserved and without stoma were also calculated.
Results
Of 63 patients, 38 (60%) were male and 25 (40%) were female, with a median (range) age of 64 (25–82) years. At baseline, the following clinical stages were found: cT2,
n
= 21 (33.3%); cT3,
n
= 42 (66.6%), 39 (61.9%) patients were cN+. At a median (range) follow-up of 108 (32–166) months, the estimated cumulative 5- and 10-year overall survival, relapse-free survival, local recurrence-free survival, and distant recurrence-free survival were 87% (95% CI 76–93) and 79% (95% CI 66–87), 89% (95% CI 78–94) and 82% (95% CI 66–91), both 91% (95% CI 81–96), and 90% (95% CI 80–95) and 86% (95% CI 73–93), respectively. Overall, 49 (77.8%) patients had their rectum preserved, and 54 (84.1%) were stoma-free.
Conclusion
In highly selected patients, the local excision approach after neoadjuvant chemoradiotherapy is associated with excellent long-term outcomes, high rates of rectum preservation and absence of permanent stoma.
Background
Rectum-preservation for locally advanced rectal cancer has been proposed as an alternative to total mesorectal excision (TME) in patients with major (mCR) or complete clinical response ...(cCR) after neoadjuvant therapy. The purpose of this study was to report on the short-term outcomes of ReSARCh (Rectal Sparing Approach after preoperative Radio- and/or Chemotherapy) trial, which is a prospective, multicenter, observational trial that investigated the role of transanal local excision (LE) and watch-and-wait (WW) as integrated approaches after neoadjuvant therapy for rectal cancer.
Methods
Patients with mid-low rectal cancer who achieved mCR or cCR after neoadjuvant therapy and were fit for major surgery were enrolled. Clinical response was evaluated at 8 and 12 weeks after completion of chemoradiotherapy. Treatment approach, incidence, and reasons for subsequent TME were recorded.
Results
From 2016 to 2019, 160 patients were enrolled; mCR or cCR at 12 weeks was achieved in 64 and 96 of patients, respectively. Overall, 98 patients were managed with LE and 62 with WW. In the LE group, Clavien–Dindo 3+ complications occurred in three patients. The rate of cCR increased from 8- to 12-week restaging. Thirty-three (94.3%) of 35 patients with cCR had ypT0–1 tumor. At a median 24 months follow-up, a tumor regrowth was found in 15 (24.2%) patients undergoing WW.
Conclusions
LE for patients achieving cCR or mCR is safe. A 12-week interval from chemoradiotherapy completion to LE is correlated with an increased cCR rate. The risk of ypT > is reduced when LE is performed after cCR.
Health-related quality of life (HRQoL), cognitive function, and psychological status represent an important focus during the treatment of glioblastoma patients. Nevertheless, few randomized, ...prospective clinical trials have analyzed these factors, and very little is known in the real-clinical world. We evaluated these characteristics in glioblastoma patients treated with standard first-line therapy outside clinical trials.
In total, 111 newly, histologically diagnosed glioblastoma patients treated at our oncology center with radiotherapy and temozolomide were prospectively enrolled. No patient was enrolled in an experimental clinical trial. We assessed HRQoL, cognitive function, and psychological status before starting treatment, at the end of radiotherapy, and every 3 months until 9 months after the end of radiotherapy using EORTC QLQ-C30, BN20, MMSE, and HADS questionnaires.
Global health status, physical, cognitive, and social functioning remained unchanged throughout the study period. A statistically significant change was found in emotional functioning as well as a clinically meaningful amelioration in role functioning between the baseline assessment and 9 months after radiotherapy. Patients older than 65 years reported greater impairment on the bladder control scale than younger patients. When considering tumor location, global health status, communication deficit, and drowsiness, scores were significantly different between the right and left hemispheres. Female patients had a clinically relevant lower score for physical functioning at baseline and 3 months after radiation therapy. Female patients also had a clinically relevant lower depression score at 9 months after radiation therapy.
In routine neurooncology practice, HRQoL, cognitive function, and psychological status did not worsen during first-line treatment in glioblastoma patients receiving standard radiotherapy and temozolomide treatment. However, some patient subgroups, such as elderly and female patients, may have different experiences with treatment, and further investigation is required.
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