Multi-Omics Profiling Suggesting Intratumoral Mast Cells as Predictive Index of Breast Cancer Lung Metastasis

Breast cancer lung metastasis has a high mortality rate and lacks effective treatments, for the factors that determine breast cancer lung metastasis are not yet well understood. In this study, data from 1067 primary tumors in four public datasets revealed the distinct microenvironments and immune composition among patients with or without lung metastasis. We used multi-omics data of the TCGA cohort to emphasize the following characteristics that may lead to lung metastasis: more aggressive tumor malignant behaviors, severer genomic instability, higher immunogenicity but showed generalized inhibition of effector functions of immune cells. Furthermore, we found that mast cell fraction can be used as an index for individual lung metastasis status prediction and verified in the 20 human breast cancer samples. The lower mast cell infiltrations correlated with tumors that were more malignant and prone to have lung metastasis. This study is the first comprehensive analysis of the molecular and cellular characteristics and mutation profiles of breast cancer lung metastasis, which may be applicable for prognostic prediction and aid in choosing appropriate medical examinations and therapeutic regimens.

Genome-wide CRISPR/Cas9 library screen identifies PCMT1 as a critical driver of ovarian cancer metastasis

Background The development of lethal cancer metastasis depends on the dynamic interactions between cancer cells and the tumor microenvironment, both of which are embedded in the extracellular matrix (ECM). The acquisition of resistance to detachment-induced apoptosis, also known as anoikis, is a critical step in the metastatic cascade. Thus, a more in-depth and systematic analysis is needed to identify the key drivers of anoikis resistance. Methods Genome-wide CRISPR/Cas9 knockout screen was used to identify critical drivers of anoikis resistance using SKOV3 cell line and found protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) as a candidate. Quantitative real-time PCR (qRT-PCR) and immune-histochemistry (IHC) were used to measure differentially expressed PCMT1 in primary tissues and metastatic cancer tissues. PCMT1 knockdown/knockout and overexpression were performed to investigate the functional role of PCMT1 in vitro and in vivo. The expression and regulation of PCMT1 and integrin-FAK-Src pathway were evaluated using immunoprecipitation followed by mass spectrometry (IP-MS), western blot analysis and live cell imaging. Results We found that PCMT1 enhanced cell migration, adhesion, and spheroid formation in vitro. Interestingly, PCMT1 was released from ovarian cancer cells, and interacted with the ECM protein LAMB3, which binds to integrin and activates FAK-Src signaling to promote cancer progression. Strikingly, treatment with an antibody against extracellular PCMT1 effectively reduced ovarian cancer cell invasion and adhesion. Our in vivo results indicated that overexpression of PCMT1 led to increased ascites formation and distant metastasis, whereas knockout of PCMT1 had the opposite effect. Importantly, PCMT1 was highly expressed in late-stage metastatic tumors compared to early-stage primary tumors. Conclusions Through systematically identifying the drivers of anoikis resistance, we uncovered the contribution of PCMT1 to focal adhesion (FA) dynamics as well as cancer metastasis. Our study suggested that PCMT1 has the potential to be a therapeutic target in metastatic ovarian cancer.

Automatic segmentation of head and neck primary tumors on MRI using a multi-view CNN

Background Accurate segmentation of head and neck squamous cell cancer (HNSCC) is important for radiotherapy treatment planning. Manual segmentation of these tumors is time-consuming and vulnerable to inconsistencies between experts, especially in the complex head and neck region. The aim of this study is to introduce and evaluate an automatic segmentation pipeline for HNSCC using a multi-view CNN (MV-CNN). Methods The dataset included 220 patients with primary HNSCC and availability of T1-weighted, STIR and optionally contrast-enhanced T1-weighted MR images together with a manual reference segmentation of the primary tumor by an expert. A T1-weighted standard space of the head and neck region was created to register all MRI sequences to. An MV-CNN was trained with these three MRI sequences and evaluated in terms of volumetric and spatial performance in a cross-validation by measuring intra-class correlation (ICC) and dice similarity score (DSC), respectively. Results The average manual segmented primary tumor volume was 11.8±6.70 cm3 with a median [IQR] of 13.9 [3.22-15.9] cm3. The tumor volume measured by MV-CNN was 22.8±21.1 cm3 with a median [IQR] of 16.0 [8.24-31.1] cm3. Compared to the manual segmentations, the MV-CNN scored an average ICC of 0.64±0.06 and a DSC of 0.49±0.19. Improved segmentation performance was observed with increasing primary tumor volume: the smallest tumor volume group (<3 cm3) scored a DSC of 0.26±0.16 and the largest group (>15 cm3) a DSC of 0.63±0.11 (p<0.001). The automated segmentation tended to overestimate compared to the manual reference, both around the actual primary tumor and in false positively classified healthy structures and pathologically enlarged lymph nodes. Conclusion An automatic segmentation pipeline was evaluated for primary HNSCC on MRI. The MV-CNN produced reasonable segmentation results, especially on large tumors, but overestimation decreased overall performance. In further research, the focus should be on decreasing false positives and make it valuable in treatment planning.

Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer

Purpose Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM. Materials and methods Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. Results A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable. Conclusion M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.

A Non-Endemic Analysis of the Patterns and Prognosis of De Novo Metastatic Nasopharyngeal Carcinomas in Old Patients Aged ≥65 years

This study aimed to investigate the prognostic factors related to overall survival (OS) and cancer-specific survival (CSS) in patients with de novo metastatic nasopharyngeal carcinoma (NPC) aged ≥65 years in non-endemic areas. The Surveillance, Epidemiology, and End Results (SEER) database was queried for elderly patients with M1 stage NPC at initial diagnosis between 2004 and 2016. This study examined 100 patients and evaluated the relationship of gender, age, race, pathological grade, T stage, N stage, number of primary tumors, site of metastasis, number of metastatic organs, and other related factors with OS and CSS. The median survival and follow-up time were 10 and 48 months, respectively. The survival curves of race, N stage, bone metastasis, radiation, and chemotherapy significantly affected OS on the log-rank test. Race, bone metastasis, and chemotherapy were independent prognostic factors of OS. Bone metastasis was associated with poor survival. The survival curves of CSS were significantly differed between races, the number of primary tumors, and bone metastasis. In Cox regression multivariate analysis, only the number of primary tumors had an independent effect on prognosis. This study revealed that chemotherapy prolonged survival in elderly patients with metastatic NPC, whereas bone metastasis shortened survival.

Influence of initial platinum-based chemotherapy on levels of He-4 protein and VEGF-A in primary tumors and metastases from ovarian cancer

Introduction. Recently, the he-4 protein has received great attention due to its diagnostic and prognostic abilities in epithelial ovarian cancer. In addition to its diagnostic value, this protein is involved in the pathogenesis of ovarian cancer. Another significant pathogenetic factor is the vascular endothelial growth factor (vegf) which plays a key role in neoangiogenesis. The purpose of the study focused on the analysis of he-4 and vegf-a levels in tissues of ovarian cancer, in healthy contralateral ovaries and in common metastatic tumors in the omentum and peritoneum to determine the place and role of these tumor markers at the stages of carcinogenesis. Material and methods. The study was performed using the abovementioned tissues of 93 patients with t2-3nхm0-1 ovarian cancer. 51 patients underwent surgery followed by chemotherapy. 42 patients received initial neoadjuvant chemotherapy followed by surgery and adjuvant cytostatic therapy. Tissue samples from 17 patients with benign diseases were used as the control for determining the reference values for he-4 and vegf-a. A comparison was made between groups of patients with and without neoadjuvant therapy, as well as in groups of patients depending on the effectiveness of cytostatic treatment. Results. The levels of he-4 in primary and metastatic tissues affected and not affected by cancer were initially elevated in patients with ovarian cancer. The chemotherapy effectiveness directly correlated with the level of he-4 reduction, which did not change or increased in tumors resistant to medical treatment. The level of vegf-a significantly differed in cancer and non-cancer tissues, which indicated its significant pathogenetic effect not “before”, but at the stages of morphological malignization. The dynamics of vegf-a decrease in this study did not depend on the chemotherapy effect. Conclusion. The he-4 marker is a pathognomonic factor in the development of ovarian cancer, preceding morphological signs of malignancy and reflecting the effectiveness of chemotherapy, while vegf-a is most likely a consequence of the cancer development.

Hospital Frailty Risk Score and Healthcare Resource Utilization After Surgery for Primary Spinal Intradural/Cord Tumors

