Association of miR-21 and miR-335 to microsatellite instability and prognosis in stage III colorectal cancer

BACKGROUND: MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE: To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS: miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. Data was confirmed by a multivariate analysis. RESULTS: MiR-21 high expression (p= 0.034) and miR-335 low expression (p= 0.0061) were significantly associated with MSI-H. A positive trend (p= 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066–6.605, p= 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749–7.815, p= 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p= 0.03). CONCLUSIONS: Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials.

Utility of Palliative Prognostic Index in Predicting Survival Outcomes in Patients With Hematological Malignancies in the Acute Ward Setting

Background: The palliative prognostic index (PPI) predicts the life expectancy of patients with terminally ill cancer in hospice settings. This study aimed to evaluate PPI as a prognostic tool for predicting the life expectancy of patients with hematological malignancies admitted to the acute ward. Methods: A total of 308 patients with hematological malignancies admitted to the hematological ward at a medical center between January 2016 and December 2017 were consecutively enrolled. PPI was scored within 24 h of admission. All patients were categorized into 3 groups by PPI for comparing survival and in-hospital mortality rates. Results: The median survival times were 38.4, 3.6, and 1.1 months for patients with good, intermediate, and poor prognostic group, respectively. The hazard ratio was 2.31 (95% CI 1.59-3.35, p < 0.001) when comparing the intermediate and good prognosis groups, and 3.90 (95% CI 2.52-6.03, p < 0.001) when comparing the poor and good prognosis groups. Forty-five (14.6%) patients died at discharge; in-hospital mortality rates among the good, intermediate, and poor prognostic groups were 9.0%, 23.4%, and 46.4%, respectively. The adjusted odds ratio for in-hospital mortality was 1.96 (95% CI, 0.80-4.82, p = 0.14) and 5.25 (95% CI, 2.01-13.7, p < 0.001) for patients in the intermediate and poor prognostic groups compared to those in the good prognostic group. Conclusion: PPI is an accurate prognostic tool for predicting survival times and in-hospital mortality rates in patients with hematological malignancies in an acute ward setting. PPI could assist clinicians in discussing end-of-life issues and in referring patients with hematological malignancies to palliative care.

Comparative evaluation of the effectiveness of primary treatment regimens in patients with classical Hodgkin’s lymphoma from the group of unfavorable prognosis

Objective. Comparative evaluation of the effectiveness and toxicity profile of intensified chemotherapy regimens BEACOPP escalated (esc.), BEACOPP-14 and EACOPP‑14 in primary patients with classical Hodgkin’s lymphoma of an unfavorable prognostic group.Materials and methods. The study included 149 patients: 84 women (56 %) and 65 men (44 %) with a newly diagnosed classic Hodgkin’s lymphoma, who received antitumor treatment in the Department of high-dose chemotherapy with a bone marrow transplantation unit at the Р. A. Hertzen Moscow Oncology Research Institute from 2006 to 2018. The median age was 31 years (17–69). The majority of patients were diagnosed with Hodgkin’s lymphoma nodular sclerosis (88.6 %). All patients belonged to an unfavorable prognostic group, despite the fact that more than 1/3 of them had local stages of the disease. The most frequent adverse factors identified in the majority of patients were: massive lymph node lesion (bulky disease) – in 111 patients (74.5 %), B-symptoms – in 84 (56.4 %), increased erythrocyte sedimentation rate – in 55 (36.9 %), extranodal lesion – in 105 (70.5 %), including bones and bone marrow – in 10 (6.7 %) and 14 (9.4 %), respectively. Antitumor treatment was performed under the BEACOPP program in the following modifications: BEACOPP‑14 – 94 (63.1 %), EACOPP-14 – 32 (21.5 %), BEACOPP-esc. – 23 patients (15.4 %). Consolidating radiotherapy was performed in the majority of patients – 132 (88.6 %).Results. After the chemotherapy, remission of the disease was achieved in 141 patients (94.6 %), a complete response was in 101 of them (67.8 %). The immediate antitumor effect was more expressed when using the program BEACOPP‑14 (in 72.3 %), compared to EACOPP‑14 and BEACOPP-esc. (in 59.4 % and 60.9 %, respectively).Chemotherapy resistance was observed in 8 patients (5.4 %). Chemotherapy results were improved in combination with radiation therapy in 40 patients (26.8 %). After the end of chemoradiotherapy, complete remissions were achieved in more than 93.6 % of patients. Relapses occurred in 8 patients: early – in 3 (2.1 %) and late – in 5 (3.5 %). Four patients died (2.7 %): 1 – from disease progression, 2 – from resistant relapse, and 1 patient from other causes.With a median follow-up of 46 months, the 5-year overall survival rate was more than 93.7 %, event-free-more than 83 %, and relapse-free – 90.3 % or more. When evaluating long-term treatment results depending on the induction chemotherapy program, the outcome was better when using the BEACOPP-esc. in comparison with EACOPP‑14 and BEACOPP‑14. The most frequent myelotoxic complication – more than 90 % – on all chemotherapy programs was deep leukopenia. Thrombocytopenia III–IV degree developed more often on the BEACOPP-esc. (in 52.2 %), severe anemia – on EACOPP‑14 (in 44 %). Among infectious complications, mucositis prevailed and was most often observed on BEACOPP-esc. (in 74 %). Febrile neutropenia and herpetic infection developed less frequently, mainly in the BEACOPP-esc. and EACOPP‑14 program. Another serious complication was pneumonia, which was more frequently reported during BEACOPP‑14 (18.1 %). Secondary tumors, as a later complication, were less likely to be detected in the treatment program BEACOPP‑14 (1 %), compared to BEACOPP-esc. and EACOPP-14 (4.3 % and 3.1 %, respectively).Conclusion. All modifications of the BEACOPP program showed good direct effectiveness. However, the best long-term results, despite slightly more expressed toxicity, were noted on the BEACOPP-esc. program.

Localized osteosarcoma analysis of very poor responders subgroup (Huvos I).

e22010 Background: Osteosarcoma is a malignant primitive bone tumor whose prognosis is not changed since 4 decades, after the introduction of neoadjuvant chemotherapy with Methotrexate, Cisplatin, Doxorubicine and Ifosfamide. Histologic response to preoperative chemotherapy is a significant prognostic factor. Huvos I (necrosis ≤ 50%) has worst prognosis . Previous studies reported a 3 years EFS of this Huvos I patients around 25% (Tsuda Y,2020). In order to evaluate if survival has changed in recent years in this unfavourable prognostic group we evaluated the outcome of osteosarcoma patients with Huvos I. Methods: from our Pathology archieves we retrieved all cases of localized osteosarcoma treated at Rizzoli with neoadjuvant chemotherapy who reported an histologic necrosis below or equal to 50% (Huvos I grade) after preoperative chemotherapy MAP (Ethical C. Approval 917/2020/Oss/IOR). Results: from 2003 to 2019 we had 70 cases of localized osteosarcoma with Huvos I necrosis after neoadjuvant chemotherapy ( MAP in 66 and MAPI in 4) evaluable. Median age 21,5 (3-70); M:F = 44:26. 10/70 had axial localization vs extremity(60), subhistotype distribution:46 osteoblastic,11 chondroblastic, 7 fibroblastic, 5 teleangectatic, one not classified. In 24 cases PgP was available(14 PgP positive). With a median follow up of 86.7 ms (IQR 41-136) 43/70 had already relapsed. The median EFS was 25 ms (95% CI 15-42) and the 3 yrs EFS was 40.6% (95% CI 29-52). The 3 yrs overall survival was 80% (95%CI 68-88) and median OS was not reached. Axial tumor site was associated with significant inferior EFS (P = .004). Conclusions: these data confirm the poor prognosis of patients with necrosis ≤50% and the need of new drugs to improve their survival in this sub-group.

DCE-MRI in Glioma, Infiltration Zone and Healthy Brain to Assess Angiogenesis: A Biopsy Study

Purpose To explore the focal predictability of vascular growth factor expression and neovascularization using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioma. Methods 120 brain biopsies were taken in vital tumor, infiltration zone and normal brain tissue of 30 glioma patients: 17 IDH(isocitrate dehydrogenase)-wildtype glioblastoma (GBM), 1 IDH-wildtype astrocytoma °III (together prognostic group 1), 3 IDH-mutated GBM (group 2), 3 anaplastic astrocytomas IDH-mutated (group 3), 4 anaplastic oligodendrogliomas and 2 low-grade oligodendrogliomas (together prognostic group 4). A mixed linear model evaluated the predictabilities of microvessel density (MVD), vascular area ratio (VAR), mean vessel size (MVS), vascular endothelial growth factor and receptors (VEGF-A, VEGFR‑2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) expression from Tofts model kinetic and model-free curve parameters. Results All kinetic parameters were associated with VEGF‑A (all p < 0.001) expression. Ktrans, kep and ve were associated with VAR (p = 0.006, 0.004 and 0.01, respectively) and MVS (p = 0.0001, 0.02 and 0.003, respectively) but not MVD (p = 0.84, 0.74 and 0.73, respectively). Prognostic groups differed in Ktrans (p = 0.007) and ve (p = 0.004) values measured in the infiltration zone. Despite significant differences of VAR, MVS, VEGF‑A, VEGFR‑2, and VE-PTP in vital tumor tissue and the infiltration zone (p = 0.0001 for all), there was no significant difference between kinetic parameters measured in these zones. Conclusion The DCE-MRI kinetic parameters show correlations with microvascular parameters in vital tissue and also reveal blood-brain barrier abnormalities in the infiltration zones adequate to differentiate glioma prognostic groups.

Baseline and post-treatment circulating tumor cell (CTC) counts with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) in men with metastatic castration-resistant prostate cancer (mCRPC).