Objective The Hospital Frailty Risk Score (HFRS) is a metric that measures frailty among patients in large national datasets using ICD-10 codes. While other metrics have been utilized to demonstrate the association between frailty and poor outcomes in spine oncology, none have examined the HFRS. The aim of this study was to investigate the impact of frailty using the HFRS on complications, length of stay, cost of admission, and discharge disposition in patients undergoing surgery for primary tumors of the spinal cord and meninges. Methods A retrospective cohort study was performed using the Nationwide Inpatient Sample database from 2016 to 2018. Adult patients undergoing surgery for primary tumors of the spinal cord and meninges were identified using ICD-10-CM codes. Patients were categorized into 2 cohorts based on HFRS score: Non-Frail (HFRS<5) and Frail (HFRS≥5). Patient characteristics, treatment, perioperative complications, LOS, discharge disposition, and cost of admission were assessed. Results Of the 5955 patients identified, 1260 (21.2%) were Frail. On average, the Frail cohort was nearly 8 years older ( P < .001) and experienced more postoperative complications ( P = .001). The Frail cohort experienced longer LOS ( P < .001), a higher rate of non-routine discharge ( P = .001), and a greater mean cost of admission ( P < .001). Frailty was found to be an independent predictor of extended LOS ( P < .001) and non-routine discharge ( P < .001). Conclusion Our study is the first to use the HFRS to assess the impact of frailty on patients with primary spinal tumors. We found that frailty was associated with prolonged LOS, non-routine discharge, and increased hospital costs.

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

Relationship between Primary Tumors of Nasopharyngeal Carcinoma with the Degree of Conductive Hearing Loss in Dr. Mohammad Hoesin Hospital Palembang

Background. Nasopharyngeal carcinoma is a malignant tumor that grows in the nasopharyngeal area with predilection in the fossa Rossenmuller and the nasopharyngeal roof adjacent to the Eustachian tube, so one of NPC’s early symptoms is ear symptoms. Hearing loss is a common symptom found in people with NPC due to dysfunction of the Eustachian tube, a continuing middle ear disorder that can result in conductive hearing loss.This study aims to find out the relationship between primary tumor of NPC and the degree of conductive hearing loss at dr. Mohammad Hoesin Hospital Palembang. Methods. This is a cross sectional study that obtained 42 samples from the medical records at Dr. Mohammad Hoesin Hospital Palembang that met the inclusion and exclusion criteria. The study subjects collected in total sampling have been conducted audiometry examinations at the ORLHNS clinic of Dr. Mohammad Hoesin Hospital Palembang during the period January 2019 - April 2021. Results. The proportion of hearing loss in NPC patients in this study was 30 subjects (71.4%) with the highest proportion of hearing loss complaints being 33.3%. The proportion of conductive hearing loss of nasopharyngeal carcinoma patients in the study was 33 subjects (78.5%) right ear and 28 subjects (66.7%) left ear. There was a significant association between the degree of the NPC primary tumor and the incidence of conductive deafness of the left ear, but there was no significant association in the right ear. There is a significant correlation between NPC primary tumors and left ear hearing thresholds at frequencies of 500 Hz and 4000 Hz, but there is no significant association between the degree of NPC primary tumor and right ear hearing loss. Conclusions. There is significant correlation between the primary tumor of NPC and the hearing threshold of the left ear but there was no significant association in the right ear.

Relationship between CD-8 Expression to Treatment Response in Nasopharyngeal Carcinoma Patient After Neoadjuvant Chemotherapy in Dr. Mohammad Hoesin Hospital Palembang

Background. Nasopharyngeal carcinoma (NPC) is the most common malignancy in head and neck in Indonesia with 19,943 new cases in 2020 resulting 13,399 deaths. Lymphocytes are cells that play a role in the anti-cancer immune response, especially CD-8 T-cells. Neoadjuvant chemotherapy is chemotherapy given before radiotherapy that aims to kill primary tumors and micrometastasis tumors. This study aims to find out the relationship of CD-8 expression to treatment response in NPC undergoing neoadjuvant chemotherapy at Dr. Mohammad Hoesin Hospital Palembang. Methods. This study is an analytical observational research study on a retrospective cohort basis. Data collection from medical records using total sampling in 15 patients pilot study of NPC patients undergoing neoadjuvant chemotherapy and conducted CD-8 examination at ORLHNS polyclinic Dr. Mohammad Hoesin Hospital Palembang from December 2018 to December 2019 that met the criteria of inclusion and exclusion. Results. From 15 samples, the average CD-8 test result before neoadjuvant chemotherapy was 24.54 ng/μL and after neoadjuvant chemotherapy was 193.56 ng/μL. There was a tendency to increase the average CD-8 from before to after completion of neoadjuvan chemotherapy with a statistically significant difference of p =0.001. ROC analysis found CD-8 cut off points is 23.76 ng/μL with an area below the curve is 0.667. There were no significant relationships between CD-8 to performance status and treatment response with p values of 0.289 and 0.219, respectively. Conclusions. There was a significant change between CD-8 before neoadjuvant chemotherapy and after neoadjuvant chemotherapy with increased CD-8 tendencies and trends from before to after 6 series neoadjuvant chemotherapy with CD-8 cut off points is 23.76 ng/μL. In this study there has not been a significant relationships between CD-8 to performance status and treatment response in NPC patients undergoing neoadjuvant chemotherapy.