158 Background: CTC counts are an independent prognostic factor in men with mCRPC; certain changes following treatment (conversion from detectable to undetectable or unfavorable to favorable) are associated with improved overall survival. Most PSMA-TRT efficacy data have focused on PSA or imaging changes. Here, we describe baseline and post-treatment CTC counts from subjects receiving PSMA-TRT. Methods: Men with mCRPC treated on prospective clinical trials of PSMA-TRT and with available CTC counts (CellSearch) were included in our analysis. Depending upon the era of the trial, post-treatment counts were performed at 4-6 (initial era) or 12 weeks (recent era) after a single cycle of PSMA-TRT (individual trial data reported elsewhere). We describe CTC counts at baseline and compare pre-treatment counts to those after PSMA-TRT. Results: 116 men treated with PSMA-TRT had baseline CTC count (90 with both pre- and post-treatment CTC). Forty-four patients (37.9%) received 177Lu-J951, 46 (39.7%) received 177Lu-PSMA-617, and 26 (22.4%) received 225Ac-J591. Median age was 71.5. Fifty-eight patients (50%) had previously received taxane chemotherapy, median PSA was 82.98 ng/mL, and 66 (56.9%) were in the high-risk Halabi (CALGB) prognostic group. Eighty-nine out of one hundred sixteen (76.7%) had detectable baseline CTC and 58/116 (50%) had unfavorable baseline CTC count. Forty-nine out of seventy (70%) had post-treatment CTC count decline, 23/70 (32.9%) converted from detectable to undetectable, and 17/47 (36.2%) converted from unfavorable to favorable. CTC changes stratified by type of PSMA-TRT are reported in the table. Conclusions: This is the largest analysis of CTC changes in patients who have received PSMA-TRT. In addition to PSA changes and other previously reported outcomes, even when low doses of radionuclide therapy as part of dose-escalation studies are included, the majority with detectable CTC counts have post-treatment CTC count decline. A significant portion of patients experience favorable CTC changes. [Table: see text]

A TP53-Associated Immune Prognostic Signature for the Prediction of Overall Survival and Therapeutic Responses in Muscle-Invasive Bladder Cancer

BackgroundTP53 gene mutation is one of the most common mutations in human bladder cancer (BC) and has been implicated in the progression and prognosis of BC.MethodsRNA sequencing data and TP53 mutation data in different populations and platforms were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database to determine and validate a TP53-associated immune prognostic signature (TIPS) based on differentially expressed immune-related genes (DEIGs) between muscle-invasive bladder cancer (MIBC) patients with and without TP53 mutations.ResultsA total of 99 DEIGs were identified based on TP53 mutation status. TIPS including ORM1, PTHLH, and CTSE were developed and validated to identify high-risk prognostic group who had a poorer prognosis than low-risk prognostic group in TCGA and GEO database. The high-risk prognostic group were characterized by a higher abundance of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages than the low-risk prognostic group. Moreover, they exhibited a lower abundance of CD56bright NK cells, higher expression of CTLA4, LAG3, PDCD1, TIGIT, and HAVCR2, as well as being more likely to respond to anti–PD-1, and neoadjuvant chemotherapy than the low-risk prognostic group. Based on TIPS and other clinical characteristics, a nomogram was constructed for clinical use.ConclusionTIPS derived from TP53 mutation status is a potential prognostic signature or therapeutic target but additional prospective studies are necessary to confirm this potential.

The mortality outcome after implantable cardioverter-defibrillator implantation according to indication for implantation and underlying etiology: a Nationwide Cohort study

Background and objectives There are few nationwide data about the mortality outcome after implantable cardioverter-defibrillator (ICD) implantation. The aim of this study was to evaluate the mortality outcome after ICD implantation according to indication for implantation (primary vs. secondary prevention) and underlying etiology (non-ischemic vs. ischemic heart disease) with a nationwide cohort data of Korea. Methods During the period from January 1, 2008 to December 31, 2017, 3,558 patients (mean age, 67.7±11.4 years) with newly-implanted ICD who were aged 19 years or older were identified by 50-percents random sampling from the Korean National Health Insurance Service database. Results Patients with primary and secondary prevention ICD were 1,097 (30.8%) and 2,461 (69.2%), respectively. Patients with non-ischemic and ischemic heart disease were 2,487 (69.9%) and 1,071 (30.1%), respectively. Overall all-cause mortality was 20.4% during the follow-up period (mean 24 months). The mortality rates in patients with primary and secondary prevention ICD were 26.2% and 17.9%, respectively. The mortality rates in patients with non-ischemic and ischemic heart disease were 16.1% and 30.4%, respectively. In Kaplan-Meier estimates of survival according to both indication for implantation and underlying etiology, the best prognostic group was patients with secondary prevention ICD and having non-ischemic etiology. The worst prognostic group was patients with primary prevention ICD and having ischemic etiology. The survival probability was below 50% (45.2%) 5 years after ICD implantation in patients with primary prevention ICD and having ischemic etiology. Conclusions In Korean nationwide data, patients with primary prevention ICD and having ischemic etiology show the worst prognosis. About half of these patients died of any cause within five years. Funding Acknowledgement Type of funding source: None